FIELD OF THE INVENTION

The invention generally concerns active materials for the treatment of a variety of lower urinary tract conditions.

BACKGROUND OF THE INVENTION

Lower urinary tract symptoms (LUTS) include increased frequency, urgency, nocturia, incontinence, recurrent urinary tract infections, and even renal dysfunction; which affect approximately 16% of the population aged over 40 years and prevalence increases with age. The etiology of the condition is varied and includes neurogenic conditions such as spinal cord lesion, multiple sclerosis as well as non-neurogenic conditions such as overactive bladder, interstitial cystitis/chronic pelvic pain syndrome (IC/CPPS) and hemorrhagic cystitis, defined by dysuria and hematuria as a complication of cyclophosphamide (CYP) therapy, in oncological and immunocompromised patients. Interstitial cystitis, chronic prostatitis, and Chronic pelvic pain syndrome (IC/CPPS) are conditions characterized by chronic pelvic pain, urinary frequency and urgency, and variable degrees of sexual dysfunction.

Current treatment of LUTS includes anticholinergic medication, which has limited efficacy and major central and peripheral side effects that result in low patient tolerability and compliance.

Recently, the presence of the endocannabinoid (eCB) system (ligands, receptors, enzymes) was reported in human and animal urinary bladder. However, the therapeutic potential of cannabinoid modulators (specifically, peripherally restricted cannabinoid- 1 receptor (CB1R) blockers) has never reported.

JD5037 is a peripherally -restricted cannabinoid inverse agonist at CB 1 receptors. It is very selective for the CB1 subtype, with a Ki of 0.35nM, >700-fold higher affinity than it has for CB2 receptors. In animal studies, JD5037 does not readily cross the blood-brain barrier and thus is not expected to produce the psychiatric side effects in humans, which are known to led to the withdrawal of rimonabant (a globally acting CB1 receptor inverse agonist) from the market.

PUBLICATIONS

[1] US Patent No. 8,088,809,

[2] US Patent No. 7,666,889,

[3] US Patent No. 7,482,470.

SUMMARY OF THE INVENTION

The inventors of the technology disclosed herein have now discovered that CB1 antagonists, such as JD5037, can dramatically improve lower urinary tract symptoms (LUTS), can bring to their treatment, and can also prevent such symptoms from occurring in subjects predisposed to suffering from such symptoms or who are likely to suffer from such symptoms in view of a prevailing medical condition or a medical treatment.

Thus, in its broadest definition, the technology disclosed herein concerns a provision of use of a peripherally restricted CB 1 antagonist, which is a material antagonist or which is carried within a peripherally restricted CB 1 antagonist carrier, for the medical management of lower urinary tract symptoms (LUTS), as defined herein.

The invention provides a composition or a medicament for medical management of lower urinary tract symptoms (LUTS), the composition having peripherally restricted CB 1 antagonistic activity.

In some embodiments, the composition is in a peripherally restricted form and comprises at least one CB1 antagonist. In other embodiments, the composition comprises at least one peripherally restricted CB 1 antagonist material.

There is further provided a composition for management of lower urinary tract symptoms (LUTS) comprising, wherein the composition having peripherally restricted CB 1 antagonistic activity. Similarly provided is a method for management of lower urinary tract symptoms (LUTS) which comprising administering such a composition.

In some embodiments, the composition comprises at least one peripherally restricted CB1 antagonist (or an effective amount thereof). In some other embodiments, the composition is in a peripherally restricted form, namely does not penetrate the CNS, and which comprises at least one CB 1 antagonist (or an effective amount thereof).

In a first aspect, the invention provides a composition or a medicament comprising at least one peripherally restricted CB1 antagonist (or an effective amount thereof), as defined and selected herein, for use in a medical management of lower urinary tract symptoms (LUTS).

The invention further provides use of at least one peripherally restricted CB1 antagonist (or an effective amount thereof), as defined and selected herein, in a method of medical management of lower urinary tract symptoms (LUTS).

Further provided is a method for a medical management of lower urinary tract symptoms (LUTS), the method comprising administering to a subject an effective amount of at least one peripherally restricted CB1 antagonist, as defined and selected herein, wherein the subject is selected from:

-a subject suffering from LUTS;

-a subject having predisposition to suffering from LUTS, such may be, e.g., interstitial cystitis/bladder pain syndrome;

-a subject undergoing a medical treatment directly or indirectly known to bring about or cause LUTS, such may be, e.g., cyclophosphamide (CYP) therapy in oncological and immunocompromised patients;

- a subject suffering from neurogenic bladder or non-neurogenic bladder; and

- a subject suffering from overactive bladder LUTS symptoms.

“Lower urinary tract symptoms (LUTS)” is a group of medical conditions, which generally involve three groups of urinary symptoms, which may be defined as storage (irritative), voiding (obstructive, and post-micturition symptoms. Storage symptoms comprise urgency, frequency, nocturia, urgency incontinence and stress incontinence, which can be associated with overactive bladder (OAB) and benign prostatic hyperplasia (BPH). Voiding symptoms may comprise hesitancy, poor flow, intermittency, straining and dysuria, while post-micturition symptoms comprise terminal dribbling, post-void dribbling and a sense of incomplete emptying. The causes of LUTS may differ and are not always clear. LUTS may be triggered by an obstruction, abnormality, infection or irritation of the urethra, bladder, bladder neck, urinary sphincter and/or prostate (in men) and may also be caused by neurological conditions or injuries. Both male and female subjects are diagnosed with LUTS, but it is most often diagnosed in men with enlarged prostate (BPH).

LUTS after radiation therapy or anticancer therapy in oncological patients is also not uncommon. Immunocompromised patients are also prone to suffering from LUTS.

Several categories of medications can also trigger LUTS or worsen LUTS in patients. Such medications may exert their effect by directly or indirectly influencing the detrusor muscle and urinary sphincter function. Antidepressants, antihistamines, bronchodilators, anticholinergics, sympathomimetics, as well as diuretics are known to be associated with or cause LUTS.

It has been shown in accordance with the invention that peripherally restricted CB 1 antagonists are capable of inhibiting or blocking symptoms associated with or characteristic of LUTS, irrespective of the cause or originator mechanism, rending such compounds suitable for both prevention and treatment regimes.

The invention thus further provides a method of treatment of a subject suffering from conditions associated with LUTS, the method comprising administering to the subject in need of such a treatment an effective amount of at least one peripherally restricted CB1 antagonists.

Further provided is a method of prevention of lower urinary tract symptoms (LUTS) in a subject having predisposition for suffering therefrom, or who is undergoing or scheduled to undergo a medical treatment known to cause LUTS (directly or indirectly), the method comprising administering to the subject an effective amount of at least one peripherally restricted CB1 antagonists.

In some embodiments, where LUTS is known or suspected to be caused by a medical treatment, the peripherally restricted CB1 antagonist may be administered prior to, concomitantly with or soon after commencement of the medical treatment suspected or capable of causing or triggering LUTS.

In some embodiments, the medical treatment suspected to cause or capable of causing LUTS may be anticancer treatment, immunotherapy or any other immunosuppressive therapy, radio therapy, administration of medication (such as antidepressants, antihistamines, bronchodilators, anticholinergics, sympathomimetics, diuretics and others), etc. The invention further provides a method of reducing side effects associated with a medical treatment in a subject undergoing the medical treatment, the side effects being one or more symptoms of the lower urinary tract, the method comprising administering to a subject prior to, during or subsequent to the medical treatment an effective amount of peripherally restricted CB 1 antagonist.

In some embodiments, the medical treatment is or comprises anticancer treatment, immunotherapy or any other immunosuppressive therapy, radio therapy, and/or administration of medication selected from antidepressants, antihistamines, bronchodilators, anticholinergics, sympathomimetics, diuretics and others.

In some embodiments, the method is for reducing side effects associated with an anticancer treatment in a subject undergoing the anticancer treatment, the side effects being one or more symptoms of the lower urinary tract, the method comprising administering to a subject prior to, during or subsequent to the treatment an effective amount of peripherally restricted CB 1 antagonist.

As used herein, reference to LUTS constitutes reference to any one or more of the following symptoms:

-Storage or irritative symptoms, including increased frequency of urination, increased urgency of urination, urge incontinence, excessive passage of urine at night and others;

-Voiding or obstructive symptoms, such as poor urine stream, hesitancy, terminal dribbling, incomplete voiding, urinary retention, overflow incontinence, episodes of near retention, and others.

In some embodiments, medical treatment or prevention according to the invention thus provides treatment or prevention of any one or more of the following conditions: increased frequency of urination, increased urgency of urination, urge incontinence, excessive passage of urine at night, poor urine stream, hesitancy, terminal dribbling, incomplete voiding, urinary retention, overflow incontinence, and episodes of near retention.

The “peripherally restricted CB1 antagonist” refers to an antagonist as well as to an inverse agonist that is more specific to CB 1 as compared to CB2 by a few folds and has a minimal activity in the CNS (blocking CB1R in the brain). For example, these compounds have a low brain/plasma ratio. The brain/plasma concentration ratio representing one of the tools available for estimation of CNS pharmacokinetics is a parameter that indicates the blood-brain barrier availability of compounds. This value describes the free drug concentration of a compound in the brain, which is believed to be the parameter that causes the relevant pharmacological response at the target site. As indicated, compounds of the invention have exhibited substantially no (or low) brain penetration. Alternatively, compounds used according to the invention may be regarded as "CB 1 receptor blockers or antagonists or neutral antagonists or inhibitors" which partially or fully block, inhibit, or neutralize a biological function of a peripheral CB 1 receptor.

Within the context of the present application, the expression “substantially no brain penetration” suggests a brain/plasma ratio ranging from 0.0001 and 0.10, or brain penetration that does not induce any CB1 -mediated CNS side effects.

Peripherally restricted CB1 antagonist materials are known in the art. Any such material may be used according to the invention. A person of skill in the art would know how to identify such materials having:

1. peripherally restricted CB 1 antagonist activity;

2. a minimal activity in the CNS; and/or

3. a low brain/plasma ratio.

Assays for determining antagonist activities are known in the art and are disclosed herein. One such assay is the GTP-gamma binding assay, which allows for identifying a compound as an agonist, a neutral antagonist, or as an inverse agonist.

In some embodiments, the peripherally restricted CB1 antagonist materials are selected from

In some embodiments, the peripherally restricted CB1 antagonist is JD5037 having the structure:

In some embodiments, the peripherally restricted CB1 antagonist is a structural analog of JD5037, namely derivatives of the compound that maintain the peripherally- restricted cannabinoid inverse agonist CB 1 receptors activity at about the efficacy and selectivity of the JD5037. Examples of such analogues and their manner of synthesis are described in ( 1 ) " JD-5006 and JD-5037 : peripherally restricted (PR) cannabinoid- 1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities", Chorvat RJ, Berbaum J, Seriacki K, McElroy JF (October 2012), and (2) Bioorganic & Medicinal Chemistry Letters. 22 (19): 6173-80, each being herein incorporated by reference, and (3) Hirsch S, and Tam, J (2019) Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome. Toxins 11(5): 275.

In some embodiments, the peripherally restricted CB 1 antagonist is selected from

In some embodiments, the peripherally restricted CB1 antagonist is

In some embodiments, the peripherally restricted CB 1 antagonist a compound of structure (1): wherein in a compound of formula (1): n is an integer between 1 and 3; R1 is a C1-C5alkyl; and each of R2, R3 and R4, independently of the other, is a C6-C10aryl, a C5-C 1 oheteroaryl or a C5-C10carbocycle.

In some embodiments, n is 1, 2 or 3. In some embodiments, n is 1.

In some embodiments, R1 is a methyl or an ethyl or a propyl or a butyl or a pentyl. In some embodiments, R1 is a methyl or an ethyl or a propyl.

In some embodiments, R1 is 2-propyl.

In some embodiments, each of R2, R3 and R4, independently of the other, is selected from a phenyl, a substituted phenyl, furanyl, a substituted furanyl, pyrronyl, a substituted pyrrolyl, thiophenyl and substituted thiophenyl.

In some embodiments, each of R2, R3 and R4, independently of the other, is selected from a fused aryl and a fused heteroaryl.

In some embodiments, each of R2, R3 and R4, independently of the other, is an optionally substituted indolyl, an optionally substituted benzofuranyl, an optionally substituted benzothiophenyl.

In some embodiments, the peripherally restricted CB1 antagonist is of structure (2): wherein each X is a heteroatom selected from O, NH and S;

Y is a heteroatom selected from O, NH and S or is a tertiary N atom; R1 is a C1-C5alkyl;

R2 is a -(C=O)NH-R ₃ ;

R3 is a C6-C10aryl or a C5-C1 oheteroaryl; and one of the bonds designated - is a double bond and the other is a single bond.

In some embodiments, each X is the same.

In some embodiments, each X is NH or O. In some embodiments, each X is NH.

In some embodiments, one or both of X are a tertiary N group.

In some embodiments, Y is S.

In some embodiments, R1 is a methyl, ethyl, propyl, butyl or pentyl. In some embodiments, R1 is methyl, ethyl or propyl.

In some embodiments, R2 is a -(C=O)NH-phenyl, wherein the phenyl is optionally substituted.

In some embodiments, the phenyl is substituted by at least one halogen or a group comprising one or more halogen atoms. In some embodiments, the group comprising one or more halogen atoms is substituted by 1, 2, 3 or more F atoms. In some embodiments, the group comprising one or more halogen atoms is a trifluorinated methyl.

In some embodiments, R3 is a substituted phenyl. In some embodiments, R3 is a phenyl substituted with a group selected from a hydroxide group, an ether group and an ester group.

In some embodiments, R3 is a phenyl substituted ether group.

In some embodiments, R3 is a phenyl substituted with a group having the structure - 0-(CH2)m-C6-C10aryl or -0-(CH2)m-C5-C10heteroaryl, wherein m is an integer between 0 and 3 and C6-C10aryl is optionally a phenyl.

In some embodiments, the group -0-(CH2)m-C6-C10aryl is -O-(CH2)m-phenyl.

In some embodiments, in the group -0-(CH2)m-C6-C10aryl, m is 1.

As used herein, the optional substitution referred to above, in groups constructing compound of formula (1) or formula (2), may be a substitution by an alkyl, an hydroxyl, an amine, a halide, an ether, an ester, a thiol, a sulfide, an aryl, or any other atom or group, as known in the art. The substitution may be of a single atom or a group of atoms or may be of multiple atoms or groups of atoms which may be the same or different.

It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration or may be a mixture thereof. Thus, any of the peripherally restricted CB1 antagonists disclosed herein may be enantiomerically pure, or in stereoisomeric or diastereomeric mixtures. In the case of amino acid residues, such residues may be of either the L- or D-form. One of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

As used herein, an alkyl contains the specified number of carbon atoms, e.g., between 1 and 5, inclusive, and are straight or branched. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, and others. As used herein, a “carbocyclyl” or a "cycloalkyl" refers to a saturated mono- or multi- cyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 5 to 10 carbon atoms. The ring system of the cycloalkyl may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion.

As used herein, "aryl" refers to aromatic monocyclic or multicyclic groups containing from 6 to 10 carbon atoms. Aryl groups include but are not limited to groups such as unsubstituted or substituted fluorenyl, unsubstituted or substituted phenyl, and unsubstituted or substituted naphthyl, or others as mentioned herein.

As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of about 5 to about 10 atoms where one or more, in one embodiment 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur. The heteroaryl group may be optionally fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl and isoquinolinyl,

As used herein, "halo", "halogen" or "halide" refers to F, Cl, Br or I.

As used herein, any substituent or variant discussed or mentioned herein, is in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem. 11:942-944).

In some embodiments, the compound used as a peripherally restricted CB 1 antagonist or as a CB1 antagonist is a phytocannabinoid. The "phytocannabinoids" may be any of the naturally occurring cannabinoids produced in plants. These may be selected amongst cannabigerols, cannabichromenes, cannabidiols, tetrahydrocannabinols, cannab-inols, cannabinodiols, and other cannabinoids. Non-limiting examples of phytocannabinoids include cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannab-inol (CBN) and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monom-ethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant

(CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), and tetrahy-drocannabivarinic acid (THCVA).

In some embodiments, the peripherally restricted CB1 antagonist is THCV.

In some embodiments, the peripherally restricted CB1 antagonist is a compound having structure: wherein

R is a substituent or a ring structure as defined in any of the structures below, X is a carbon containing group (C, C=, CH), a nitrogen containing group (N, N=, NH) or is absent; provided that R is different from H.

In some embodiments, each of the phenyl groups, independently of the other, may or may not be substituted by 1, 2, 3, 4 or 5 same or different substituents.

In some embodiments, the CBi receptor-binding lipophilic compound is a P-gp substrate.

In some embodiments, the CBi receptor-binding lipophilic compound has a brain/plasma ratio below 0.3.

In some embodiments, the peripherally restricted CBI antagonist is compound of formula (3):

wherein each of R1 and R2, independently of the other, is a group selected from -H, halide, - CN, -C1-C ₅ alkyl-OH and -OH; each of n and m, independently of the other, is an integer between 0 and 5, designating the number of substituents on the ring;

X is selected from nitrogen and -CH-; or X-R4 may optionally be N=R4 or C=R4;

R3 is selected from H, a carbon containing group comprising between 1 and 3 carbon atoms, being optionally substituted, and a nitrogen atom or a nitrogen containing group;

R4 is selected from a carbon containing group comprising between 1 and 3 carbon atoms, being optionally substituted, and a nitrogen atom or a nitrogen containing group; or R3 and R4 together with atoms to which they are bonded (carbon atom and X, respectively) form a 5- or 6-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S; or R3 and R4 together with the atoms to which they are bonded form a fused ring system optionally containing between 1 and 6 heteroatoms selected from N, O and S.

In some embodiments, X is N.

In some embodiments, X-R4 is C=R4-

In some embodiments, X-R4 is N=R4-

In some embodiments, X is a nitrogen atom and R4 is a nitrogen containing group. In such embodiments, moiety X-R4 may thus be selected from -N-NH-, -N=N- and -N-N= (wherein in the selection the N on the left is X and the N on the right is R4). In some embodiments, R3 is a carbon containing group and R4 is a nitrogen containing group.

In some embodiments, R3 and R4 together with the atoms to which they are bonded form a 6-membered carbocyclic ring optionally containing 1 or 2 nitrogen atoms.

In some embodiments, R3 and R4 together with the atoms to which they are bonded form a 5-membered carbocyclic ring optionally containing 1 or 2 nitrogen atoms.

In some embodiments, R3 and R4 together with the atoms to which they are bonded form a fused ring system optionally containing 1, 2, 3, 4, 5, or 6 heteroatoms such as nitrogen atoms.

In some embodiments, the fused ring system is a two-ring fused system comprising a 5-membered ring that is fused to a 5 -membered ring, or fused to a 6-membered ring, or fused to a 7-memebred ring, or fused to a 8-memebred ring. In some embodiments, the fused ring system is a two-ring fused system comprising a 5 -membered ring that is fused to a 6- membered ring, wherein the fused system comprises 1, 2, 3, 4, or 5 heteroatoms. The fused system may further be substituted.

In some embodiments, the compound is of the general formula (4): wherein one of L, Li and L2 is a nitrogen atom and the others of L, Li and L2 are each a carbon atom (being selected from C, CH or CH2); each of R5, R6 and R7, independently of the other, may be selected from -H, -C1- C ₃ alkyl, -C(=O)-OH, -C(=O)-O-R ₈ , -C(=O)-NR'R ₈ , halide, -CN, -OH, and -NR'R"; or one of R5 and R6 or R6 and R7 together with the atoms to which they bond may form a 5-, 6-, 7- or 8-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S; the 5-, 6-, 7- or 8 -membered carbocyclic ring is further optionally substituted by at least one functionality selected from - radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH2C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; the 5-, 6-, 7- or 8-membered carbocyclic ring may be optionally substituted by at least one functionality selected from structures (A) through (H): wherein in each functionality (A) through (H), the wavy line indicates point or bond of connectivity, j is 0 or 1 and Ra is selected from -H, -C1-C ₂₅ alkyl, -C ₂ -C ₂₅ alkenyl, -C ₂ - C ₂₅ alkynyl, -C(=O)-C6-C10aryl and -C(=O)-C ₃ -C10heteroaryl, wherein in functionalities (G) and (H) the pendant -NH-Ra group may appear between 1 and 11 times at any position along the carbocycle (in some embodiments, it may be positioned at a ring atom once removed, twice removed or three times removed from the existing group or endocyclic N atom; in some embodiments, the position of the functionality is 1 , 2 or 1 , 3 or 1 ,4, wherein 1 designates the position of the existing group or the endocyclic

N atom); one of R5, R6 and R7 may be absent; R8 is selected from -H, -C1-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -C6-C10aryl and C3-C10heteroaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C2- C5alkenyl, -S-C ₂ -C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C ₂ -C ₅ alkenyl, -C(=O)-O-C ₂ -C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)-C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C2-C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R ’R -NH-C2-C ₂₅ alkenyl-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ -C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C2-C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂ 5alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”\ -NH-C2- C ₂₅ alkenylene-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1- C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, - NHC(=O)C2-C ₂₅ alkynyl, -NHC(=O)C1-C25alkylene-NR’R”R”’, -NHC(=O)C ₂ -

C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C2-C ₂ 5alkynylene-NR’R”R’”, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, - NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C2-C25alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH3)2-O-aryl-Cl, NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'; Rio is selected from -H, -C1-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -C1-C5alkyl, -C2-C5alkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)- C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, - C(=O)-NR'R"R"', -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -S-, -S-C1-C5 alkyl, -S- C1-C5alkenyl, -S-C1-C5alkynyl, -ONO2, -NO2, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, - NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'; each of R', R" and R'" is independently selected from -H, C1-C5alkyl, C2-C5alkenyl, C2- C5alkynyl, -C(=O)-C2-C25alkyl, -C(=O)-C2-C25alkenyl and C5-C25alkynyl; or wherein one of R', R" and R'" is absent; and wherein each bond between N-L, L-Li, L1-L2 and L2-C (designated — ) is a single or double bond.

In some embodiments, R8 is -C1-C25alkyl.

In some embodiments, R8 is -C2-C25alkenyl.

In some embodiments, R8 is -C2-C25alkynyl.

In some embodiments, R8 is -C6-C10aryl.

In some embodiments, R8 is C3-C10heteroaryl.

In some embodiments, R8 is -C1-C25alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C5alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR'-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C2-C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R ’R -NH-C2-C ₂₅ alkenyl-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ -C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C2-C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂ 5alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1- C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkynylene-C(=O)-O-C1-C ₂₅ alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -

C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C ₂ 5alkenylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH3) ₂ -O-aryl-Cl, NHC(=O)CH ₂ C(CH3) ₂ -O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and -

NR'R"R"'.

In some embodiments, R8 is -C ₂ -C ₂ 5alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)- ORio, -O-C1-C5alkyl, -O-C1-C5alkenyl, -O-C1-C5alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R”R”’, -NH-C ₂ -C ₂ 5alkenyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-NR’R”R”\ - NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ -C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C25alkylene-C(=O)-NR’R”R”’, -NH-C2- C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2-C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1- C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ -C25alkynylene-NR’R”R’”, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C ₃ -C10heteroaryl, -NHC(=O)C2-C25alkynylene-C ₃ -C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ )2-O-aryl-Cl, NHC(=O)CH2C(CH ₃ )2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'.

In some embodiments, R8 is -C ₂ -C ₂ 5alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C2-C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R”R”’, -NH-C2-C ₂₅ alkenyl-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ -C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C2-C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C ₃ -C10heteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2- C ₂₅ alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”\ -NH-C2- C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C2-C ₂ 5alkynylene-C(=O)-NR’R”R’”, -NH-C1- C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C25alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C25alkylene-NR’R”R”’, -NHC(=O)C ₂ - C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C2-C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C ₃ -C10heteroaryl, -NHC(=O)C2-C25alkynylene-C ₃ -C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ )2-O-aryl-Cl, NHC(=O)CH2C(CH ₃ )2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'.

In some embodiments, R8 is -C6-C10aryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C2-C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C ₂ -C25alkynyl-C(=O)-NR’R”R”’, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ -C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C2-C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C ₃ -C10heteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2- C ₂₅ alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”\ -NH-C2- C ₂₅ alkenylene-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1- C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C25alkylene-NR’R”R”’, -NHC(=O)C ₂ -

C ₂ 5alkenylene-NR’R”R’”, -NHC(=O)C ₂ -C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C ₂ 5alkenylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C ₃ -C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'.

In some embodiments, R8 is C ₃ -C10heteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C5alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR'-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)- ORio, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R ’R -NH-C ₂ -C ₂ 5alkenyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-NR’R”R”\ - NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ -C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C ₃ -C10heteroaryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1- C ₂ 5alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkynylene-C(=O)-O-C1-C ₂₅ alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂₅ alkylene-NR’R”R”\ -NHC(=O)C ₂ -

C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂₅ alkynylene-NR’R”R”\ -NHC(=O)C1- C ₂ 5alkylene-OH, -NHC(=O)C ₂ -C25alkenylene-OH, -NHC(=O)C ₂ -C25alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂ 5alkylene-C ₆ -C10aryl, - NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C2-C25alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂ 5alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C ₃ -C10heteroaryl, -NHC(=O)C2-C25alkynylene-C ₃ -C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ )2-O-aryl-Cl, NHC(=O)CH2C(CH ₃ )2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'.

In some embodiments, the 5-, 6-, 7- or 8-membered carbocyclic ring substituted by at least one functionality selected from structures (A) through (H):

In some embodiments, in each functionality (A) through (H), j is 0.

In some embodiments, in each functionality (A) through (H), j is 1.

In some embodiments, the pendant -NH-Ra group appears once. In some embodiments, -NH-Ra is positioned at a ring atom once removed from the existing group or endocyclic N atom. In some embodiments, the -NH-Ra is positioned at a ring atom twice removed from the existing group or endocyclic N atom. In some embodiments, the -NH-Ra is positioned at a ring atom three times removed from the existing group or endocyclic N atom.

The invention further provides a compound of formula (4), as defined herein.

As used herein, a “carbon containing group having between 1 and 3 carbon atoms” is any carbon chain or carbon-containing group or a carbon-containing functionality that comprises one to three carbon atoms, inclusive, which may be bonded to each other or may be separated or interrupted by one or more atoms that are not carbon. In some embodiments, the carbon containing group is a group comprising a chain of one to three carbon atoms, each of which being connected to another atom. Non-limiting examples of such carbon groups include -CH, -CH ₂ -, -CH ₃ , -CH-CH-, -CH ₂ -CH-, -CH=CH-, -CH-CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -, - CH ₂ -CH-CH-, -CH ₂ -CH=CH- and others. Non-limiting examples of such carbon groups that include one or more atoms that are not carbon, e.g., a heteroatom such as nitrogen, include - CH-NH-, -C=N-, -CH ₂ -NH-, -N-CH ₃ , -CH-NH-CH-, -CH ₂ -CH-NH-, -CH=N-CH-, -CH- NH-CH ₂ -, -CH ₂ -NH- CH ₂ -CH ₂ -, -CH ₂ -CH-NH-CH-, -CH ₂ -CH=CH-NH-, -CH ₂ -N=CH-NH- , -CH ₂ -NH-CH=CH-NH-, -CH ₂ -N=CH-, and others. Such groups may be optionally substituted.

The carbon-containing group containing between 1 and 3 carbon atoms may be alternatively designated as -C1-C ₃ alkyl, -C ₂ -C ₃ alkenyl or -C ₂ -C ₃ alkynyl, or any substituted for thereof.

A “nitrogen atom or a nitrogen-containing group” is similarly any group of atoms or a functionality that comprises one or more nitrogen atoms. The nitrogen(s) atom may be substituted with hydrogen atoms or with a carbon group or any other functionality. In some embodiments, the nitrogen containing group is a group such as -NH-, -NH ₂ -, -NHR’, NH ₂ R’, NHR’R”, NR’R”R”’, wherein each of R’, R” and R’” is as further defined herein. The nitrogen containing group may additionally be selected from nitrogen- containing cycles. Non-limiting examples of such nitrogen-containing cycles include aziridinyl, azetidinyl, pyrrolidinyl, Imidazolidinyl, imidazolyl, Pyrazolidinyl, Pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, diazinyl, triazinyl, trihydrotriazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl and others. The nitrogen atom or nitrogen-containing group may be presented in a form of a charged nitrogen atom (an ammonium).

As disclosed herein, e.g., with reference to variables R3 and R4, any two groups, as recited, together with atoms to which they are bonded (carbon atom and X, respectively, when in reference to variables R3 and R4) may form a 5- or 6-membered carbocyclic ring optionally containing a heteroatom, e.g., between 1 and 3 heteroatoms, inclusive, wherein the heteroatoms may be selected from N, O and S. Other non-carbon atoms may also be present. The 5- or 6-membered ring comprises one or more carbon atoms in a cyclic form (forming a carbocyclic structure). The carbon chain forming the carbocycle may be interrupted by one or more heteroatoms, together forming a heterocyclic ring structure.

In some embodiments, the heterocyclic ring may comprise 1, 2 or 3 nitrogen atoms. In some embodiments, the heterocyclic ring may comprise 1, 2 or 3 oxygen atoms. In some embodiments, the heterocyclic ring may comprise 1, 2 or 3 sulfur atoms.

In some embodiments, the heterocyclic ring may comprise 1, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms.

In some embodiments, the heterocyclic ring may comprise 1 or 2 nitrogen atoms.

Alternatively, variables R3 and R4 together with atoms to which they are bonded (carbon atom and X, respectively, when in reference to variables R3 and R4) may form a fused ring system as defined. R8 is selected from -H, -C1-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -C6-C10aryl and -C3-C10heteroaryl. As used herein with reference to R8 or to any other variable, the alkyl, alkenyl and alkynyl are each as known in the art.

Where R8 or any other group is a C1-C25alkyl, it may be linear, branched or cyclic and may optionally be substituted by one or more substituents as defined. In some embodiments, R8 is a linear alkyl comprising a number of carbon atoms selected from between 1 and 25, 1 and 20, 1 and 10, 5 and 25, 5 and 20, 10 and 25, 10 and 20, 15 and 25, 15 and 20 or between 20 and 25 carbon atoms. In some embodiments, the linear alkyl comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. In some embodiments, the linear alkyl comprises 6, 10, 16 or 18 carbon atoms.

Where the alkyl group is substituted on both ends, it may be regarded as an alkylene group. In some embodiments, the alkyl group is a non-linear, branched or cyclic -C5- C ₂₅ alkyl.

Where R8 or any other group is a C5-C ₂ 5alkenyl, it may be linear, branched or cyclic and comprising one or more double bonds in cis or trans configuration. The double bond may be a mid-chain double bond or a terminal double bond. Where R8 is a cyclic alkenyl, the double bond may be endocyclic or exocyclic. In some embodiments, R8 is a linear alkenyl comprising a number of carbon atoms selected from between 5 and 25, 5 and 20, 5 and 10, 10 and 25, 10 and 20, 15 and 25, 15 and 20 or between 20 and 25 carbon atoms. In some embodiments, the linear alkenyl comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. In some embodiments, the linear alkenyl comprises between 1 and 10 double bonds, each double bond may independently be in a cis or trans configuration. Where the alkenyl group is substituted on both ends, it may be regarded as an alkenylene group.Where R8 or any other group is a C5-C ₂ 5alkynyl, it may be linear, branched or cyclic and comprising one or more triple bonds. The triple bond may be a mid-chain bond or a terminal bond. Where R8 is a cyclic alkynyl, the triple bond may be endocyclic or exocyclic. In some embodiments, R8 is a linear alkynyl comprising a number of carbon atoms selected from between 5 and 25, 5 and 20, 5 and 10, 10 and 25, 10 and 20, 15 and 25, 15 and 20 or between 20 and 25 carbon atoms. In some embodiments, the linear alkynyl comprises 5, 6,

7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. In some embodiments, the linear alkynyl comprises between 1 and 5 triple bonds. Where the alkynyl group is substituted on both ends, it may be regarded as an alkynylene group.

In some embodiments, the alkyl, alkenyl or alkynyl may be selected from CH3(CH ₂ )3-

and alkenylene derived from DHA (all-cis-docosa- 4,7,10,13,16,19-hexa-enoic acid).

Where R8 or any other group is a C6-C10aryl, the aryl group, as known in the art, may be any aromatic system comprising between 6 and 10 atoms, typically carbon atoms. The aryl group may be a single aromatic ring, such as a phenyl or a benzyl ring; a group containing two or more rings structures, one or more of which being aromatic, such as a diphenyl group; or a fused ring system comprising at least one aromatic ring, such as fused phenyl rings and naphthyl groups.

Where R8 or any other group is a C3-C10heteroaryl, the group comprises one or more heteroatom in the ring structure. Such groups may contain nitrogen oxygen or sulfur atoms as ring atoms. Non-limiting examples include pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, furyl, thienyl, oxazolyl, benzoxazolyl, thiazolyl, benzo thiazolyl, benzofuranyl, benzdioxolyl, benzothiophenyl and others. Substitution of the heteroaryl group may be at any position, typically at any carbon atom of the heteroaryl group. For example, the pyridyl group may be substituted ortho, meta or para to the N atom.

In some embodiments, in a compound of formula (4), R5 or R6 or R7 is -C(=O)-O-Rs or -C(=O)-NR'Rs, and R8 is -C1-C ₂₅ alkyl selected, for example, from - (CH ₂ )8CH=CH(CH ₂ )7CH3, -(CH ₂ ) ₂ -, -(CH ₂ )I ₅ CH ₃ , -(CH ₂ )I ₅ CH ₃ and

(CH2)2CH=CH(CH ₂ CH=CH)5CH ₂ CH ₃ .

In some embodiments, in a compound of formula (4), R6 or R7 is -C(=O)-O-R8 or - C(=O)-NR'Rs, and R8 is selected from 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, - NHC(=O)CH2C(CH ₃ )2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'.

The group “2,2,6,6-tetramethylpiperidin-l-ol-4-yV is the radical having the structure: , wherein z is 1 , Rf is H and wherein the dashed bond is a single bond.

Yet, also encompassed are groups wherein Z is zero, the dashed bond is a single bond or a double bond and wherein Rf is H or is selected from halide, -CN, -OH, -C1-C ₂₅ alkyl, -C2- C ₂₅ alkenyl, -C2-C ₂₅ alkynyl, -C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -C1-C5alkyl, -C2- C5alkenyl, -C ₂ -C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O- C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-ORio, -O-C1-C ₅ alkyl, -O- C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1- C5alkynyl, -ONO2, -NO2, and -NR'R"R"', as defined herein.

In some embodiemnts, in a group wherein Z is zero, the groups may be selected from:

The group designates a substituted aryl group, wherein the chloride atom and the ether group are substituted on the aryl structure ortho, meta or para to each other. In some embodiments, the group has the structure:

The "iclebenonyl-clerivative " is a group of the structure:

In some embodiemnts, k is between 1 and 25, 1 and 20, 1 and 15, 1 and 10, 1 and 5, 5 and 25, 5 and 20, 5 and 10, 10 and 25 or between 10 and 20. In some embodiemnts, k is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In some embodiemnts, k is 10.

The group is a niacin acid derivative, wherein the substitution on the pyridine ring may be at any position relative to the carboxylic acid group or to the ring nitrogen atom.

The group “-NR ’R”R’”” designates an amine which may be a primary amine, a secondary amine, a tertiary amine or a quaternary amine. Each of the R groups may be selected as disclosed herein. In some embodiments, each of R', R" and R'" is independently -H, -C1-C5alkyl, -C ₂ -C ₅ alkenyl, -C ₂ -C ₅ alkynyl, -C(=O)-C ₂ -C ₂₅ alkyl, -C(=O)-C ₂ -C ₂₅ alkenyl or C5- C ₂ 5alkynyl. In cases where the group designates a charged nitrogen atom (an ammonium), the three R groups are presented and may be selected as indicated. In cases where the group designates an uncharged nitrogen atom, one of R', R" and R'" is absent and the remaining two groups may be each selected as indicated herein.

As recited herein, in a compound of formula (4), R8 or R6 or R? may be -C(=O)-O- R8 or -C(=O)-NR'Rs, wherein R8 is selected as above. Each of the groups selected for R8 may be substituted or unsubstituted. In some embodiments, the groups selected for Rs, namely - C1-C ₂₅ alkyl, -C ₂ -C ₂₅ alkenyl, -C ₂ -C ₂₅ alkynyl and -C6-C10aryl, may be substituted by at least one functionality selected from an hydroxyl (-OH), an amine (primary, secondary, tertiary or quaternary amine), a halide (selected F, Br, Cl and I), -C1-C5alkyl, -C ₂ -C5alkenyl, -C ₂ - C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, - C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C5alkynyl, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, -ONO ₂ , -NO ₂ , 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, -NHC(=O)CH ₂ C(CH3) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'.

In some embodiments, R8 or R6 or R? is -C(=O)-O-R8 and R8 is selected as above. In some embodiments, R8 is -C1-C ₂₅ alkyl. In some embodiments, the -C1-C ₂₅ alkyl is selected from optionally substituted -(CH ₂ ) ₈ CH=CH(CH ₂ ) ₇ CH3, -(CH ₂ ) ₂ -, -(CH ₂ )I ₅ CH ₃ , - (CH ₂ )I ₅ CH ₃ and -(CH ₂ ) ₂ CH=CH(CH ₂ CH=CH) ₅ CH ₂ CH ₃ . In some embodiments, the aforementioned groups are substituted by -NR'R"R"', wherein one of said R', R" and R'" is absent and the other of R', R" and R'" is selected from -H, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, - C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"' and -C(=O)-ORw, as defined herein. In some embodiments, the group -NR'R"R"' is thus - NHR'" (R’ absent and R”=H), wherein R ” is -H, -C(=O)-, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"' or -C(=O)-ORio. In some embodiments, R ” is -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1- C5alkenyl, or -C(=O)-O-C1-C5alkynyl. In some embodiments, R’” is -C(=O)- or -C(=O)-C1- C ₂₅ alkyl. In some embodiments, R8 or R6 or R7 is -C(=O)-O-R8 and R8 is selected from - (CH ₂ )8CH=CH(CH ₂ )7CH3, -(CH ₂ ) ₂ -, -(CH ₂ )I ₅ CH ₃ , -(CH ₂ )I ₅ CH ₃ , -(CH ₂ ) ₂ -

NHC(=O)(CH ₂ ) ₇ CH=CH(CH ₂ ) ₇ CH ₃ and -(CH ₂ ) ₂ CH=CH(CH ₂ CH=CH) ₅ CH ₂ CH ₃ .

In some embodiments, R8 or R6 or R7 is -C(=O)-O-(CH ₂ ) ₈ CH=CH(CH ₂ )7CH ₃ , -C(=O)-O- (CH ₂ ) ₂ -, -C(=O)-O-(CH ₂ )I ₅ CH ₃ , -C(=O)-O-(CH ₂ )I ₅ CH ₃ , -C(=O)-O-(CH ₂ ) ₂ -

NHC(=O)(CH ₂ ) ₇ CH=CH(CH ₂ ) ₇ CH ₃ and -C(=O)-O-(CH ₂ ) ₂ CH=CH(CH ₂ CH=CH) ₅ - CH ₂ CH ₃ .

In some embodiments, R8 or R6 or R7 is -C(=O)-NR'R8 and R8 is selected as above. In some embodiments, R8 is -C1-C ₂₅ alkyl. In some embodiments, the -C1-C ₂₅ alkyl is selected from optionally substituted -(CH ₂ ) ₈ CH=CH(CH ₂ ) ₇ CH ₃ , -(CH ₂ ) ₂ -, -(CH ₂ )I ₅ CH ₃ , - (CH ₂ )I ₅ CH ₃ and -(CH ₂ ) ₂ CH=CH(CH ₂ CH=CH) ₅ CH ₂ CH ₃ .

In some embodiments, R8 or R6 or R7 is -C(=O)-NR’R8 and R8 is selected from - (CH ₂ ) ₈ CH=CH(CH ₂ ) ₇ CH ₃ , -(CH ₂ ) ₂ -, -(CH ₂ )I ₅ CH ₃ , -(CH ₂ )I ₅ CH ₃ , -(CH ₂ ) ₂ -

NHC(=O)(CH ₂ )7CH=CH(CH ₂ ) ₇ CH ₃ and -(CH ₂ ) ₂ CH=CH(CH ₂ CH=CH) ₅ CH ₂ CH ₃ . In some embodiments, R’ is H.

In some embodiments, R8 or R6 or R7 is -C(=O)-NH-(CH ₂ ) ₈ CH=CH(CH ₂ )7CH ₃ , - C(=O)-NH-(CH ₂ ) ₂ -, -C(=O)-NH-(CH ₂ )I ₅ CH ₃ , -C(=O)-NH-(CH ₂ )I ₅ CH ₃ and -C(=O)-NH- (CH ₂ ) ₂ -NHC(=O)(CH ₂ ) ₇ CH=CH(CH ₂ ) ₇ CH ₃ and -C(=O)-NH- (CH ₂ ) ₂ CH=CH- (CH ₂ CH=CH) ₅ CH ₂ CH ₃ .

In some embodiments, in a compound of formula (4), L is a nitrogen atom (or a nitrogen containing group of atoms) and each of Li and L ₂ is a carbon atom (or a carbon containing group of atoms).

In some embodiments, L is a nitrogen atom (or a nitrogen containing group of atoms), each of Li and L ₂ is a carbon atom (or a carbon containing group of atoms), the bond between N and L is a single bond, the bond between L and Li is a double bond, and the bond between Li and L ₂ is a single bond.

In some embodiments, R5 is absent.

In some embodiments, the compound is of formula (5):

wherein each of Ri, R2, n, m, R6 and R7 are as defined herein, and wherein — designates a single or a double bond (in case it is a double bond, the carbon atom bearing variant R7 does not carry a bond to a hydrogen atom).

As indicated herein, each of R6 and R7, independently of the other, may be selected from -H, -C1-C ₃ alkyl, -C(=O)-OH, -C(=O)-O-R ₈ , -C(=O)-NR'R ₈ , halide, -CN, -OH, and - NR'R"; or R6 and R7 together with the atoms to which they bond may form a 5-, 6-, 7- or 8- membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S. Substitution may be as indicated above.

In some embodiments, R7 is H and R6 is selected from -C1-C5alkyl, -C(=O)-O-R ₈ , - C(=O)-NR'-R ₈ , a halide, -CN, -OH, and -NR'R"; wherein R8 is as defined herein.

In some embodiments, R6 is -C(=O)-NR'R ₈ ; and R ₈ is as defined herein.

In some embodiments, R6 is -C(=O)-NHR ₈ ; and R ₈ is as defined herein.

In some embodiments, the bond — is a double bond.

In some embodiments, the bond — is a single bond.

In some embodiments, the compound is of general formula (6): wherein each of Ri, R2, n, m and R8 is as defined herein.

In some embodiments, R8 is a C1-C ₂₅ alkyl, optionally substituted, as disclosed and selected herein.

In some embodiments, n is 2 and m is 1.

In some embodiments, R1 and R2 are each a halide.

In some embodiments, each of R1 and R2 is a chloride atom.

In some embodiments, the compound is of the formula (7): wherein R8 is as defined herein.

In some embodiments, for a compound of formula (6) and/or (7), R8 may be: -C1-C ₂₅ alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -C(=O)- , -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂ 5alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C25alkenyl-C(=O)-OH, -NH-C2- C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C25alkenyl-C(=O)- NR’R’R ”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2- C ₂ 5alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C25alkyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C1-C25alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2-

py ( ) ;

-C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, - C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C ₂₅ alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R”’, -NHC(=O)C2-C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂ 5alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C25alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C25alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C25alkylene-C ₃ -C10heteroaryl, -NHC(=O)C2-C25alkenylene-C ₃ -C10heteroaryl, NHC(=O)C2-C25alkynylene-C ₃ -C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C2-C ₂₅ alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C25alkenyl-C(=O)-OH, -NH-C2- C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C25alkenyl-C(=O)- NR’R”R”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2- C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C25alkyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C1-C25alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C ₂₅ alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂ 5alkynyl, -NHC(=O)C1- C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C2-C ₂ 5alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C25alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂ 5alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C ₃ -C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C ₃ -C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C6-C10aryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C5alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R ”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R”\ -NH-C ₂ -C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C ₂ - C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C25alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C25alkylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkenylene-C3-C10heteroaryl, NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ )2-O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or -C5-C10heteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C25alkenyl-C(=O)-OH, -NH-C2- C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂ 5alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂ 5alkenyl-C(=O)- NR’R’R ”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2- C ₂ 5alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C25alkyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C1-C25alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C25alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂ 5alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R”’, -NHC(=O)C2-C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂ 5alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C25alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-C6-C10aryl, NHC(=O)C ₂ -C25alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C25alkylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkenylene-C3-C10heteroaryl, NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH2C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'.

In some embodiments, in a compound of formula (4), L is a nitrogen atom, each of Li and L2 is a carbon atom, the bond between N and L is a single bond, the bond between L and Li is a double bond, the bond between Li and L2 is a single bond and the bond between L2 and C is a double bond.

In some embodiments, the compound is of the general formula (8): wherein each of Ri, R2, n, m, R6 and R7 is as defined herein.

In some embodiments, R6 is selected from -C1-C ₃ alkyl, -C(=O)-O-R ₈ , -C(=O)-NR'-

R ₈ , a halide, -CN, -OH, and -NR'R";

R7 is a C1-C3 alkyl;

R ₈ is as defined herein.

In some embodiments, R6 is -C(=O)-NR'-R ₈ ; and R ₈ is a C1-C25alkyl.

In some embodiments, the compound is of general formula (9): wherein each of Ri, R2, n, m and R ₈ is as defined herein. In some embodiments, for a compound of formula (9), R8 may be:

-C1-C ₂₅ alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -C(=O)- , -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂ 5alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C25alkenyl-C(=O)-OH, -NH-C2- C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C25alkenyl-C(=O)- NR’R’R ”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2- C ₂ 5alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C25alkyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C1-C25alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C25alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂ 5alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R’”, -NHC(=O)C2-C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂ 5alkylene-OH, -NHC(=O)C ₂ -C ₂ 5alkenylene- OH, -NHC(=O)C ₂ -C25alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-C6-C10aryl, NHC(=O)C ₂ -C25alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C25alkylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkenylene-C3-C10heteroaryl, NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ )2-O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R ”’, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂₅ alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C ₂ - C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1-C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R’”, -NHC(=O)C ₂ -C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C ₂ -C ₂ 5alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C5alkyl, -O-C1- C5alkenyl, -O-C1-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -Ci ₀ aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂ 5alkyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R ”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R”\ -NH-C ₂ - C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C6-C10aryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C5alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C25alkyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R ”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R”\ -NH-C ₂ - C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or -C5-C10heteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R”R”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C25alkylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C25alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R”’, -NHC(=O)C2-C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂ 5alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C25alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C25alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C25alkylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkenylene-C3-C10heteroaryl, NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ )2-O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'.

In some embodiments, compounds of formulae herein (all formulae recited generically or specifically herein) exclude compounds wherein R8 is C7-C12alkyl.

In some embodiments, R8 is a C1-C25 alkyl.

In some embodiments, R8 is 2,2,6,6-tetramethylpiperidin-l-ol-4-yl.

In some embodiments, the compound is of the general formula (10):

In some embodiments, n is 2 and m is 1.

In some embodiments, R1 and R2 are each a halide. In some embodiments, each of R1 and R2 is a chloride atom.

In some embodiments, the compound is of the formula (11): wherein R8 is as defined herein.

In some embodiments, for a compound of formula (11), R8 may be:

-C1-C25alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂ 5alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C25alkenyl-C(=O)-OH, -NH-C2- C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂ 5alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂ 5alkenyl-C(=O)- NR’R’R ”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2- C ₂ 5alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C25alkyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C1-C25alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C25alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C ₃ -C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C ₃ -C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C ₂ - C ₂₅ alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R”R”’, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂₅ alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C ₂ - C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1-C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂₅ alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R’”, -NHC(=O)C ₂ -C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-

-C2-C25alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, -

In some embodiments, R8 is 2,2,6,6-tetramethylpiperidin-l-ol-4-yl. In some embodiments, the compound is of the formula (12):

In some embodiments, in a compound of formula (12): each of R1 and R2, independently of the other is a group selected from H, a halide and -CN; each of n and m, independently of the other, is an integer between 0 and 5, designating the number of substituents on the ring;

X is selected from a nitrogen atom (or a nitrogen containing group) and CH; or X-R4 may optionally be C=R4; and

R3 is H or a carbon containing group and R4 is a nitrogen containing group.

In some embodiments, X is CH and R4 is a carbon containing group having between 1 and 3 carbon atoms.

In some embodiments, R3 is H.

In some embodiments, the compound is of the general formula (13): wherein each of Rl, R2, n, m and R8 is as defined herein, optionally excluding compounds wherein R8 is C7-C12alkyl. In some embodiments, for a compound of formula (13), R8 may be:

-C1-C ₂₅ alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂ 5alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C25alkenyl-C(=O)-OH, -NH-C2- C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C25alkenyl-C(=O)- NR’R’R ”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2- C ₂ 5alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C25alkyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C1-C25alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C25alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂ 5alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R’”, -NHC(=O)C2-C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂ 5alkylene-OH, -NHC(=O)C ₂ -C ₂ 5alkenylene- OH, -NHC(=O)C ₂ -C25alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-C6-C10aryl, NHC(=O)C ₂ -C25alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C25alkylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkenylene-C3-C10heteroaryl, NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ )2-O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R ”’, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂₅ alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C ₂ - C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1-C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R’”, -NHC(=O)C ₂ -C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C ₂ -C ₂ 5alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C5alkyl, -O-C1- C5alkenyl, -O-C1-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -Ci ₀ aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂ 5alkyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R ”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R”\ -NH-C ₂ - C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C6-C10aryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C5alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C25alkyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R ”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R”\ -NH-C ₂ - C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or -C5-C10heteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R”R”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C ₂ - C ₂ 5alkynylene-C(=O)-NR’R”R’”, -NH-C1-C ₂ 5alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂ 5alkylene-NR’R”R’”, -NHC(=O)C ₂ -C25alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂ 5alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ )2-O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'.

In some embodiments, R8 is a C1-C25 alkyl.

In some embodiments, R8 is 2,2,6,6-tetramethylpiperidin-l-ol-4-yl.

In some embodiments, the compound is of the general formula (14):

In some embodiments, in a compound of formula (14), R8 is an idebenonyl derivative.

In some embodiments, the compound is of the formula (15):

wherein each of Ri, R2, n and m are as defined above and wherein k is an integer between 0 to 25.

In some embodiments, n is 2 and m is 1.

In some embodiments, R1 and R2 are each a halide.

In some embodiments, each of R1 and R2 is a chloride atom.

In some embodiments, the compound is of the general formula (16): wherein R8 is as defined herein.

In some embodiments, for a compound of formula (16), R8 may be:

-C1-C25alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO ₂ , -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -C(=O)- , -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂ 5alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R ”’, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂₅ alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C ₂ - C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1-C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R’”, -NHC(=O)C ₂ -C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C ₂ -C ₂ 5alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R’R -NH-C ₂ -C25alkynyl-C(=O)-NR’R”R” -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-NR’R”R”\ -NH-C ₂ - C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ - C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C ₂ 5alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C3-C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C ₂ -C ₂ 5alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkenyl-C(=O)- NR’R”R”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ - C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂ 5alkyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C25alkylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C25alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R”’, -NHC(=O)C2-C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C25alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C25alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C25alkylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkenylene-C3-C10heteroaryl, NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ )2-O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C6-C10aryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C25alkenyl-C(=O)-OH, -NH-C2- C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C25alkenyl-C(=O)- NR’R”R”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2- C ₂ 5alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C25alkyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C1-C25alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C25alkylene-C(=O)-NR’R”R”’, -NH-C2-C ₂ 5alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C ₂ 5alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-O-C1-C ₂ 5alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1- C ₂₅ alkylene-NR’R”R”’, -NHC(=O)C2-C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C25alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C25alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1- C25alkylene-C ₃ -C10heteroaryl, -NHC(=O)C2-C25alkenylene-C ₃ -C10heteroaryl, NHC(=O)C2-C25alkynylene-C ₃ -C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'; or

-C ₃ -C10heteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, - C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1- C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1- C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1- C5alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1-C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ - C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)- C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ -C25alkenyl-C(=O)-OH, -NH-C2- C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂ 5alkyl-C(=O)-NR’R”R’”, -NH-C ₂ -C ₂ 5alkenyl-C(=O)- NR’R”R”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, -NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2- C ₂ 5alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C25alkyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH- C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C1-C25alkyl, -NH- C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C6-C10aryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₆ -C10aryl, -NH-C1-C ₂ 5alkyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2- C25alkenyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C2-C25alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-C1-C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C2- C25alkenylene-C(=O)-O-C1- C ₂₅ alkyl, -NH-C2-C25alkynylene-C(=O)-O-C1-C ₂₅ alkyl, NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, -NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-

C ₂₅ alkylene-NR’R”R’”, -NHC(=O)C ₂ -C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene- OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, -NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, - NHC(=O)C1-C ₂ 5alkylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, NHC(=O)C ₂ -C ₂₅ alkynylene-C6-C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-

C ₂ 5alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkenylene-C ₃ -C10heteroaryl, NHC(=O)C ₂ -C ₂ 5alkynylene-C ₃ -C10heteroaryl, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ ) ₂ -O-aryl-Cl, -NHC(=O)CH ₂ C(CH ₃ ) ₂ -O-aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'.

In some embodiments, R8 is 2,2,6,6-tetramethylpiperidin-l-ol-4-yl.

In some embodiments, the compound is of the formula (17):

In some embodiments, R8 is an idebenonyl derivative.

In some embodiments, the compound is of the formula (18): wherein k is as defined above. In some embodiments, in a compound of formula (9), R8 is C1-C25alkyl optionally substituted by at least one functionality selected from -C(=O)-, -C(=O)-C1-C25alkyl, -C(=O)- O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', - C(=O)-ORw, wherein each of R', R", R'" and Rio is as defined above.

In some embodiments, the at least one functionality is selected from -C(=O)- NR'R"R"', -C(=O)-C1-C ₂₅ alkyl and -C(=O)-ORio, wherein each of R', R", R'" and Rio is as defined above.

In some embodiments, R’ is H, R” is absent and R’” is Rn, wherein R11 is selected from -H or a C1-C ₂₅ alkyl, C2-C ₂₅ alkenyl, C2-C ₂₅ alkynyl, C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, C1-C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O- C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)- ORio, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -S-, -S-C1-C5 alkyl, -S-C1- C5alkenyl, -S-C1-C5alkynyl, -ONO2, -NO2, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, - NHC(=O)CH2C(CH3)2-O-Aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"', and wherein R’, R”, R’” and Rio are as defined above.

In some embodiments, the compound is of the general formula (19): wherein each of Ri, R2, n, m and R11 is as defined herein.

In some embodiments, n is 2 and m is 1.

In some embodiments, R1 and R2 are each a halide.

In some embodiments, each of R1 and R2 is a chloride atom.

In some embodiments, the compound is of the general formula (20):

wherein R11 is as defined herein.

In some embodiments, R11 is selected from -H or a C1-C25alkyl, C2-C25 alkenyl, C2- C ₂₅ alkynyl, C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, C1-C5alkyl, C2-C5alkenyl, C2- C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, - C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -ONO2, -NO ₂ , 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, -NHC(=O)CH2C(CH3)2-O-Aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'.

In some embodiments, in a compound of formula (13), R8 is -C1-C25alkyl optionally substituted by at least one functionality selected from -C(=O)-, -C(=O)-C1-C25alkyl, -C(=O)- O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', - C(=O)-ORw, wherein each of R', R", R'" and Rio is as defined above.

In some embodiments, the at least one functionality is selected from -C(=O)- NR'R"R"', -C(=O)-C1-C25alkyl and -C(=O)-ORio, wherein each of R', R", R'" and Rio is as defined above.

In some embodiments, the compound is of the general formula (21):

wherein each of Ri, R2, n, m and Rio is as defined herein.

In some embodiments, Rio is selected from -H, -C1-C ₂₅ alkyl, -C2-C25 alkenyl, -C2- C ₂₅ alkynyl, -C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -C1-C5alkyl, -C2-C5alkenyl, -C2- C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, - C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1- C5alkynyl, -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -ONO2, -NO ₂ , 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl, -NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, - pyridine-3-C(=O)-OH and -NR'R"R"'; each of R', R" and R'" is independently selected from -H, C1-C5alkyl, C2-C5alkenyl, C2-C5alkynyl, -C(=O)-C2-C25alkyl, -C(=O)-C2-C25alkenyl and C5-C25alkynyl; or wherein one of R', R" and R'" is absent.

In some embodiments, n is 2 and m is 1.

In some embodiments, R1 and R2 are each a halide.

In some embodiments, each of R1 and R2 is a chloride atom.

In some embodiments, the compound is of the general formula (22): wherein Rio is as defined herein.

In some embodiments, Rio is selected from -H, -C1-C ₂₅ alkyl, -C2-C25 alkenyl, -C2- C ₂₅ alkynyl, -C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -C1-C5alkyl, -C2-C5alkenyl, -C2- C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, - C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1- C5alkynyl, -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -ONO2, -NO ₂ , 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl, -NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, - pyridine-3-C(=O)-OH and -NR'R"R"'; each of R', R" and R'" is independently selected from -H, C1-C5alkyl, C2-C5alkenyl, C2-C5alkynyl, -C(=O)-C2-C25alkyl, -C(=O)-C2-C25alkenyl and C5-C25alkynyl; or wherein one of R', R" and R'" is absent.

In some embodiments, in a compound of formula (6), R8 is C1-C25alkyl optionally substituted by at least one functionality selected from an hydroxyl, an amine, -OR10, and a halide.

In some embodiments, the at least one functionality is a hydroxyl, an amine or -OR10, wherein the amine having the structure -NR'R"R"', wherein each of R', R", R'" and Rio is as defined above.

In some embodiments, R’ is H, R” is absent and R’” is Rn, wherein R11 is selected from -H, a -C1-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, C1-C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O- C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -S-, -S-C1-C5 alkyl, -S-C1- C5alkenyl, -S-C1-C5alkynyl, -ONO2, -NO2, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, - NHC(=O)CH2C(CH3)2-O-Aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"', and wherein R’, R”, R’” and Rio are as defined above.

In some embodiments, the compound is of the general formula (23): wherein each of Ri, R2, n, m and R11 is as defined herein.

In some embodiments, R11 is selected from -H or a C1-C ₂₅ alkyl, C2-C25 alkenyl, C2- C ₂₅ alkynyl, C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, C1-C5alkyl, C2-C5alkenyl, C2- C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, - C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-ORio, -O-C1-C5alkyl, -O-C1-C5alkenyl, -O-C1-C5alkynyl, -S-, -S-C1-C5alkyl, -S-C1-C5alkenyl, -S-C1-C5alkynyl, -ONO2, -NO2, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, -NHC(=O)CH2C(CH3)2-O-Aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'.

In some embodiments, R’ is H, R” is absent and R’” is Rn, wherein R11 is - NHC(=O)CH ₂ C(CH3)2-O-Aryl-Cl.

In some embodiments, the compound is of the general formula (24): wherein each of Ri, R2, n and m is as defined herein.

In some embodiments, n is 2 and m is 1.

In some embodiments, R1 and R2 are each a halide. In some embodiments, each of R1 and R2 is a chloride atom.

In some embodiments, the compound is of the general formula (25): wherein R11 is as defined herein.

In some embodiments, R11 is selected from -H or a C1-C25alkyl, C2-C25 alkenyl, C2- C ₂₅ alkynyl, C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, C1-C5alkyl, C2-C5alkenyl, C2- C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, - C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -ONO2, -NO ₂ , 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, -NHC(=O)CH2C(CH3)2-O-Aryl-Cl, idebenonyl- derivative, -pyridine-3-C(=O)-OH and -NR'R"R"'.

In some embodiments, the compound is of the formula (26): In some embodiments, in a compound of formula (13), R8 is C1-C25alkyl optionally substituted by at least one functionality selected from an hydroxyl, an amine, -OR10, and a halide.

In some embodiments, the at least one functionality is a hydroxyl, an amine or -OR10, wherein the amine having the structure NR'R"R"', wherein each of R', R", R'" and Rio is as defined above.

In some embodiments, the compound is of the general formula (27): wherein each of Ri, R2, n, m and Rio is as defined herein.

In some embodiments, Rio is selected from -H, -C1-C ₂₅ alkyl, -C2-C25 alkenyl, -C2- C ₂₅ alkynyl, -C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -C1-C5alkyl, -C2-C5alkenyl, -C2- C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, - C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1- C5alkynyl, -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -ONO2, -NO ₂ , 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl, -NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, - pyridine-3-C(=O)-OH and -NR'R"R"'; each of R', R" and R'" is independently selected from -H, C1-C5alkyl, C2-C5alkenyl, C2-C5alkynyl, -C(=O)-C2-C25alkyl, -C(=O)-C2-C25alkenyl and C5-C25alkynyl; or wherein one of R', R" and R'" is absent.

In some embodiments, n is 2 and m is 1.

In some embodiments, R1 and R2 are each a halide.

In some embodiments, each of R1 and R2 is a chloride atom.

In some embodiments, the compound is of the general formula (28): wherein Rio is as defined herein.

In some embodiments, Rio is selected from -H, -C1-C25alkyl, -C2-C25 alkenyl, -C2- C ₂₅ alkynyl, -C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -C1-C5alkyl, -C2-C5alkenyl, -C2- C5alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, - C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1- C5alkynyl, -S-, -S-C1-C ₅ alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -ONO2, -NO ₂ , 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl, -NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, - pyridine-3-C(=O)-OH and -NR'R"R"'; each of R', R" and R'" is independently selected from -H, C1-C5alkyl, C2-C5alkenyl, C2-C5alkynyl, -C(=O)-C2-C25alkyl, -C(=O)-C2-C25alkenyl and C5-C25alkynyl; or wherein one of R', R" and R'" is absent.

In some embodiments, the compound is of the general formula (29): wherein each of Ri, R2, n, m is as defined herein; R5 is absent or selected from H, -C1-C5alkyl, -C(=O)-O-Rs, -C(=O)-NR'-Rs, halide, CN, and OH; and R9 is selected from -C(=O)-O-Rs, - C(=O)-NR'-R ₈ , -NH-C(=O)-O-R ₈ , -NH-C(=O)-NR'-R ₈ , -O-C(=O)-O-R ₈ and -O-C(=O)-NR'- R ₈ ; R ₈ is as defined herein.

In some embodiments, R5 is a -C1-C3 alkyl and R9 is selected from -C(=O)-C1- C ₂₅ alkyl, -C(=O)-O-R ₈ , -C(=O)-NR'-R ₈ , -NH-C(=O)-O-R ₈ , -NH-C(=O)-NR'-R ₈ , -O-C(=O)- O-R ₈ and -O-C(=O)-NR'-R ₈ ; R ₈ is as defined herein.

In some embodiments, R ₉ is -NH-C(=O)-O-R ₈ , -NH-C(=O)-NR'-R ₈ , -O-C(=O)-O-R ₈ or -O-C(=O)-NR'-R ₈ ; R ₈ is as defined herein.

In some embodiments, R9 is -NH-C(=O)-O-R ₈ or -O-C(=O)-O-R ₈ ; R ₈ is as defined herein.

In some embodiments, the compound is of the general formula (30): wherein each of Ri, R ₂ , n, m and R ₈ is as defined herein.

In some embodiments, R ₈ is -C1-C ₂ 5alkyl.

In some embodiments, R ₈ is -C ₂ -C ₂ 5alkenyl.

In some embodiments, R ₈ is -C ₂ -C ₂ 5alkynyl.

In some embodiments, R ₈ is -C6-C10aryl.

In some embodiments, R ₈ is C3-C10heteroaryl.

In some embodiments, R ₈ is -C1-C ₂ 5alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkenyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkynyl, -C(=O)- OR10, -O-C1-C5alkyl, -O-C1-C5alkenyl, -O-C1-C5alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C2-C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R ’R -NH-C2-C ₂₅ alkenyl-C(=O)-NR’R”R’”, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ -C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂ 5alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R’”, -NH-C2- C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2-C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1- C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R’”, -NHC(=O)C ₂ -

C ₂ 5alkenylene-NR’R”R’”, -NHC(=O)C ₂ -C25alkynylene-NR’R”R’”, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH3)2-O-aryl-Cl, NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'.

In some embodiments, R8 is -C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R’R -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C ₂ 5alkynyl-C(=O)-NR’R”R’”, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ -C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C2-C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkylene-C(=O)-NR’R”R’”, -NH-C2- C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2-C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1- C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ -C25alkynylene-NR’R”R’”, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH3)2-O-aryl-Cl, NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'.

In some embodiments, R8 is -C2-C25alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C2-C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R”R”’, -NH-C2-C ₂₅ alkenyl-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C2-C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1- C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkynylene-C(=O)-O-C1-C ₂₅ alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -

C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C ₂ 5alkenylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH3) ₂ -O-aryl-Cl, NHC(=O)CH ₂ C(CH3) ₂ -O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and -

NR'R"R"'.

In some embodiments, R8 is -C6-C10aryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C5alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR'-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)- ORio, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R”R”’, -NH-C ₂ -C ₂ 5alkenyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-NR’R”R”\ - NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ -C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1- C ₂₅ alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkynylene-C(=O)-O-C1-C ₂₅ alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -

C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C ₂ 5alkenylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH3) ₂ -O-aryl-Cl, NHC(=O)CH ₂ C(CH3) ₂ -O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and -

NR'R"R"'.

In some embodiments, R8 is C3-C10heteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO ₂ , -NO ₂ , -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR'-C(=O)-C1-C ₂₅ alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂₅ alkynyl, -C(=O)- ORio, -O-C1-C5alkyl, -O-C1-C5alkenyl, -O-C1-C5alkynyl, -NH-NH ₂ , -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C ₂ - C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R”R”’, -NH-C ₂ -C ₂ 5alkenyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-NR’R”R”\ - NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ -C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂ 5alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C25alkylene-C(=O)-NR’R”R”’, -NH-C2- C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2-C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1- C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C25alkylene-NR’R”R”’, -NHC(=O)C ₂ - C ₂₅ alkenylene-NR’R”R”’, -NHC(=O)C2-C ₂₅ alkynylene-NR’R”R’”, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C ₃ -C10heteroaryl, -NHC(=O)C2-C25alkynylene-C ₃ -C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ )2-O-aryl-Cl, NHC(=O)CH2C(CH ₃ )2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'.

In some embodiments, each of n and m is 1.

In some embodiments, R1 is CN and R2 is a halide.

In some embodiments, R2 is a chloride atom.

In some embodiments, the compound is of the formula (31): wherein R8 is as defined herein.

In some embodiments, in a compound of formula (I) each of R1 and R2, independently of the other is a group selected from H, a halide and -CN; each of n and m, independently of the other, is an integer between 0 and 5, designating the number of substituents on the ring;

X is CH, CH2 or wherein the group C-R4 is C=R4;

R3 is H or a carbon containing group having between 1 and 3 carbon atoms, further optionally substituted;

R4 is a nitrogen atom or a nitrogen containing group, or a carbon containing group having between 1 and 3 carbon atoms, further optionally substituted; or R3 and R4 together with the atoms to which they are bonded (carbon atom and X, respectively) form a 5- or 6-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S.

In some embodiments, X-R4 is C=R4 and R4 is a nitrogen atom.

In some embodiments, R3 is a carbon containing group and R4 is a nitrogen containing group.

In some embodiments, R3 and R4 together with the atoms to which they are bonded form a 5-membered carbocyclic ring optionally containing 1 or 2 nitrogen atoms.

In some embodiments, the compound is of the general formula (32): wherein one of LI and L2 is a nitrogen atom and the other of LI and L2 is a carbon atom (being selected from C, CH or CH2); each of R5, R6 and R7, independently of the other, may be absent or selected from - H, C1-C ₃ alkyl, -C(=O)-O-Rs, -C(=O)-NR'-Rs, halide, CN, OH, and NR'R"; and wherein R8, R’, R” and R’” is as defined above, and wherein each bond between C-N, N-Li, L1-L2 and L2-C (designated — ) is a single or double bond.

In some embodiments, Li is nitrogen atom and L2 is a carbon atom.

In some embodiments, Li is a nitrogen and L2 is a carbon atom, the bond between C and N is a double bond, the bond between N and Li is a single bond, and the bond between Li and L2 is a single bond.

In some embodiments, the compound is of formula (33): wherein each of Ri, R2, n, m, R6 and R7 are as defined herein.

In some embodiments, R7 is H and R6 is selected from -C1-C5alkyl, -C(=O)-O-Rs, - C(=O)-NR'-Rs, a halide, -CN, -OH, and -NR'R"; and wherein R8 is as defined above.

In some embodiments, R6 is a substituted -C1-C3alkyl and R7 is H.

In some embodiments, the compound is of the formula (34): wherein R8 is as defined herein. In some embodiments, the compound is of the formula (35): wherein R9 is selected from -O-R8 and -NR’-Rs; R8 is as defined herein.

In some embodiments, the compound is of the formula (36): wherein R9 is selected from -O-R8 and -NR’ -R8; wherein each of R’ and R8 is as defined herein.

In some embodiments, the compound is of the formula (37):

wherein R9 is selected from -O-R8 and -NR’ -R8; wherein each of R’ and R8 is as defined herein.

In some embodiments, the compound is of the formula (38): wherein R9 is selected from -O-R8 and -NR’ -Rs; wherein each of R’ and R8 is as defined herein.

As stated herein, the invention provides a compound that is of the general formula (4), as defined herein. In other words, the compound is of the formula:

wherein one of L, Li and L2 is a nitrogen atom and the others of L, Li and L2 are each a carbon atom (being selected from C, CH or CH2); each of R5, R6 and R7, independently of the other, may be selected from -H, -C1- C ₃ alkyl, -C(=O)-OH, -C(=O)-O-R ₈ , -C(=O)-NR'R ₈ , halide, -CN, -OH, and -NR'R"; or one of R5 and R6 or R6 and R7 together with the atoms to which they bond may form a 5-, 6-, 7- or 8-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S; the 5-, 6-, 7- or 8 -membered carbocyclic ring is further optionally substituted by at least one functionality B selected from -H, -C1-C ₂₅ alkyl, -C2-C ₂₅ alkenyl, -C2-C ₂₅ alkynyl, - C6-C10aryl, an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C2- C5alkenyl, -S-C ₂ -C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C ₂ -C ₅ alkenyl, -C(=O)-O-C ₂ -C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C ₂ -C25alkenyl, -C(=O)-NR’-C(=O)-C ₂ -C25alkynyl, -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)-C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C2-C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R ’R -NH-C2-C ₂₅ alkenyl-C(=O)-NR’R”R’”, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ -C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C1-C25alkyl, -NH-C2-C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C25alkyl-NH-C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂ 5alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C25alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C25alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C25alkylene-C(=O)-NR’R”R”’, -NH-C2- C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2-C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1- C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ -C25alkynylene-NR’R”R’”, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkynylene-C3-C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH3)2-O-aryl-Cl, NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'; the 5-, 6-, 7- or 8-membered carbocyclic ring may be optionally substituted by at least one functionality B selected from structures (A) through (H): wherein in each functionality (A) through (H), the wavy line indicates point or bond of connectivity, j is 0 or 1 and Ra is selected from -H, -C1-C25alkyl, -C2-C25alkenyl, -C2- C ₂₅ alkynyl, -C(=O)-C6-C10aryl and -C(=O)-C3-C10heteroaryl, wherein in functionalities (G) and (H) the pendant -NH-Ra group may appear between 1 and 11 times at any position along the carbocycle (in some embodiments, it may be positioned at a ring atom once removed, twice removed or three times removed from the existing group or endocyclic N atom; in some embodiments, the position of the functionality is 1 , 2 or 1 , 3 or 1 ,4, wherein 1 designates the position of the existing group or the endocyclic N atom); one of R5, R6 and R7 may be absent; R8 is selected from -H, -C1-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -C6-C10aryl and Cs-C10heteroaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1- C5alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)- O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR’-C(=O)-C1- C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkenyl, -C(=O)-NR’-C(=O)-C1-C ₂ 5alkynyl, -C(=O)- OR10, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH-C(=O)- C1- C ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkenyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkynyl, -NH-NH-C(=O)- C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, -NH-C2- C ₂ 5alkenyl-C(=O)-OH, -NH-C ₂ -C25alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R ’R -NH-C2-C ₂₅ alkenyl-C(=O)-NR’R”R”’, -NH-C2-C ₂₅ alkynyl-C(=O)-NR’R”R’”, - NH-C1-C ₂ 5alkyl-NH ₂ , -NH-C ₂ -C25alkenyl-NH ₂ , -NH-C ₂ -C25alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C25alkenyl-NH-C(=O)-C1-C ₂ 5alkyl, -NH-C ₂ -C ₂ 5alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂ 5alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C2- C ₂ 5alkynyl-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C25alkylene-C(=O)-NR’R”R”’, -NH-C2- C ₂₅ alkenylene-C(=O)-NR’R”R’”, -NH-C2-C ₂₅ alkynylene-C(=O)-NR’R”R’”, -NH-C1- C25alkylene-C(=O)-O-C1-C ₂ 5alkyl, -NH-C ₂ -C25alkenylene-C(=O)-O-C1-C25alkyl, -NH-C2- C25alkynylene-C(=O)-O-C1-C ₂ 5alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂ 5alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R’”, -NHC(=O)C ₂ - C ₂₅ alkenylene-NR’R”R’”, -NHC(=O)C ₂ -C25alkynylene-NR’R”R’”, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C ₃ -C10heteroaryl, -NHC(=O)C ₂ - C25alkenylene-C ₃ -C10heteroaryl, -NHC(=O)C2-C25alkynylene-C ₃ -C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH ₃ )2-O-aryl-Cl, NHC(=O)CH2C(CH ₃ )2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"';

Rio is selected from -H, -C1-C ₂₅ alkyl, -C ₂ -C ₂ 5alkenyl, -C ₂ -C ₂ 5alkynyl, -C6-C10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -C1-C5alkyl, -C ₂ -C5alkenyl, -C ₂ -C5alkynyl, -C(=O)-, -C(=O)- C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, -C(=O)-O-C1-C ₅ alkenyl, -C(=O)-O-C1-C ₅ alkynyl, - C(=O)-NR'R"R"', -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -S-, -S-C1-C5 alkyl, -S- C1-C5alkenyl, -S-C1-C5alkynyl, -ONO2, -NO2, 2,2,6,6-tetramethylpiperidin-l-ol-4-yl, - NHC(=O)CH2C(CH ₃ )2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'; each of R', R" and R'" is independently selected from -H, C1-C5alkyl, C ₂ -C5alkenyl, C2-C5alkynyl, -C(=O)-C ₂ -C ₂ 5alkyl, -C(=O)-C ₂ -C ₂ 5alkenyl and C5-C ₂ 5alkynyl; or wherein one of R', R" and R'" is absent; and wherein each bond between N-L, L-Li, L1-L2 and L2-C (designated — ) is a single or double bond.

In some embodiments, in a compound of formula (4), L2 is a nitrogen atom and each of L and L is a carbon atom. In some embodiments, R7 is absent and R5 and R6 together with the atoms to which they bond form a 5-, 6-, 7- or 8-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S. In some embodiments, the compound is of the formula (39):

wherein each of Ri, R2, R5, Re, n and m is as defined above.

In some embodiments, R5 and R6 together with the atoms to which they bond may form a 5-, 6-, 7- or 8-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S.

In some embodiments, the compound is of formula (40): wherein each of Ri, R2 and m is as defined above, ring A is a 5-, 6-, 7- or 8-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S, and further optionally substituted by a group B selected from -H, -C1-C25alkyl, -C2- C ₂₅ alkynyl, -C6-C10aryl, an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-C1-C5alkyl, -S-C1-C ₅ alkenyl, -S-C1-C ₅ alkynyl, -C(=O)-, -C(=O)-C1-C ₂₅ alkyl, -C(=O)-O-C1-C ₅ alkyl, - C(=O)-O-C ₂ -C ₅ alkenyl, -C(=O)-O-C ₂ -C ₅ alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR'-C(=O)- C1-C ₂₅ alkyl, -C(=O)-NR’-C(=O)-C ₂ -C25alkenyl, -C(=O)-NR’-C(=O)-C ₂ -C25alkynyl, - C(=O)-ORio, -O-C1-C ₅ alkyl, -O-C1-C ₅ alkenyl, -O-C1-C ₅ alkynyl, -NH-NH2, -NH-NH- C(=O)- C1-c ₂₅ alkyl, -NH-NH-C(=O)-C ₂ -C ₂ 5alkenyl, -NH-NH-C(=O)-C ₂ -C ₂₅ alkynyl, -NH- NH-C(=O)-C ₆ -C10aryl, -NH-NH-C(=O)-C ₃ -C10heteroaryl, -NH-C1-C ₂₅ alkyl-C(=O)-OH, - NH-C ₂ -C ₂₅ alkenyl-C(=O)-OH, -NH-C ₂ -C ₂₅ alkynyl-C(=O)-OH, -NH-C1-C ₂₅ alkyl-C(=O)- NR’R ’R -NH-C ₂ -C ₂ 5alkenyl-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂ 5alkynyl-C(=O)-NR’R”R”’, - NH-C1-C ₂₅ alkyl-NH ₂ , -NH-C ₂ -C ₂₅ alkenyl-NH ₂ , -NH-C ₂ -C ₂₅ alkynyl-NH ₂ , -NH-C1-C ₂₅ alkyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂₅ alkynyl- NH-C(=O)-C1-C ₂₅ alkyl, -NH-C1-C ₂₅ alkyl-NH-C(=O)-C6-C10aryl, -NH-C ₂ -C ₂₅ alkenyl-NH- C(=O)-C ₆ -C10aryl, -NH-C ₂ -C ₂₅ alkynyl-NH-C(=O)-C6-C10aryl, -NH-C1-C ₂₅ alkyl-NH- C(=O)-C3-C10heteroaryl, -NH-C ₂ -C ₂ 5alkenyl-NH-C(=O)-C3-C10heteroaryl, -NH-C ₂ - C ₂₅ alkynyl-NH-C(=O)-C3-C10heteroaryl, -NH-C1-C ₂ 5alkylene-C(=O)-NR’R”R”’, -NH-C ₂ - C ₂ 5alkenylene-C(=O)-NR’R”R”’, -NH-C ₂ -C ₂ 5alkynylene-C(=O)-NR’R”R”’, -NH-C1- C ₂ 5alkylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ -C ₂ 5alkenylene-C(=O)-O-C1-C ₂₅ alkyl, -NH-C ₂ - C ₂ 5alkynylene-C(=O)-O-C1-C ₂₅ alkyl, -NHC(=O)C1-C ₂₅ alkyl, -NHC(=O)C ₂ -C ₂₅ alkenyl, - NHC(=O)C ₂ -C ₂₅ alkynyl, -NHC(=O)C1-C ₂ 5alkylene-NR’R”R”’, -NHC(=O)C ₂ -

C ₂ 5alkenylene-NR’R”R”’, -NHC(=O)C ₂ -C ₂ 5alkynylene-NR’R”R”’, -NHC(=O)C1-

C ₂₅ alkylene-OH, -NHC(=O)C ₂ -C ₂₅ alkenylene-OH, -NHC(=O)C ₂ -C ₂₅ alkynylene-OH, - NHC(=O)C ₆ -C10aryl, -NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C6-C10aryl, - NHC(=O)C ₂ -C ₂ 5alkenylene-C6-C10aryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C6-C10aryl, NHC(=O)C ₃ -C10heteroaryl, -NHC(=O)C1-C ₂₅ alkylene-C3-C10heteroaryl, -NHC(=O)C ₂ - C ₂ 5alkenylene-C3-C10heteroaryl, -NHC(=O)C ₂ -C ₂ 5alkynylene-C3-C10heteroaryl, 2, 2,6,6- tetramethylpiperidin-l-ol-4-yl free radical, -NHC(=O)C(CH3) ₂ -O-aryl-Cl, NHC(=O)CH ₂ C(CH3) ₂ -O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and - NR'R"R"'; the 5-, 6-, 7- or 8-membered carbocyclic ring may be optionally substituted by at least one functionality B selected from structures (A) through (H):

wherein in each functionality (A) through (H), the wavy line indicates point or bond of connectivity, j is 0 or 1 and Ra is selected from -H, -C1-C ₂₅ alkyl, -C2-C ₂₅ alkenyl, -C2- C ₂₅ alkynyl, -C(=O)-C6-C10aryl and -C(=O)-C3-C10heteroaryl, wherein in functionalities (G) and (H) the pendant -NH-Ra group may appear between 1 and 11 times at any position along the carbocycle (in some embodiments, it may be positioned at a ring atom once removed, twice removed or three times removed from the existing group or endocyclic N atom; in some embodiments, the position of the functionality is 1 , 2 or 1 , 3 or 1 ,4, wherein 1 designates the position of the existing group or the endocyclic N atom).

In some embodiments, ring A is a 5-membered ring. In some embodiemnts, the ring is a heterocyclic ring comprising one or more heteroatom selected from N, O and S.

In some embodiemnts, ring A is a 6-membered ring. In some embodiemnts, the ring is a heterocyclic ring comprising one or more heteroatom selected from N, O and S. in some embodiemnts, the ring is an atromatic ring or a heteroaryl ring.

In some embodiments, ring A is a 7-memebered ring. In some embodiemnts, the ring is a heterocyclic ring comprising one or more heteroatom selected from N, O and S.

In some embodiemnts, ring A comprises one or more doubel bonds.

In some emboidments, the compound is a compound of the formula (41):

wherein each of Ri, R2, n, m and B is as defined above.

In some embodiemnts, the compound is a compound of formula (42): wherein wherein each of Ri, R2, n, m and B is as defined above.

In some embodiments, the compound if a compound of formula (43): wherein wherein each of Ri, R2, n, m and B is as defined above.

In some embodiemnts, the compound of formula (II) is a compound having the structure of formula (44): wherein each of Ri, R2, m and B is as defined above.

In some embodiments of compounds of the invention, n is 2 and m is 1, or m is 2 and n is 1, or each of m and n is either 2 or 1. In some embodiments, R1 and R2 are each a halide. In some embodiments, each of R1 and R2 is a chloride atom.

In some embodiments of compounds of the invention, n and m together represent 2 or 3 halide atoms. In some embodiments, the halide atoms are each a chloride atom.

In some embodiments, the following compounds of the invention are provided:

In some embodiments, in each compound of the invention, R8 is a lipophilic moiety as defined herein.

As disclosed herein, methods of the invention comprise medical management of lower urinary tract symptoms (LUTS), which involves administering to a subject an effective amount of at least one peripherally restricted CB 1 antagonist, as defied and selected herein, wherein the subject is a subject suffering from LUTS or a subject having predisposition for suffering from LUTS, or a subject undergoing a medical treatment directly or indirectly known to bring about or cause LUTS or a subject who is immunocompromised. Thus, in some embodiments, for example, a subject as selected may be administered with an effective amount of the at least one peripherally restricted CB 1 antagonist for the purpose of achieving treatment of LUTS, prevention of LUTS or short or prolonged management of LUTS.

The at least one peripherally restricted CB 1 antagonist may be administered to the subject by any means known in the art, including for example by oral, aerosol, parenteral, subcutaneous, intravenous, intramuscular, interperitoneal, rectal, or vaginal administration, and intravesical administration.

The at least one peripherally restricted CB1 antagonist may be administered alone, in combination with one or more other peripherally restricted CB1 antagonists, or active materials, or may be administered as part of or contained in a composition comprising also a variety of carriers, excipients and/or diluents.

Peripherally restricted CB 1 antagonist compositions of the invention comprising at least one active agent may be one of the following:

1. a composition that comprises active agents that are peripherally restricted CB 1 antagonist.

2. a composition that comprises active agents that are CB1 antagonists but not peripherally restricted (namely they can enter the CNS system), but are present in carriers, especially particulate carriers that prevent or decrease their entry to the CNS by the size, charge or chemistry of the particulate carrier.

The carriers used in compositions of the invention are generally pharmaceutically acceptable carriers such as vehicles, adjuvants, excipients, or diluents, which are well-known to those who are skilled in the art and are readily available to the public. Typically, the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.

The choice of carrier will be determined in part by the particular active agent, e.g., whether it is an antagonist as defined or not, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.

Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft- shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.

The materials or compounds disclosed and used as herein, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.

Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3- dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants. Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxy-ethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-alpha-aminopriopionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.

The parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multidose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

The urinary bladder has a unique anatomical structure which in practicality forms a barrier to toxic substances diffusing from the urine into the blood. Diseases of the urinary bladder, such as those defining conditions of LUTS, such as bladder carcinomas and interstitial cystitis, cause acute damage to the bladder wall and cannot be effectively treated by systemic administration of drugs. Therefore, intravesical administration, which involves direct instillation of the active agent into the bladder via a catheter may be a preferred route of administration.

Liposomes, gelatin nanoparticles, polymeric nanoparticles as well as magnetic particles may be used to devise drug-encapsulated nanoparticles that can improve chemical interactions and enhance penetration of drugs into the bladder wall.

Intravesical delivery may also or alternatively involve mucoadhesive biomaterials which are strongly adhered to the urothelial cell lining, thus preventing the carrier from being washed away during urine voiding. This may increase the residence time of the active agent at the target site and enable sustained delivery of the active over a prolonged time span.

Thus, in some embodiments, antagonists of the invention may be administered by intravesical administration directly into the bladder of a patient. In some embodiments, the antagonist or a composition comprising same is administered via a catheter. In some embodiments, the catheter is a urethral catheter.

Compositions of the invention and/or methods of administration are configured or aimed at administering the subject with an effective amount of the antagonist. The term “effective amount’ relates to an amount of the compounds that is effective to achieve a desired therapeutic effect as described herein, depending, inter alia, on the type and severity of the symptom or collection of symptoms associated with LUTS to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, an effective amount depends on a variety of factors including the affinity of the compound to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, on factors such as age and gender, etc.

Where the antagonist compound is JD5037, which structure is provided hereinabove, the effective amount may be selected to be not higher than 30 mg/kg (as doses higher than that can penetrate the brain).

In some embodiments, the effective amount is between 0.1- 30 mg/kg, between 1-10 mg /kg, or below about 5 mg/kg or 3 mg/kg or higher. As used herein in reference to any aspects and embodiments of the invention, the term "treatment " and the term "prevention " refer to the administering of a therapeutically effective amount of an antagonist compound or an antagonist composition of the invention which is effective to achieve a therapeutic effect associated with LUTS. Such a therapeutic effect may involve amelioration of undesired symptoms associated with the condition, prevention of the manifestation of such symptoms before they occur, slowing down the progression of the condition, slowing down the deterioration of symptoms, enhancement of the onset of a remission period, slowing down the irreversible damage caused in the progressive chronic stage of the condition, delaying the onset of said progressive stage, lessening the severity or curing the subject, improving survival rate or more rapid recovery, or preventing the condition form occurring or a combination of two or more of the above.

The invention further provides a kit comprising an antagonist compound as disclosed herein and instructions of use. In some embodiments, the kit is a medical package comprising instructions of using the compound for any of the medicinal purposes disclosed herein.

In accordance with aspects of the invention relating to compositions, uses and methods of use or methods of medical use, the invention provides:

A composition or a medicament for medical management of lower urinary tract symptoms (LUTS), the composition having peripherally restricted CB1 antagonistic activity.

In some configurations of compositions, uses and methods of the invention, the composition is in a peripherally restricted form and comprises at least one CB 1 antagonist.

In some configurations of compositions, uses and methods of the invention, the composition comprises at least one peripherally restricted CB1 antagonist material.

In some configurations of compositions, uses and methods of the invention, a composition or a medicament comprising at least one peripherally restricted CB 1 antagonist for use in a medical management of lower urinary tract symptoms (LUTS).

In some configurations of compositions, uses and methods of the invention, the composition is for use in a method for the medical management of LUTS in a subject, wherein the subject is a subject suffering from LUTS; a subject having predisposition to suffering from LUTS; a subject undergoing a medical treatment directly or indirectly causing LUTS; a subject suffering from neurogenic bladder or non-neurogenic bladder; or a subject suffering from overactive bladder LUTS symptoms. In some configurations of compositions, uses and methods of the invention, the composition is for managing LUTS comprising storage symptoms selected from urgency, frequency, nocturia, urgency incontinence and stress incontinence.

In some configurations of compositions, uses and methods of the invention, the composition is for managing LUTS comprising voiding symptoms selected from hesitancy, poor flow, intermittency, straining and dysuria.

In some configurations of compositions, uses and methods of the invention, the composition is for managing LUTS comprising post-micturition symptoms selected from terminal dribbling, post-void dribbling and a sense of incomplete emptying.

In some configurations of compositions, uses and methods of the invention, the CB 1 antagonist i

A method is provided for medical management of lower urinary tract symptoms (LUTS), the method comprising administering to a subject an effective amount of at least one peripherally restricted CB1 antagonist, wherein the subject is a subject suffering from LUTS; a subject having predisposition to suffering from LUTS; a subject undergoing a medical treatment directly or indirectly or causing LUTS; a subject suffering from neurogenic bladder or non-neurogenic bladder; or a subject suffering from overactive bladder LUTS symptoms.

In some configurations of compositions, uses and methods of the invention, the method is for treatment of a subject suffering from conditions associated with LUTS, the method comprising administering to the subject in need of such a treatment an effective amount of the at least one peripherally restricted CB 1 antagonist.

In some configurations of compositions, uses and methods of the invention, the method is for prevention of lower urinary tract symptoms (LUTS) in a subject having predisposition for suffering therefrom, or who is undergoing or scheduled to undergo a medical treatment causing LUTS, the method comprising administering to the subject an effective amount of the at least one peripherally restricted CB 1 antagonist.

In some configurations of compositions, uses and methods of the invention, the peripherally restricted CB 1 antagonist is administered prior to, concomitantly with or soon after commencement of the medical treatment suspected or capable of causing or triggering LUTS.

In some configurations of compositions, uses and methods of the invention, the medical treatment suspected to cause or capable of causing LUTS is an anticancer treatment, an immunotherapy, an immunosuppressive therapy, a radio therapy or an administration of medication.

A method is provided for reducing side effects associated with a medical treatment in a subject undergoing the medical treatment, the side effects being one or more symptoms of the lower urinary tract, the method comprising administering to a subject prior to, during or subsequent to the medical treatment an effective amount of peripherally restricted CB 1 antagonist.

In some configurations of compositions, uses and methods of the invention, for reducing side effects associated with an anticancer treatment in a subject undergoing the anticancer treatment.

In some configurations of compositions, uses and methods of the invention, wherein LUTS comprises any one or more of the following symptoms:

-Storage or irritative symptoms;

-Voiding or obstructive symptoms.

In some configurations of compositions, uses and methods of the invention, medical management comprises treatment or prevention of any one or more of the following conditions: increased frequency of urination, increased urgency of urination, urge incontinence, excessive passage of urine at night, poor urine stream, hesitancy, terminal dribbling, incomplete voiding, urinary retention, overflow incontinence, and episodes of near retention.

In some configurations of compositions, uses and methods of the invention, the peripherally restricted CB1 antagonist having a peripherally restricted CB1 antagonist activity, a minimal activity in the CNS; and a low brain/plasma ratio. In some configurations of compositions, uses and methods of the invention, the peripherally restricted CB 1 antagonist is

In some configurations of compositions, uses and methods of the invention, the at least one peripherally restricted CB1 antagonist is administered by oral, aerosol, parenteral, subcutaneous, intravenous, intramuscular, interperitoneal, rectal, vaginal or intravesical administration.

In some configurations of compositions, uses and methods of the invention, the at least one peripherally restricted CB1 antagonist is administered by intravesical administration.

A peripherally restricted CB 1 antagonist composition, wherein the composition is: a composition comprising at least one peripherally restricted CB 1 antagonist, or a peripherally restricted composition comprising at least one CB 1 antagonist.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

Figs. 1A-M. CYP-induced cystitis exacerbates micturition events and bladder inflammation. CYP-induced cystitis — experimental design (see Methods) (A). CYP- induced cystitis elevated micturition events (B, C), the bladder-to-BW ratio (D), and the bladder mRNA expression levels of inflammatory markers (E-I). The mRNA levels of fibrotic markers showing elevation in the expression of Col3 (J) but not Coll and Fnl (K, L) following injection of CYP. Representative panoramic H&E staining of the bladders from each group, original magnification x5, scale bar - 500 pm (M). Data represent the mean±SEM. For C-D, n= 9 mice per group, for E-L, n= 7 mice per group. **p < 0.01, ***p < 0.001, and ****p < 0.0001. Veh, vehicle; CYP, cyclophosphamide.

Figs. 2A-L CYP-induced cystitis upregulates CBiR and TRPV1 expression. No significant changes in the bladder mRNA expression levels of Cnrl or Cnr2 in CYP-injected mice (A, B). Significant elevations in the bladder protein expression levels of CBiR (C, D) and TRPV1 (E, F). Representative immunohistochemical staining of CBiR in the bladder’s urethra cells (G) and detrusor muscle (H), and quantification of CBiR positive areas in these cells (I) for each group, magnification x40, scale bar - 50 pm. Data represent the mean±SEM. For A-B, n= 7 mice per group, for D, F and I, n= 5 mice per group. *p < 0.05, ***p < 0.001. Veh, vehicle; CYP, cyclophosphamide.

Figs. 3A-H. Peripherally restricted CBiR antagonism attenuates CYP-induced cystitis severity and inflammation. A CYP-induced cystitis model with CBiR antagonism — experimental design (see Methods) (A). Treatment with the peripherally restricted CBiR antagonist JD5037 (3 mg/kg, IP) significantly reduced micturition events (B, C), the bladder-to-BW ratio (D), submucosal edema and hemorrhage, as shown in the representative panoramic H&E staining of the bladders from each group, (original magnification x5, scale bar - 500 pm and x40 scale bar - 50 pm) (E), as well as normalized the elevated bladder mRNA (F) and protein (G) levels of TNFa and its circulating levels (H). Data represent the mean±SEM. For C, n= 16 mice per group, for D, n= 27 mice per group, for F, n= 7 mice per group, for G, n= 7 mice for the Veh group and 17 mice for the CYP-treated groups, for H, n= 18 mice for the Veh group and 22 mice for the CYP -treated groups. **p < 0.01, ***p < 0.001, and ****p < 0.0001. Veh, vehicle; CYP, cyclophosphamide; JD, JD5037.

Figs. 4A-J. Peripherally restricted CBiR antagonism restores ECS ‘tone’. JD5037 treatment restored bladder protein expression levels of CBiR (A, B) in CYP-injected mice but not the elevated protein levels of TRPV 1 (A, C), as shown in the representative immunoblots. CYP did not induce any significant changes in the mRNA expression levels of NAPE-PLD (D); however, it did induce a significant reduction in FAAH (E) accordingly, the actual amount of AEA increased in the CYP-injected mice and was normalized by JD5037 (F). CYP induced a significant reduction in the bladder mRNA levels of DAGLB (G) and a significant upregulation of MAGL (H) accordingly, the actual amount of 2AG was significantly reduced in the CYP-injected mice and normalized by JD5037 (I). Bladder protein concentrations (J). Data represent the mean±SEM. For B-E and G-H, n= 7 mice per group, for F, I and J, n= 9 mice per group. *p < 0.05, **p< 0.01, ***p < 0.001, and ****p < 0.0001. Veh, vehicle; CYP, cyclophosphamide; JD, JD5037; FAAH, fatty acid amide hydrolase; NAPE-PLD, N-acyl phosphatidylethanolamine phospholipase D; AEA, Anandamide; MAGL, monoacylglycerol lipase; DAGLB, diacylglycerol lipase b; 2AG, 2- Arachidonoylglycerol.

DETAILED DESCRIPTION OF THE INVENTION

Methods:

Materials and Methods

Animals. The Institutional Animal Care and Use Committee of the Hebrew University (AAALAC accreditation #1285; Ethic approval number MD-19-15994-3) approved the experimental protocol used. Animal studies are reported, in compliance with the ARRIVE guidelines.

CYP-incluced cystitis animal model. To establish the CYP-induced cystitis mouse model, 12-week-old C57B1/6 female mice were divided into three groups: 1. A control group, treated with vehicle (Veh; 1% Tween80, 4% DMSO in saline, IP) for three consecutive days. 2. CYP + Veh group, treated with Veh on the first day, CYP (300 mg/kg, IP) + Veh on the second day, and Veh on the third day. 3. CYP + JD5037 group, treated with JD5037 (3 mg/kg, IP) on the first day, CYP + JD5037 on the second day, and JD5037 on the third day (see the scheme in Fig. 3A). On the fourth day, mice were euthanized by a cervical dislocation under anesthesia, the bladder was removed and weighed, and it was either snap- frozen or fixed in buffered 4% formalin. Trunk blood was collected, and serum was separated and stored at -80°C until processed for biochemical evaluation. The number of samples in each experiment was determined according to the tissue availability, which was limited due to the small size of a mouse bladder. Voiding spot assay (VSA) — non-invasive assessment of bladder dysfunction. On the third day, bladder dysfunction was assessed using a non-invasive VSA; each mouse was placed in a single cage with an absorbent filter paper and was allowed to move freely for 4 hours; during this time the micturition events were captured and retained as void spots on the paper. Normal mice tend to urinate only a few times in the cage corner, whereas CYP- treated mice urinate numerous times all over the filter paper. Urine spots were illuminated with an UV light using the 2UV Transilluminator (UVP, USA), and the number and area of the urine spots were analyzed using ImageJ software (NIH, Bethesda, MD).

Materials. CYP (ENDOXAN) was purchased from Baxter Oncology (Germany). JD5037 was purchased from MedChemExpress (China).

Serum and Bladder TNFa Analyses. Serum and bladder levels of tumor necrosis factor alpha (TNFa) were measured by an ELISA kit (MHSTA50, R&D Systems) according to the manufacturer’s protocol.

Histopathological Analyses. Paraffin-embedded bladder sections (3 pm) from each group were stained with hematoxylin and eosin. Panoramic bladder images were captured with a Zeiss AxioCam ICc5 color camera mounted on a Zeiss Axio Scope Al light microscope and taken with x5 magnification.

Immunohistochemistry. Bladder tissues from Veh- and CYP-injected mice (five animals per group), were fixed in buffered 4% formalin for 48 hr and then embedded in paraffin. Sections were deparaffinized and hydrated. Heat-mediated antigen retrieval was performed with 10 mM citrate buffer pH 6.0 (Thermo Scientific, IL, USA). Endogenous peroxide was inhibited by incubating with a freshly prepared 3% H2O2 solution in MeOH. Unspecific antigens were blocked by incubating sections for 1 hr with 2.5% horse serum (VE-S-2000, Vector Laboratories). Next, 3 pm bladder sections were stained for rabbit-anti CBiR (ACR-001, Alomone), followed by a goat anti-rabbit HRP conjugate (ab97085, Abeam). Color was developed after incubation with 3,3'-Diaminobenzidine (DAB) substrate (SK-4105, ImmPACT DAB Peroxidase (HRP) Substrate, Vector Laboratories), followed by hematoxylin counterstaining and mounting (Vecmount H-5000, Vector laboratories). Stained sections were photographed as described above. Positive areas were quantified using Image J software with a minimum of four random images for the detrusor muscle or urothelium per mouse. Western Blotting. Bladder homogenates were prepared in a RIPA buffer (25mM Tris-HCl pH 7.6, 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS) by using the BulletBlender® and zirconium oxide beads (Next Advanced, Inc., NY, USA). Protein concentrations were measured with a Pierce™ BCA Protein Assay Kit (Thermo Scientific, IL, USA). Samples were resolved by SDS-PAGE (4-15% acrylamide, 150V) and transferred to PVDF membranes using the Trans-Blot®Turbo™ Transfer System (Bio-Rad, CA). Membranes were then incubated for 1 hr in 5% milk (in lx TBS-T) to block unspecific binding, and then incubated overnight with rabbit anti-CBiR (#301214, Immunogen) and TRPV1 (# ACC-029, Alomone) antibodies at 4°C. Anti -rabbit horseradish peroxidase (HRP)-conjugated secondary antibody (#97085, Abeam) was used for 1 hr at room temperature, followed by chemiluminescence detection using Clarity™ Western ECL Blotting Substrate (Bio-Rad, CA). Densitometry was quantified using Bio-Rad CFX Manager software. Quantification was normalized to anti-P actin antibody (#ab49900, Abeam).

Real-time PCR. Total bladder mRNA was extracted using Bio-Tri RNA lysis buffer (Bio-Lab, Israel), followed by DNase I treatment (Thermo Scientific, IL, USA), and reverse transcribed using the Iscript cDNA kit (Bio-Rad, CA). Real-time PCR was performed using iTaq Universal SYBR Green Supermix (Bio-Rad, CA) and the CFX connect ST system (BioRad, CA). The primers used to detect mouse genes are listed in Table 1. Mouse genes were normalized to Ubc.

Sample preparation and endocannabinoid measurements by LC-MS/MS. eCBs were extracted, purified, and quantified from bladder lysates. In brief, bladders were added with ice-cold Tris Buffer, homogenized using the BulletBlender® and zirconium oxide beads (Next Advanced, Inc., NY, USA); the protein concentration was determined by the BCA assay. Samples were then supplemented with an ice-cold extraction buffer [1: 1 methanol/Tris buffer + an internal standard (IS)] and chloroform/methanol (2:1), vortexed, and centrifuged. The lower organic phase was transferred into borosilicate tubes; this step was repeated three times by adding ice-cold chloroform to the samples and transferring the lower organic phase into the same borosilicate tubes. The samples were dried and kept overnight at -80°C, then reconstituted with ice-cold chloroform and acetone, kept at -20°C for 30 min, and then centrifuged to precipitate proteins. Next, the supernatant was dried and reconstituted in an ice-cold LC/MS grade methanol and analyzed on an AB Sciex (Framingham, MA, USA) QTRAP® 6500 + mass spectrometer coupled with a Shimadzu (Kyoto, Japan) UHPLC System. Liquid chromatographic separation was achieved using 5 pL injections of samples onto a Kinetex 2.6pm C18 (100*2.1 mm) column from Phenomenex (Torrance, CA, USA). The autosampler was set at 4°C and the column was maintained at 40°C during the entire analysis. The gradient elution mobile phases consisted of 0.1% formic acid in water (phase A) and 0.1% formic acid in acetonitrile (phase B). eCBs were detected in a positive ion mode using electron spray ionization (ESI) and the multiple reaction monitoring (MRM) mode of acquisition, using d4-AEA as IS. The collision energy (CE), declustering potential (DP), and the collision cell exit potential (CXP) for the monitored transitions are presented in Table 2. The levels of AEA and 2-AG in the samples were measured against standard curves, and normalized to the bladder lysate protein concentration.

Statistics. Values are expressed as the mean ± SEM. Unpaired Two-tailed Student’s /-test was used to determine the differences between the two groups. Results in multiple groups were compared by One-way ANOVA, followed by one-sided Tukey test, using GraphPad Prism v6 for Windows (San Diego, CA). Significance was set at p<0.05.

Results

CYP-induced cystitis exacerbates micturition events and bladder inflammation.

To evaluate the severity of CYP-induced cystitis in our mouse model (Fig. 1A), non- invasive VS A was conducted. Significant increases in urine spots (Fig. IB, C) and the bladder-to-body weight (BW) ratio (Fig. ID) were found in the CYP-injected mice. The cystitis was associated with enhanced bladder mRNA expression levels of the inflammatory cytokines CxcllO, Ccl2, 1118, Tgfb, and Tnfa (Fig. 1E-I). In contrast, only the expression levels of the fibrotic marker Col3 (Fig. 1J), and not Coll and Fnl (Fig. IK, L), were enhanced following CYP injection, as expected from an acute model. Nevertheless, histological examination of the bladders revealed a typical appearance of cystitis with excessive submucosal edema and hemorrhage (Fig. IM). CYP-induced cystitis upregulates CBiR and TRPV1 expression.

CYP-induced cystitis did not significantly change the mRNA expression levels of Cnrl or Cnr2 (Fig. 2A, B); however, the protein expression levels of CBiR were markedly elevated (Fig. 2C, D), indicating an elevated ECS ‘tone’. CB2R protein levels were not examined due to the lack of a reliable antibody for this receptor. Since the ECS can also activate other off-target receptors, such as the TRPV1, we examined its expression and detected a significant upregulation in its protein expression levels (Fig. 2E, F) in the CYP- treated mice. Elevated CBiR protein expression levels were further validated using immunohistochemistry, revealing significant elevated expression levels in urethral cells, particularly in the umbrella cells, the lamina propria as well as in the detrusor muscle cells (Fig. 2G-I).

Peripherally restricted CBiR antagonism attenuates CYP-induced cystitis and inflammation.

Treatment with the peripherally restricted CBiR antagonist JD5037, a day before, in combination with, and a day after CYP injection (Fig. 3A), significantly reduced the elevated urine spots (Fig. 3B, C) and the bladder-to-body weight ratio (Fig. 3D) in CYP-injected mice. Histologically, JD5037 reduced the area affected by edema and hemorrhage (Fig. 3E). Moreover, CBiR antagonism resulted in normalization of the elevated mRNA (Fig. 3F) and protein (Fig. 3G) levels of the inflammatory cytokine TNFa as well as its circulating levels in the serum (Fig. 3H). Taken together, these results indicate that peripheral CBiR antagonism attenuates cystitis severity.

Peripherally restricted CBiR antagonism normalizes bladder ECS ‘tone’.

To assess the involvement of the ECS in CYP-induced cystitis and its reversal by JD5037, we assessed the changes in the expression of the receptors and ligands in this system in our model. Interestingly, the improvements in bladder function by JD5037 were accompanied by downregulating CBiR (Fig. 4A, B), but not the TRPV1 expression levels (Fig. 4A, C). We next determined the mRNA levels of the degrading and synthesizing enzymes as well as the amount of AEA and 2- AG in the bladder. Whereas CYP-injected mice displayed no significant changes in the expression levels of AEA’s synthesizing enzyme JV-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) (Fig. 4D), a significant reduction in the expression of its degrading enzyme, FAAH, (Fig. 4E) was measured. These changes were found to be in accordance with the actual amount of AEA found in the bladder (Fig. 4F). Interestingly, JD5037 treatment normalized the AEA levels in the treated mice (Fig. 4F), although it did not affect the expression of its related enzymes. In contrast to AEA, decreased synthesis and enhanced catabolism of 2-AG, resulting in reduced bladder levels, were found in mice injected with CYP, as manifested by the changes in the expression levels of 2-AG’s synthetizing enzyme diacylglycerol lipase beta (DAGLP) and its degrading enzyme monoacylglycerol lipase (MAGL) (Fig. 4G-H), respectively. Yet, similar to the effect of JD5037 on AEA levels, the treatment also normalized the bladder’s amount of 2-AG (Fig. 41) without affecting the expression of its related enzymes. Both AEA and 2-AG levels were normalized to the protein levels in each bladder (Fig. 4J), which were not affected by CYP or JD5037 treatments. These findings indicate that peripheral CBiR antagonism can restore bladder ECS ‘tone’.

Discussion

The present study reveals, for the first time, the relevance of CBiR antagonism in ameliorating hemorrhagic cystitis. We found that peripheral CBiR antagonism reduces the elevated micturition events, bladder edema, and inflammation as well as restores bladder ECS ‘tone’. Our findings are unique, since most publications in this field indicate that activation of CBiR or CB2R is an effective strategy to decrease LUTS in animal models. These studies mostly refer to the modulatory action of CBiR on the sensory neurons innervating the bladder as well as to the anti-inflammatory effect of CB2R agonism. In contrast, our findings suggest an alternative pathway by which bladder dysfunction can be mitigated via reducing the enhanced activity of the CB iR present on the urothelial cells and the detrusor muscle.

The ECS, ubiquitously present in humans and animals, acts both centrally and peripherally to maintain cellular and organ homeostasis. Thus, changes in ECS ‘tone’, evidenced by modulation in the expression of the cannabinoid receptors, their functional activity (upregulated or downregulated), and the relative number of eCBs, may render the subject susceptible to different diseases. The analgesic effect of CBiR agonists are well established in many chronic disorders. The upregulation of CBiR during cystitis revealed here could be one of the compensatory mechanisms to ameliorate pain and inflammation in acute hemorrhagic cystitis in mice. Indeed, bladder cystitis is characterized by an imbalanced ECS ‘tone’, as manifested here by enhanced bladder expression of CBiR, altered AEA and 2-AG levels as well as changes in their corresponding synthesizing and degrading enzymes. These findings are in accordance with ones reporting elevated AEA levels and bladder inflammation in rats but not in mouse models for cystitis. However, in contrast to others, they showed no changes in 2-AG levels in a CYP-induced mouse model for cystitis. These discrepancies may be related to differences in the model established, the number of mice used in each experiment, the eCB extraction method, and the normalization method used for calculating the eCB levels. Regarding the eCB levels, we used normalization to the bladder’s protein content rather than the bladder weight, since its increased weight could arise from the edema and water absorbent, resulting in higher chances for errors in calculating the eCB levels. Nevertheless and surprisingly, we found that peripheral CBiR blockade results in a modulatory effect on the ECS, and ‘normalizes’ its action under these conditions, both regarding the receptor expression levels and the amount of ligands produced in the bladder. Although CBiR blockade normalized AEA and 2-AG levels, the mRNA expression levels of their synthetizing and degrading enzymes were not significantly changed; these contracting results may be explained by changes in their protein expression levels or their activities. Future experiments would needed to assess these assumptions experimentally.

In attempting to determine the specific effects of AEA and 2-AG on bladder function, we suggest that the two ligands may play opposing roles. Whereas some studies imply that AEA increases micturition interval and threshold pressure, and may decrease pain behavior and bladder hypersensitivity, others have shown that elevated bladder AEA levels may activate the pro-nociceptive TRPV 1 channels and induce pain. Our results support the latter observations, since we found that CYP elevates AEA levels and TRPV 1 expression. In fact, normalization of AEA levels by JD5037 therefore has great importance in ameliorating pain sensation and further suggest that peripheral CBiR blockade may have an indirect analgesic effect in this model; however, this hypothesis should be further tested experimentally with behavioral and pain tests. Regarding the role of 2-AG in the bladder and its opposite pattern to AEA, reduced inflammation in CB iR antagonist-treated mice may be due to the recovery of 2-AG (preferential CB2R ligand) levels, and may support the anti-inflammatory role of the CB2R that were well-established in cystitis ^25,26 . Since we have not measured the protein expression of CB2R (due to a lack of a valid antibody), we cannot further comment on its role in our settings.

Peripheral CBiR overactivation is strongly related to metabolic inflammation, and its peripheral antagonism has great therapeutic potential in reducing it. Specifically, CBiR activation has been associated with increased TNFa secretion in human bladder carcinoma cells, whereas CBiR antagonism was reported to inhibit TNFa production of inflamed small intestine in rats. Moreover, its genetic deletion reduces TNFa secretion by Kupffer cells, and pharmacological CBiR antagonism or its genetic deletion inhibits TNFa expression in diabetic cardiomyopathy. Moreover, we have previously shown that peripheral CBiR antagonism or its genetic deletion from renal proximal tubule cells normalizes the elevated TNFa levels in both Type-1 diabetes and diet-induced obesity mouse models. In agreement with all of these studies, we show here that peripheral CBiR antagonism also normalizes bladder TNFa levels as well as systemic inflammation. Although CYP-induced cystitis is not defined as a chronic metabolic disease, there is ample evidence that acute pathologies are also accompanied by an imbalanced ECS ‘tone’ and enhanced CBiR activity. In fact, this upregulation may be manifested as a compensatory effect by the damaged organ to restore its function. However, this imbalance may promote unwanted effects such as a destructive inflammatory response.

In conclusion, hemorrhagic cystitis is characterized by bladder dysfunction, inflammation, and altered ECS ‘tone’. Peripheral CBiR blockade has the potential to ameliorate these characteristics and to restore normal bladder function. These findings support the rationale for clinical testing of peripheral CBiR blockers that are currently being developed in preclinical settings for the treatment of CYP-induced cystitis in oncologic patients as well as other systemic conditions associated with LUTS.

Table 1. Mouse Primers used for RT-PCR Analysis, Cnr, cannabinoid receptor; Col, collagen; Dagl, diacylglycerol lipase; Faah, fatty acid amide hydrolase; Fn, fibronectin; CxcllO (IplO), C-X-C motif chemokine ligand 10; II, interleukin; Ccl2 (Mcpl), mast cell proteinase; Mgll, monoacylglycerol lipase; Napepld, N-acyl phosphatidylethanolamine phospholipase D; Tgf, transforming growth factor; Ubc, ubiquitin C; Tnf, tumor necrosis factor.

Table 2. MRM transitions for eCB measurements in ESI+ and ESI-, 2-

Arachidonoylglycerol, 2- AG; Anandamide, AEA; Palmitoylethanolamide.