Compositions and methods for targeted degradation of CB1 receptor

Abstract

The technology that is a subject of the present application concerns targeted degradation of the cannabinoid receptor type 1 (CB1 receptor or CB1R) as a therapeutic strategy for treatment and prevention of diseases associated with CB1R activity or dysregulation.

Description

[0001] COMPOSITIONS AND METHODS FOR TARGETED DEGRADATION OF CB1 RECEPTOR

[0002] TECHNOLOGICAL FIELD

[0003] The technology generally concerns compositions and methods for degrading CB 1 receptor, as means for achieving therapeutic prophylaxis and treatment of cancers and other diseases.

[0004] BACKGROUND

[0005] The cannabinoid receptor type 1 (CB1) is a G-protein-coupled receptor (GPCR) primarily expressed in the central nervous system (CNS) but also found in peripheral tissues, including the liver, adipose tissue, pancreas, and gastrointestinal tract. CB1 plays a key role in energy homeostasis, glucose metabolism, and lipid storage, making it a crucial target for metabolic disorders such as obesity, non-alcoholic fatty liver disease (NAFLD) or type 2 diabetes. Additionally, CB 1 activation has been implicated in cancer progression, particularly in tumors where endocannabinoid signaling promotes cell proliferation, migration, and survival. Notably, CB1 reduction in expression via antagonists has been shown to provide therapeutic benefits for both cancer and diabetes, further supporting the importance of CB1 modulation in disease treatment. CB1 has also been implicated in the development and progression of certain cancers, including breast cancer and hepatocellular carcinoma (HCC). In breast cancer, CB1 signaling has been linked to tumor cell proliferation, migration, and resistance to therapy, making it a potential therapeutic target. Studies suggest that CB1 inhibition via antagonists may suppress tumor growth and metastasis in certain triple-negative breast cancers (TNBC), which is the most prevalent cancer type nowadays and currently lacks targeted treatment options. The CB1 receptor antagonists / inverse agonists emerged also as promising drug candidates for obesity and metabolic syndrome due to their ability to reduce appetite, improve insulin sensitivity, and enhance lipid metabolism. The most well-known CB1 antagonist, rimonabant, was approved in Europe for obesity treatment but was later withdrawn from the market due to severe neuropsychiatric side effects (anxiety, depression, and suicidal thoughts) resulting from CB1 inhibition in the brain. To overcome the CNS-related adverse effects of CB1 antagonists, recent research has focused on developing peripherally restricted CB1 inhibitors that do not cross the blood-brain barrier (BBB). These compounds retain metabolic benefits (e.g., improving glucose and lipid metabolism) while avoiding psychiatric risks.

[0006] Dysregulation of CB1R, including overexpression or chronic stimulation, can disrupt this balance and contribute to pathological conditions. Overactivity of CB1R has been implicated in various metabolic disorders, such as insulin resistance, obesity, and dyslipidemia. Moreover, its involvement in cellular signaling pathways has been linked to cancer progression, influencing tumor growth, invasion, and survival. This dual role of CB1R, as an essential regulator in physiological contexts and a driver of disease when dysregulated, highlights its therapeutic potential.

[0007] CB1R activation in the kidneys has been associated with increased glucose reabsorption due to upregulation of sodium-glucose co-transporter 2 (SGLT2) expression, further contributing to hyperglycemia in diabetic conditions. CB1R interacts with insulin receptors and alpha (Gαi) to form a heteromeric complex, which directly binds to the activation loop of the tyrosine kinase domain in the insulin receptor, thereby inhibiting its kinase activity in β-cells. CB1R activation has been associated with diet-induced intraislet inflammation, which can damage β-cells. Chronic inflammation contributes to β-cell dysfunction and accelerates the progression of DM. Overactivation of the renal endocannabinoid (eCB) system via CB 1R has been linked to the development of diabetic nephropathy (DN), emphasizing its role in disease progression. Studies have demonstrated that blocking CB1R, either globally or with peripherally restricted antagonists, can improve renal function in various murine models of diabetes. These results highlight the therapeutic potential of targeting CBIRto mitigate renal dysfunction associated with diabetes. CB1R up-regulation is likely caused by hyperglycemia, which shows the activation of CB1R in diabetes and diabetic kidney disease (Fig. 1). CB1R blockade improved insulin resistance and protected against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Transgenic mice with CB1R overexpression exhibited both albuminuria and a reduction in nephrin levels.

[0008] One of the most significant areas of research involving CB1R is its role as a potential regulator of mTORCl and SGLT2 in proximal kidney tubule. The eCB system also plays a key role in regulating kidney function. Notably, the kidneys produce significant amounts of eCBs, mainly CB1R, is widely expressed across various kidney cell types. In physiological conditions, glucose reabsorption in the kidney occurs primarily in the proximal tubule through SGLT2 on the apical membrane of tubular cells.SGLT2 is an active transporter that uses energy indirectly from ATP, as it relies on the sodium gradient established by the Na+ / K+ATPase pump on the basolateral membrane to co-transport one sodium ion with each glucose molecule into the cell. Once inside, glucose exits the cell into the peritubular capillaries via facilitated diffusion through GLUT2, a passive transporter on the basolateral membrane that does not require ATP (Fig. 1A)

[0009] However, in diabetes, the elevated glucose concentration increases the workload of SGLT2, which continues to co-transport sodium and glucose. This excessive sodium reabsorption may impair tubule-glomerular feedback and contribute to hyperfiltration, a mechanism implicated in diabetic kidney disease. Over time, the chronic overactivity of SGLT2 and hyperglycemia can lead to structural and functional damage in the kidneys, exacerbating diabetic complications. As a consequence, renal proximal tubule cells (RPTCs) become sensitive to prolonged hyperglycemia, causing the overactivation of CB1R. It has been demonstrated that hyperglycemia specifically enhances the eCB / CB1R tone in RPTCs, promoting a cascade of molecular events that activate rapamycin complex (mTORC1) (Fig. 1B). This activation subsequently triggers transcriptional changes in the GLUT2 promoter, ultimately leading to its increased expression. The interplay between CB1R and miR-29a plays a major role in DKD. CB1R overactivation is linked to renal fibrosis and inflammation, while miR-29a acts as an antifibrotic regulator, often reduced in fibrotic conditions (Fig. 1C). MiR-29a can suppress CB1R expression, mitigating its profibrotic effects. For example, overexpressing miR-29a in diabetic mice decreases CB1R levels in glomeruli, reducing fibrosis and improving kidney function. Targeting the CB1R offers potential for treating renal complications in diabetes.

[0010] Additionally, studies show that hyperglycemic conditions can trigger the translocation of GLUT2 from the basolateral to the apical membrane, further exacerbating glucose reabsorption and contributing to glucotoxicity (Fig. 1D). The presence of GLUT2 protein at the brush border membrane of rat proximal tubules is closely associated with increased plasma glucose levels and activation of protein kinase C (PKC)-β1. Hyperglycemia-induced PKC-β1 activation drives the aberrant localization of GLUT2 to the apical membrane, promoting excessive glucose reabsorption and contributing to diabetic kidney dysfunction.SUMMARY OF THE INVENTION

[0011] The technology that is a subject of the present application concerns targeted degradation of the cannabinoid receptor type 1 (CB1 receptor or CB1R) as a therapeutic strategy for treatment and prevention of diseases associated with CB1R activity or dysregulation. Rather than modulating receptor activity solely through inhibition or antagonism, the approach described herein is directed to modulating selective recognition and induced degradation of the CB1R, thereby eliminating the receptor protein from the cellular environment. By promoting degradation of the receptor itself, the strategy enables sustained suppression of CBlR-mediated signaling pathways and may provide advantages over conventional pharmacological approaches that rely on reversible receptor binding.

[0012] In most general terms, the invention disclosed herein concerns design and use of molecular degraders (herein “degrader molecules”) capable of recruiting the cellular ubiquitin-proteasome system to selectively degrade CB1R. In particular, degrader molecules of the invention may be structured as Proteolysis Targeting Chimeric Molecules (PROTACs) or as molecular glues, both being therapeutic modalities used for inducing targeted protein degradation through the ubiquitin-proteasome pathway. Such degrader molecules are capable of bringing a protein of interest (POI) into proximity with an E3 ubiquitin ligase, thereby promoting ubiquitination of the target protein and subsequent proteasomal degradation.

[0013] The degrader molecule is a heterobifunctional compound comprising two functional domains. A first domain comprises an E3 ubiquitin ligase recruiter moiety, which is capable of binding to or recruiting a cellular E3 ubiquitin ligase complex. A second domain comprises a target-recognition moiety capable of recognizing and binding selectively to a POI, e.g., to the CB 1R. When the degrader molecule simultaneously binds the E3 ligase and the CB1 receptor, a ternary complex is formed that promotes ubiquitination of the CB 1R and its subsequent recognition and degradation by the cellular proteasome machinery.

[0014] The association of the two moieties, namely the E3 ligase recruiter moiety and the CBlR-recognizing moiety, may occur in different structural arrangements depending on the mechanism of action of the degrader molecule. In some embodiments, the two moieties may be directly associated in a single molecular structure capable of inducing cooperative binding interactions between the CB1 receptor and the E3 ligase. Suchmolecules may function as molecular glues, which promote or stabilize protein-protein interactions between the E3 ligase and the target protein. In other embodiments, the compound may be configured as a P ROT AC, in which the E3 ligase recruiter moiety and the CBlR-recognizing moiety are connected through a linker moiety. As will be further detailed hereinbelow, the linker may be selected to provide appropriate spatial separation, flexibility, and orientation between the two functional domains to facilitate formation of the ternary complex between the E3 ligase, the degrader molecule, and the CB1R.

[0015] Upon formation of a ternary complex between the E3 ubiquitin ligase, the degrader molecule, and the CB1R, the E3 ligase catalyzes transfer of ubiquitin molecules to the CB1R. Polyubiquitination of the receptor serves as a signal for recognition by the cellular 26S proteasome, which subsequently degrades the ubiquitinated CB1R into peptide fragments. This process effectively removes the receptor protein from the cell, thereby terminating CBlR-mediated signaling pathways.

[0016] An advantage of the targeted protein degradation strategy described herein is that it relies on catalytic degradation rather than simple occupancy -based inhibition. A single degrader molecule may induce degradation of multiple CB 1R molecules by repeatedly engaging the E3 ligase and target protein. As a result, effective suppression of receptor function may be achieved at relatively low concentrations of the degrader compound.

[0017] The degrader molecules disclosed herein are also capable of achieving sufficient tissue distribution and intracellular accessibility to reach the CB 1R expressed within cells or cellular membranes.. Because the degradation mechanism relies on endogenous cellular machinery, compounds of the invention (namely degrader molecules) may be administered directly to cells or delivered to a subject without the need for genetic vectors or gene-editing systems. Once inside the target cells, the compounds recruit endogenous E3 ligase complexes and trigger ubiquitin-mediated degradation of the CB1 receptor. Accordingly, the technology described herein provides a therapeutic approach for treating diseases or conditions associated with CB1R activity by selectively eliminating the receptor through proteasomal degradation.

[0018] In a first of its aspects, the invention concerns a degrader molecule comprising a E3 ubiquitin ligase recruiter moiety and a CB1 receptor (CB1R) recognizing moiety, wherein said ligase recruiter moiety and CB1R recognizing moiety are associated directly (thereby yielding a molecular glue) or indirectly through a linker moiety (thereby producing a proteolysis-targeting chimeric molecule, PROTAC).As will be further disclosed below, degrader molecules of the invention are capable of inducing degradation of the CB 1 receptor through the ubiquitin-proteasome pathway.

[0019] As noted herein, compounds or degrader molecules of the invention are heterobifunctional small molecules comprising at least two functional moieties, including a moiety capable of recruiting a E3 ubiquitin ligase (herein “E3 ubiquitin ligase recruiter moiety” or “a recruiter moiety ) and a second moiety capable of recognizing and binding a protein, or CB1R (herein “a CB1R recognizing moiety or “a protein recognizing moiety”. The degrader molecules are structured such that, upon binding, a ternary complex is formed between the POI, e.g., the CB1R, the degrader molecule and the E3 ubiquitin ligase, thereby spatially approximating the POI to catalytic moieties of the ubiquitin-proteasome system.. This induced proximity enables transfer of one or more ubiquitin molecules from an E2 conjugating enzyme to lysine residues on the target protein, resulting in polyubiquitination and subsequent recognition and degradation of the target protein by the 26S proteasome.

[0020] Effective recruitment of E3 ubiquitin ligases for CB1R degradation presents substantial technical challenges. Many cellular E3 ligases, particularly members of the RING-type E3 ligase family, exist as large, multi-subunit protein complexes that often lack a well-defined, deep ligand-binding pocket suitable for engagement by small molecules. Unlike enzymes that possess catalytic active sites that can be readily targeted by conventional inhibitors, RING E3 ligases typically function as scaffolding proteins that facilitate protein-protein interactions between E2 ubiquitin-conjugating enzymes and substrate proteins. As a consequence, the de novo design of small-molecule recruiters capable of selectively binding these ligases is inherently difficult, and only a limited subset of E3 ligases has thus far been successfully exploited in the development of targeted protein degradation strategies.

[0021] These challenges are particularly relevant in the context of degrading membrane-associated receptors such as CB1R, where the degrader must efficiently engage the receptor while simultaneously recruiting an intracellular ubiquitin ligase capable of catalyzing ubiquitin transfer. CB1R is a G protein-coupled receptor (GPCR) primarily localized to cellular membranes, which further complicates degrader design because the molecule must access and bind the receptor in its cellular context while still enabling productive formation of a ternary complex with the recruited E3 ligase. To address thesechallenges, a variety of ligase-recruitment strategies have been developed and may be implemented in the design of the heterobifunctional degraders described herein. These strategies typically rely on the use of small-molecule ligands that bind to E3 ligases for which ligandable binding sites have been identified. For example, one commonly used recruiter motif binds to the von Hippel -Lindau (VHL) tumor suppressor protein, which functions as the substrate-recognition component of a Cullin-RING E3 ligase complex. VHL contains a defined ligand-binding pocket that accommodates hydroxyprolinecontaining ligands, making it a suitable target for small-molecule recruitment.

[0022] Additional recruiter moieties include immunomodulatory imide drug (IMiD)-based ligands, such as pomalidomide, thalidomide, lenalidomide, and related analogs, which bind to cereblon (CRBN), another substrate receptor within a Cullin-RING E3 ligase complex. These ligands are employed as E3 ligase recruiters in targeted protein degradation technologies due to their favorable binding properties and ability to promote efficient ubiquitination of recruited substrates.

[0023] Further ligase recruiters include ligands capable of engaging DCAF16 and other adaptor proteins that confer substrate specificity within multi-protein E3 ligase assemblies. In some embodiments, recruiter moieties targeting selected RING-type E3 ligases may also be used where ligandable surfaces have been identified or engineered.

[0024] By leveraging these E3 ligase recruiter motifs, degrader molecules of the present invention enable selective recruitment of ubiquitin ligase machinery to the CB1R, thereby promoting ubiquitination and subsequent proteasomal degradation of CB1R. This approach overcomes limitations associated with traditional pharmacological strategies that rely solely on receptor antagonism or inhibition. Instead of transiently blocking receptor activity, the heterobifunctional degrader architecture allows catalytic and sustained elimination of CB1R protein from the cell.

[0025] As a result, the technology described herein provides a robust and durable strategy for modulating CB IR-mediated signaling pathways by directly removing the receptor through the ubiquitin-proteasome system. Targeted degradation of CB1R may therefore provide therapeutic advantages in diseases in which CB1R signaling plays a pathogenic role, including metabolic disorders, neurological conditions, inflammatory diseases, and other CBlR-associated pathologies. By harnessing carefully selected E3 ligase recruitment strategies, the invention expands the range of druggable mechanisms for regulating CB1 receptor function through targeted protein degradation.Thus, in some embodiments, the E3 ligase recruiter moiety may be selected from Hippel-Lindau (VHL) moiety, a pomalidomide-based moiety (CRBN), a DCAF15 moiety, a DCAF16 moiety, a MDM2 moiety and a variety of RING E3 ligase recruiter moieties. Structures of representative recruiter moieties that may be used in the compounds described herein may be selected from:

[0026]

[0027] DCAF16-1, DCAF16-2,RING 2,

[0028]

[0029] It should be noted that each of the aforementioned recruiter moieties may be further substituted by one or more functionality and that each of the structures shown are mere non-limiting embodiments. For instance, the recruiter moiety CRBN having the

[0030] structure

[0031]

[0032] is a mere example of CRBN moieties. The CRBN moiety may be substituted at any available position and may be represented by the generalR2 o (D R<

[0033] i Q* R R R

[0034] formula

[0035]

[0036] Rs7 8 9,wherein each of Ri through Rw, independently, may be selected from -H, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi-C6alkyl, -ON(Ci-C6alkyl)2, -N(Ci-C6alkyl)2, -N(CI-C6alkyl)3+, -NH(Ci-C6alkyl)2+, -NH2(Ci-C6alkyl)1+, -NH3+, -N(OCi-C6alkyl)(Ci-C6alkyl), -N(OH)(Ci-C6alkyl), -NH(OH), -SH, -SCi-C6alkyl, -SS(Ci-C6alkyl), -C(=O)(Ci-C6alkyl), -CO2H, -CO2(Ci-C6alkyl), -OC(=O)(Ci-C6alkyl), -OCO2(Ci-C6alkyl), -C(=O)NH2, -C(=O)N(Ci-C6alkyl)2, -OC(=O)NH(Ci-C6alkyl), -NHC(=O)(Ci-C6alkyl), -N(Ci-C6alkyl)C(=O)(Ci-C6alkyl), -NHCO2(Ci-C6alkyl), -NHC(=O)N(Ci-C6alkyl)2, -NHC(=O)NH(Ci-C6alkyl), -NHC(=O)NH2, -C(=NH)O(Ci-C6alkyl), -OC(=NH)(Ci-C6alkyl), -OC(=NH)OCi-C6alkyl, -C(=NH)N(Ci-C6alkyl)2, -C(=NH)NH(Ci-C6alkyl), -C(=NH)NH2, -OC(=NH)N(Ci- C6alkyl)2, -OC(=NH)NH(Ci-C6alkyl), -OC(NH)NH2, -NHC(NH)N(Ci- C6alkyl)2, -NHC(=NH)NH2, -NHSO2(Ci-C6alkyl), -SO2N(Ci-C6alkyl)2, -SO2NH(CI-C6alkyl), -SO2NH2, -SO2Ci-C6alkyl, -SO2OCi-C6alkyl, -OSO2Ci-C6alkyl, -SOCi-C6alkyl, -Si(Ci-C6alkyl)3, -OSi(Ci-C6alkyl)3-C(=S)N(Ci-C6alkyl)2, -C(=S)NH(Ci-C6alkyl), -C(=S)NH2, -C(=O)S(Ci-C6alkyl), -C(=S)SCi-C6alkyl, -SC(=S)SCi-C6alkyl, -P(=O)(OCi-C6alkyl)2, -P(=O)(Ci-C6alkyl)2, -OP(=O)(Ci-C6alkyl)2, -OP(=O)(OCi-Cealkyl)2, -Ci-Cioalkyl, -Ci-Cioperhaloalkyl, -C2-Cioalkenyl, -C2-Cioalkynyl, heteroCi-Cioalkyl, heteroC1-C10alkenyl, heteroCi-Cioalkynyl, -C3-Ciocarbocyclyl, -Ce-Cioaryl, 3-to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal substituents may be joined to form =0 or =S; wherein the carbonyl oxygen atom marked with * may or may not be present. In case the O* is not present, the compound may be a cyclic amide. One of R1 through R5 is a bond linking to the linker moiety or the moiety recognizing the POI, as further disclosed herein.

[0037] Similarly, any of the other disclosed structures may be further substituted by at least one substituent as disclosed herein.

[0038] Further E3 ligase recruiter moieties are known in the art, for example from US2023 / 0132823 as well as other sources, each of these recruiters are herein incorporated by reference.

[0039] The CB 1R recognizing moiety is a structural moiety that is capable of recognizing and interacting (binding) with the CB1R in any way. The recognizing moiety may be derived from different kinds of small molecules that have been used to target CB1R for various diseases. Such may be, for example, rimonabant, taranabant, otenabant, ibipinabant, and surinabant, shown in Fig. 2, derivatives thereof or functional or active fragments thereof, as further shown in the Figures.

[0040] The CB1R recognizing moiety that selectively interacts with the CB1R is typically designed to process structural and electronic features that promote favorable binging interactions with the receptor binding pocket. Generally, the protein (e.g., CB1R) recognizing moiety includes functional groups capable of participating in 7t-7t stacking interactions, hydrogen bonding or a combination thereof. Such interactions play an important role in ligand recognition and stabilization within the hydrophobic and partially aromatic binding environment characteristic of G protein-coupled receptors such as CB1R. Accordingly, the protein recognizing moiety may comprise at least one aromatic,or heteroaromatic system that can engage in π-π interactions with e.g., aromatic amino acid residues within the receptor, together with a hydrogen-bond donor or acceptor functionality capable of forming hydrogen bonds with residues present in the receptor binding site. In some embodiments, the protein recognizing moiety may include an aromatic ring system, a heteroaromatic ring system, a fused aromatic system, a multicyclic aromatic ring system, a heterocyclic system, or a heterocyclic fused system. In some cases, the protein recognizing moiety may alternatively comprise or include a ring system containing at least one endocyclic double bond, which can contribute to the electronic properties required for receptor recognition. Where heteroaromatic or heterocyclic systems are used, the ring may include one or more heteroatoms selected from N, O and S.

[0041] In some embodiments, the protein recognizing moiety, e.g., CB1R recognizing moietyis an optionally substituted aromatic, heteroaromatic, fused aromatic system, multicyclic aromatic or heteroaromatic, or heterocyclic ring system having optionally a substitution selected from amine (primary, secondary, tertiary or quaternary), hydroxy, amide, carboxylic acid, ester, ether, and others as disclosed hereinbelow.

[0042] In some embodiments, the CB1R recognizing moiety comprises a heterocyclic or a heteroaryl ring system that is an optionally substituted -C₃-C₁₀heterocyclic or an optionally substituted -C₃-C₁₀heteroaryl system. The substitution may be by a group selected from amine (primary, secondary, tertiary or quaternary), hydroxy, amide, carboxylic acid, ester, ether, aryl, heteroaryl, carbocyclic and others, as disclosed herein.

[0043] In some embodiments, the -C₃-C₁₀heterocyclic or -C₃-C₁₀heteroaryl may comprise one or more ring heteroatoms selected from N, O and / or S.

[0044] In some embodiments, the -C₃-C₁₀heterocyclic or -C₃-C₁₀heteroaryl may be selected amongst monocyclic, bicyclic or fused ring systems, such as substituted or unsubstituted indoles, substituted or unsubstituted pyrroles, substituted or unsubstituted imidazoles, substituted or a substituted pyrrolopyrdines, substituted or unsubstituted benzothiophenes, substituted or unsubstituted thieno pyridines, substituted or unsubstituted pyridines, substituted or unsubstituted piperidines, substituted or unsubscribed pyrazines, substituted or unsubstituted pyrazoles, substituted or unsubstituted triazoles and others.

[0045] In some embodiments, the CB1R recognizing moiety is a substituted or an unsubstituted nitrogen-containing heterocycle or heteroaromatic ring structure.In some embodiments, the nitrogen-containing heterocycle or heteroaromatic ring structure may be substituted by a -C₆-C₁₀aryl, a -C₃-C₁₀heteroaryl, a -C₁-C₅alkylene-C₆-C₁₀aryl, a -C₁-C₅alkylene-C₃-C₁₀heteroaryl and / or by a -C₃-C₁₀carbocyclic ring structure.

[0046] Accordingly, the CBlR-recognizing moiety used in the degrader molecules of the invention may include a variety of aromatic, heteroaromatic, and heterocyclic scaffolds that provide the structural features necessary for selective recognition of the CB1R. These scaffolds may be selected and modified to achieve optimal binding affinity, receptor selectivity, and compatibility with the overall degrader architecture, including the linker and E3 ligase recruiter components of the molecule. In some embodiment, the moiety R1Ri r-N r"NVRt / ZNX V selectively interacting with the CB1R is selected from:

[0047]

[0048] ■><, ■><, N I

[0049] uwv

[0050] N V

[0051] J 'v J

[0052]

[0053] N, N N or fused forms thereof (wherein fusion is by a benzene ring or any -C₃-C₁₀crabocycle), and others, wherein each of the moieties being substituted or unsubstituted, and wherein each of R and Rl, independently, is a substitution on any carbon atom of the ring structure, as substitution rules permit.

[0054] In some embodiments, the moiety selectively interacting with the CB 1R is derived from a compound having a diphenyl ethylene or diphenyl methylene moiety of formula (A):

[0055]

[0056] wherein

[0057] 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.The moiety selectively interacting with the CB1R may be derived from compounds of general formulae (I) through (XXXXI) or any of the compounds specifically disclosed herein.

[0058] The moiety selectively interacting with the CB1R may be derived from a compound of formula (I):

[0059]

[0060] wherein

[0061] each of R₁ and R₂, independently of the other, is a group selected from -H, halide, -CN, -C₁-C₅alkyl-OH and -OH;

[0062] each of n and m, independently of the other, is an integer between 0 and 5, designating the number of substituents on the ring;

[0063] 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;

[0064] 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;

[0065] 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.

[0066] In some embodiments, X is N.

[0067] In some embodiments, X-R4 is C=R4.In some embodiments, X-R4 is N=R4.

[0068] 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).

[0069] In some embodiments, R3 is a carbon containing group and R4 is a nitrogen containing group.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] In some embodiments, the moiety selectively interacting with the CB1R may be derived compound of the general formula (II):

[0075] R5

[0076]

[0077] whereinone 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);

[0078] each of R₅, R₆ and R₇, independently of the other, may be selected from -H, -C₁-C₃alkyl, -C(=O)-OH, -C(=O)-O-R₈, -C(=O)-NR'R₈, 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;

[0079] the 5-, 6-, 7- or 8-membered carbocyclic ring is further optionally substituted by at least one functionality selected from –H, -C₁-C₂₅alkyl, -C₂-C₂₅alkenyl, -C₂-C₂₅alkynyl, -C₆-C₁₀aryl, an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-C2-C5alkenyl, -S-C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-C2-C5alkenyl, -C(=O)-O-C2-C5alkynyl, -C(=O)-NR'R"R"', -C(=O)-NR'-C(=O)-C₁-C₂₅alkyl, -C(=O)-NR'-C(=O)-C₂-C₂₅alkenyl, -C(=O)-NR'-C(=O)-C₂-C₂₅alkynyl, -C(=O)-OR₁₀, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)-Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C2salkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, -NHC(=0)Ci-C25alkylene-C6-Cioaryl, -NHC(=0)C2- C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"';

[0080] the 5-, 6-, 7- or 8-membered carbocyclic ring may be optionally substituted by at least one functionality selected from structures (A) through (H):

[0081]

[0082] 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, -Ci-C25alkyl, -C2-C2salkenyl, -C2-C25alkynyl, -C(=0)-Ce-Cioaryl and -C(=0)-C3-Cioheteroaryl,

[0083] 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 thefunctionality is 1, 2 or 1, 3 or 1,4, wherein 1 designates the position of the existing group or the endocyclic N atom);

[0084] one of Rs, Re and R7 may be absent;

[0085] 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-Ci-C5alkyl, -S-C2-C5alkenyl, -S-C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-C2-C5alkenyl, -C(=O)-O-C2-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)-Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=O)-C3-Ci0heteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2- C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH- C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci- C25alkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2- C2salkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)Ce-Cioaryl, NHC(=O)C3-Cwheteroaryl, -NHC(=0)Ci-C25alkylene-Ce-Cioaryl, -NHC(=O)C2- C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-Ce-Cioaryl, -NHC(=O)C3- Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"';

[0086] R₁₀ 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, -Ci-Csalkyl, -C2-C5alkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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"';

[0087] 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

[0088] each bond between N-L, L-L₁, L₁-L₂ and L₂-C (designated ---) is a single or double bond.

[0089] In some embodiments, R₈ is -C₁-C₂₅alkyl.

[0090] In some embodiments, R₈ is -C₂-C₂₅alkenyl.

[0091] In some embodiments, R₈ is -C₂-C₂₅alkynyl.

[0092] In some embodiments, R₈ is -C₆-C₁₀aryl.

[0093] In some embodiments, R₈ is C₃-C₁₀heteroaryl.

[0094] 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-Ci-Csalkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R”’, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0095] In some embodiments, R₈ is -C₂-C₂₅alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C2salkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0096] 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-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C2salkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0097] In some embodiments, Rs is -Ce-Cioaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0098] In some embodiments, Rs is Cs-Cioheteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2- C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0099] In some embodiments, in all compounds of the invention, excluded are compounds wherein R8 is C7-C12alkyl. In such cases, where Rs is said to be an alkyl having between 1 and 25 carbon atoms (inclusive), namely an alkyl of the form C1-C25alkyl or C1-C25alkylene, in consideration of the aformentoned exclusion, the alkyl or alkylene may be stated to be Ci-Cealkyl / alkylene and Ci3-C25alkyl / alkylene.

[0100] In some embodiments, the 5-, 6-, 7- or 8-membered carbocyclic ring substituted by at least one functionality selected from structures (A) through (H):

[0101]

[0102] In some embodiments, in each functionality (A) through (H), j is 0.

[0103] 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.

[0104] 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, -CH2-, -CH3, -CH-CH-, -CH2-CH-, -CH=CH-, -CH-CH2-, -CH2-CH2-CH2-, -CH2-CH-CH-, -CH2-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-, -CH2-NH-, -N-CH3, -CH-NH-CH-, -CH2-CH-NH-, -CH=N-CH-, -CH-NH-CH2-, -CH2-NH- CH2-CH2-, -CH2-CH-NH-CH-, -CH2-CH=CH-NH-, -CH2-N=CH-NH-, -CH2-NH-CH=CH-NH-, -CH2-N=CH-, and others. Such groups may be optionally substituted.

[0105] The carbon-containing group containing between 1 and 3 carbon atoms may be alternatively designated as -Ci-C3alkyl, -C2-C3alkenyl or -C2-C3alkynyl, or any substituted for thereof.

[0106] 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-, -NH2-, -NHR’, NH2R’, 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 nitrogencontaining 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.

[0107] 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.

[0108] In some embodiments, the heterocyclic ring may comprise 1, 2 or 3 nitrogen and / or oxygen and / or sulfur atoms.

[0109] 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.

[0110] R8 is selected from -H, -C1-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -C6-C10aryl and -C3-C10heteroaryl. As used herein with reference to Rs or to any other variable, the alkyl, alkenyl and alkynyl are each as known in the art.

[0111] 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.

[0112] Where the alkyl group is substituted on both ends, it may be regarded as an alkylene group.

[0113] In some embodiments, the alkyl group is a non-linear, branched or cyclic -C5-C25alkyl.Where R8 or any other group is a C5-C25alkenyl, 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-C25alkynyl, 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.

[0114] In some embodiments, the alkyl, alkenyl or alkynyl may be selected from CH3(CH2)3-, CH3(CH2)4-, CH3(CH2)5-, CH3(CH2)6-, CH3(CH2)7-, CH3(CH2)8-, CH3(CH2)9-, CH3(CH2)10-, CH3(CH2)11-, CH3(CH2)12-, CH3(CH2)13-, CH3(CH2)14-, CH3(CH2)15-, CH3(CH2)16-, CH3(CH2)17-, CH3(CH2)18-, CH3(CH2)19-, CH3(CH2)20-, CH3(CH2)21-, CH3(CH2)22-, CH3(CH2)23-, (CH3)2CHCH2-, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)8CH=CH(CH2)4-, CH3(CH2)7CH=CH(CH2)7-, CH3(CH2)7CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)9-, CH3(CH2)4CH=CHCH2CH=CH(CH2)7-, CH3(CH2)4CH= CHCH2CH=CH(CH2)7-, CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7-, CH3(CH=CH)2-, CH3(CH2)4CH=CHCH2CH=CHCH2-CH=CHCH2CH=CH(CH2)3-, CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2-CH=CH(CH2)3-, CH3(CH2)7CH=CH(CH2)11-, CH3CH2CH=CHCH2CH=CHCH2CH=CH-CH2CH=CHCH2CH=CHCH2CH=CH(CH2)2-,CH3CH2CH=CHCH2CH=CHCH2CH=CH-CH2CH=CH(CH2)4-, CH3(CH2)4CH=CHCH2CH=CHCH2CH=CH(CH2)4-, CH3(CH2)4CH= CHCH2CH=CHCH2CH=CH(CH2)6-, CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2-CH=CH(CH2)5-, CH3(CH2)5CH=CH(CH2)11-, CH3(CH2)7CH=CH(CH2)9-, CH3(CH2)7CH=CH(CH2)13-, CH3(CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)3-, C6H5CH=CH-, CH3(CH2)3C≡C(CH2)7-, CH3(CH2)5C≡C(CH2)7-, CH3(CH2)8C≡C(CH2)4-, CH3(CH2)7C≡C-(CH2)7-, CH3(CH2)7C≡C(CH2)7-, CH3(CH2)5C≡C(CH2)9-, CH3(CH2)4C≡CCH2CH=CH(CH2)7-, CH3(CH2)4CH=CHCH2C≡C(CH2)7-, CH3(CH2)4C≡CCH2C≡C(CH2)7-, CH3CH2C≡CCH2CH=CHCH2CH=CH(CH2)7-, CH3(C≡C)2-, CH3(CH2)4C≡CCH2CH=CHCH2-CH=CHCH2CH=CH(CH2)3-, CH3(CH2)4CH=CHCH2CH=CHCH2C≡CCH2CH=CH(CH2)3-, CH3CH2CH=CHCH2CH=CHCH2C≡CCH2CH=CHCH2-CH=CH(CH2)3-, CH3(CH2)7C≡C(CH2)11-, CH3CH2C≡CCH2CH=CHCH2C≡CCH2CH=CHCH2C≡CCH2-CH=CH(CH2)2-, CH3CH2CH=CHCH2CH=CHCH2C≡C-CH2C≡C(CH2)4-, CH3(CH2)4C≡CCH2CH=CHCH2C≡C(CH2)4-, CH3(CH2)4CH= CHCH2CH=CHCH2C=C(CH2)6-, CH3(CH2)4C≡CCH2CH=CHCH2C≡CCH2-CH=CH(CH2)5-, CH3(CH2)5C =C(CH2)II-, CH3(CH2)7C≡C(CH2)9-, CH3(CH2)7C≡C(CH2)13-, CH3(CH2)7C≡CCH2CH=CH-CH2C≡C(CH2)3- C6H5C≡C- and alkenylene derived from DHA (a / / -cz -docosa-4,7,10,13,16,19-hexa-enoic acid).

[0115] Where R8or 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.

[0116] Where R8or 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, benzothiazolyl, benzofuranyl, benzdioxolyl, benzothiophenyl and others. Substitution of the heteroaryl group may be at any position, typically at any carbon atom of the heteroarylgroup. For example, the pyridyl group may be substituted ortho, meta or para to the N atom.

[0117] In some embodiments, in a compound of formula (II), R5 or R6 or R7 is -C(=O)-O-R8 or -C(=O)-NR'R8, and Rs is -Ci-C2salkyl selected, for example, from - (CH2)8CH=CH(CH2)7CH3, -(CH2)2-, -(CH2)15CH3, -(CH2)15CH3and - (CH2)2CH=CH(CH2CH=CH)5CH2CH3.

[0118] In some embodiments, in a compound of formula (II), R6 or R7 is -C(=O)-O-R8 or -C(=O)-NR'R8, and Rs is selected from 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"'.

[0119] The group “2,2,6,6-tetramethylpiperidin-l-ol-4-yV is the radical having the structure:

[0120] S y I z \

[0121] -S - C N— O*

[0122]

[0123] Rf, 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-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -Ce-Cioaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, - Ci-C5alkyl, -C2-C5alkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci- C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)- OR10, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci- Csalkenyl, -S-Ci-Csalkynyl, -ONO2, -NO2, and -NR'R" R"', as defined herein.

[0124] In some embodiments, in a group wherein Z is zero, the groups may be selected from:

[0125]

[0126] The group "-NHC(=O)CH2C(CH3)2-O-aryl-Cl" 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:

[0127] HN

[0128] o

[0129]

[0130] The "idebenonyl-derivative" is a group of the structure:

[0131]

[0132] , wherein k is an integer between 0 and 25.

[0133] In some embodiments, 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 embodiments, k is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In some embodiments, kis 10.

[0134] The groupii-pyridine-3-C(=O)-OH" 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.

[0135] The group “-NRR" 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, -C2-C5alkenyl, -C2-C5alkynyl, -C(=O)-C2-C25alkyl, -C(=O)-C2-C25alkenyl or C5-C25alkynyl. 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 (II), R5 or R6 or R7 may be -C(=O)-O-R8 or -C(=O)-NR'R8, 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 R8, namely-C1-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl 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, -C2-C5alkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-C1-C5alkynyl, -ONO2, -NO2, 2,2,6,6-tetramethylpiperidin-1-ol-4-yl, NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and -NR'R" R"'.

[0136] In some embodiments, R5 or R6 or R7 is -C(=O)-O-R8 and R8 is selected as above. In some embodiments, R8 is -C1-C25alkyl. In some embodiments, the -Ci-C25alkyl is selected from optionally substituted -(CH2)8CH=CH(CH2)7CH3, -(CH2)2-, -(CH2)15CH3, -(CH2)I5CH3 and -(CH2)2CH=CH(CH2CH=CH)5CH2CH3. 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)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"' and -C(=0)-ORio, 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-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"' or -C(=0)-ORio. In some embodiments, R’” is -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-Csalkyl, -C(=O)-O-Ci-C5alkenyl, or -C(=O)-O-Ci-C5alkynyl. In some embodiments, R’” is -C(=O)- or -C(=O)-Ci-C25alkyl.

[0137] In some embodiments, R5 or Re or R7 is -C(=O)-O-Rs and Rs is selected from -(CH2)8CH=CH(CH2)7CH3, -(CH2)2-, -(CH2)15CH3, -(CH2)15CH3, -(CH2)2- NHC(=O)(CH2)7CH=CH(CH2)7CH3and -(CH2)2CH=CH(CH2CH=CH)5CH2CH3.

[0138] In some embodiments, R5 or Rs or R7 is -C(=O)-O-(CH2)8CH=CH(CH2)7CH3, -C(=O)-O-(CH2)2-, -C(=O)-O-(CH2)15CH3, -C(=O)-O-(CH2)15CH3, -C(=O)-O-(CH2)2-NHC(=O)(CH2)7CH=CH(CH2)7CH3and -C(=O)-O-(CH2)2CH=CH(CH2CH=CH)5-CH2CH3.

[0139] In some embodiments, R5 or R6 or R7 is -C(=O)-NR'Rs and Rs is selected as above. In some embodiments, Rs is -Ci-C25alkyl. In some embodiments, the -Ci-C25alkyl is selected from optionally substituted -(CH2)8CH=CH(CH2)7CH3, -(CH2)2-, -(CH2)15CH3, -(CH2)15CH3and -(CH2)2CH=CH(CH2CH=CH)5CH2CH3.In some embodiments, Rs or Rs or R7 is -C(=O)-NR’R8and Rs is selected from -(CH2)8CH=CH(CH2)7CH3, -(CH2)2-, -(CH2)15CH3, -(CH2)15CH3, -(CH2)2- NHC(=O)(CH2)7CH=CH(CH2)7CH3and -(CH2)2CH=CH(CH2CH=CH)5CH2CH3. In some embodiments, R’ is H.

[0140] In some embodiments, Rs or Re or R7 is -C(=O)-NH-(CH2)sCH=CH(CH2)7CH3, -C(=O)-NH-(CH2)2-, -C(=O)-NH-(CH2)15CH3, -C(=O)-NH-(CH2)15CH3and -C(=O)-NH-(CH2)2-NHC(=O)(CH2)7CH=CH(CH2)7CH3and -C(=O)-NH- (CH2)2CH=CH-(CH2CH=CH)5CH2CH3.

[0141] In some embodiments, in a compound of formula (II), L is a nitrogen atom (or a nitrogen containing group of atoms) and each of Li and L2is a carbon atom (or a carbon containing group of atoms).

[0142] In some embodiments, L is a nitrogen atom (or a nitrogen containing group of atoms), each of Li and L2is 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 L2is a single bond.

[0143] In some embodiments, R5 is absent.

[0144] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (III):

[0145]

[0146] wherein each of Ri, R2, n, m, Re 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).

[0147] As indicated herein, each of Re and R7, independently of the other, may be selected from -H, -Ci-C3alkyl, -C(=O)-OH, -C(=O)-O-R8, -C(=O)-NR'R8, halide, -CN, -OH, and -NR'R"; orRe 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.

[0148] In some embodiments, R7 is H and Rs is selected from -Ci-Csalkyl, -C(=O)-O-Rs, -C(=O)-NR'-Rs, a halide, -CN, -OH, and -NR'R"; wherein R8 is as defined herein.

[0149] In some embodiments, Re is -C(=O)-NR'Rs; and Rs is as defined herein.

[0150] In some embodiments, Re is -C(=O)-NHRs; and Rs is as defined herein.

[0151] In some embodiments, the bond — is a double bond.

[0152] In some embodiments, the bond — is a single bond.

[0153] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of general formula (IV):

[0154]

[0155] wherein each of Ri, R2, n, m and Rs is as defined herein.

[0156] In some embodiments, Rs is a Ci-C2salkyl, optionally substituted, as disclosed and selected herein.

[0157] In some embodiments, n is 2 and m is 1.

[0158] In some embodiments, Ri and R2 are each a halide.

[0159] In some embodiments, each of Ri and R2 is a chloride atom.

[0160] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (V):

[0161]

[0162] (V)

[0163] wherein Rs is as defined herein.

[0164] In some embodiments, for a compound of formula (IV) and / or (V), Rs may be: -Ci-C2salkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=O)C6-C10aryl, -NHC(=O)C3-C10heteroaryl, -NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-C6-C10aryl, -NHC(=O)C2-C25alkynylene-C6-C10aryl, -NHC(=O)C3-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(CH3)2-O-aryl-Cl, -NHC(=O)CH2C(CH3)2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(=O)-OH and -NR'R" R"'; or

[0165] -C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 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"'; or

[0166] -C2-C2salkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 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"'; or

[0167] -Ce-Cioaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=0)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=0)-0-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=O)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=O)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0168] -C3-Cioheteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R’R”’, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R”’, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R”’, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)C1-C25alkylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkenylene-C3- Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2, 6, 6-tetramethylpiperi din- 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"'.

[0169] In some embodiments, in a compound of formula (II), L is a nitrogen atom, each of Li and L2is 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 L2is a single bond and the bond between L2and C is a double bond.

[0170] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (VI):

[0171]

[0172] wherein each of Ri, R2, n, m, Re and R7 is as defined herein.

[0173] In some embodiments, Re is selected from -Ci-C3alkyl, -C(=O)-O-R8, -C(=O)-NR'-R8, a halide, -CN, -OH, and -NR'R";

[0174] R7 is a C1-C3 alkyl;

[0175] R8is as defined herein.

[0176] In some embodiments, Re is -C(=O)-NR'-R8; and R8is a Ci-C2salkyl.

[0177] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of general formula (VII):

[0178]

[0179] (VII)

[0180] wherein each of Ri, R2, n, m and R8is as defined herein.

[0181] In some embodiments, for a compound of formula (VII), R8may be:

[0182] -Ci-C25alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0183] -C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0184] -C2-C25alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0185] -Ce-Cioaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”,NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0186] -C3-Cioheteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R”’, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C2salkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R”’, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R”’, -NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R”’, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C6-Cioaryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2-C25alkenylene-C3- Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2, 6, 6-tetramethylpiperi din- 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"'.

[0187] In some embodiments, Rs is a Ci-C25alkyl.

[0188] In some embodiments, Rs is 2,2,6,6-tetramethylpiperidin-l-ol-4-yl.

[0189] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (VIII):

[0190]

[0191] In some embodiments, n is 2 and m is 1.

[0192] In some embodiments, Ri and R2 are each a halide.

[0193] In some embodiments, each of Ri and R2 is a chloride atom.

[0194] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (IX):

[0195]

[0196] wherein Rs is as defined herein.

[0197] In some embodiments, for a compound of formula (IX), Rs may be:-Ci-C2salkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 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"'; or

[0198] -C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=O)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=O)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0199] -C2-C25alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0200] -Ce-Cioaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0201] -C3-Cioheteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R”’, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C2salkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene- C(=O)-NR’R”R”’, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene- C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci- C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci- C25alkylene-NR’R”R”’, -NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2- C25alkynylene-NR’R”R”’, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene- OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=O)C3- Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C6-Cioaryl, -NHC(=O)C2-C25alkenylene-Ce- Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2-C25alkenylene-C3- Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2, 6, 6-tetramethylpiperi din- 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"'.

[0202] In some embodiments, Rs is 2,2,6,6-tetramethylpiperidin-l-ol-4-yl.

[0203] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (X):

[0204] N.

[0205] N '

[0206] NH

[0207]

[0208] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (I):

[0209] each of Ri and R2, independently of the other is a group selected from H, a halide and -CN;

[0210] each of n and m, independently of the other, is an integer between 0 and 5, designating the number of substituents on the ring;

[0211] X is selected from a nitrogen atom (or a nitrogen containing group) and CH; or X-R4 may optionally be C=R4;and

[0212] 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.

[0213] In some embodiments, R3 is H.

[0214] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XI):

[0215]

[0216] wherein each of Ri, R2, n, m and Rs is as defined herein, optionally excluding compounds wherein R8is C7-C12alkyl.

[0217] In some embodiments, for a compound of formula (XI), Rs may be:

[0218] -Ci-C25alkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0219] -C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C2salkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=O)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=O)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0220] -C2-C25alkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2-C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0221] -Ce-Cioaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 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"'; or

[0222] -C3-Cioheteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R’R”’, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C2salkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R”’, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R”’, -NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R”’, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C6-Cioaryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2-C25alkenylene-C3- Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2,2,6,6-tetramethylpiperi din- 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"'.

[0223] In some embodiments, Rs is a Ci-C2salkyl.In some embodiments, Rs is 2,2,6,6-tetramethylpiperidin-l-ol-4-yl.

[0224] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XII):

[0225]

[0226] (XII)

[0227] In some embodiments, in a compound of formula (XI), Rs is an idebenonyl derivative.

[0228] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XIII):

[0229]

[0230] (XIII)

[0231] wherein each of Ri, R2, n and m are as defined above and wherein k is an integer between 0 to 25.

[0232] In some embodiments, n is 2 and m is 1.

[0233] In some embodiments, Ri and R2 are each a halide.

[0234] In some embodiments, each of Ri and R2 is a chloride atom.

[0235] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XIV):

[0236]

[0237] Cl (XIV)

[0238] wherein Rs is as defined herein.

[0239] In some embodiments, for a compound of formula (XIV), Rs may be:

[0240] -Ci-C2salkyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C2salkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2-C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0241] -C2-C25alkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 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"'; or

[0242] -C2-C2salkynyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R”’, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 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"'; or

[0243] -Ce-Cioaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-Csalkynyl, -C(=0)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=0)-0-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkenyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2- C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-Ce-Cioaryl, -NHC(=0)C2-C25alkenylene-C6-Cioaryl, -NHC(=O)C2- C25alkynylene-Ce-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cioheteroaryl, -NHC(=O)C2-C25alkynylene-C3-Cwheteroaryl, 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"'; or

[0244] -C3-Cioheteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R”’, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R’R”’, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cioheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R”’, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, -NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, -NHC(=O)C2-C25alkynylene-NR’R”R”’, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-C6-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=O)C1-C25alkylene-C3-C10heteroaryl, -NHC(=O)C2-C25alkenylene-C3- Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2,2,6,6-tetramethylpiperi din- 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"'.

[0245] In some embodiments, Rs is 2,2,6,6-tetramethylpiperidin-l-ol-4-yl.

[0246] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XV):

[0247]

[0248] (XV)

[0249] In some embodiments, Rs is an idebenonyl derivative.

[0250] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XVI):

[0251]

[0252] wherein k is as defined above.

[0253] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound formula (IV), Rs is Ci-C2salkyl optionally substituted by at least one functionality selected from -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-ORio, wherein each of R1, R", R1" and Rio is as defined above.

[0254] In some embodiments, the at least one functionality is selected from -C(=O)-NR'R" R"', -C(=O)-Ci-C25alkyl and -C(=O)-ORw, wherein each of R', R", R'" and Rio is as defined above.

[0255] In some embodiments, R’ is H, R” is absent and R’” is Rn, wherein Rn is selected from -H or a Ci-C2salkyl, C2-C2salkenyl, C2-C2salkynyl, Ce-Cioaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, Ci-C5alkyl, C2-C5alkenyl, C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-Csalkenyl, -S-C1-C5alkynyl, -ONO2, -NO2, 2,2,6,6-tetramethylpiperidin-1-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.

[0256] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XVII):

[0257]

[0258] wherein each of Ri, R2, n, m and Rn is as defined herein.

[0259] In some embodiments, n is 2 and m is 1.

[0260] In some embodiments, Ri and R2 are each a halide.

[0261] In some embodiments, each of Ri and R2 is a chloride atom.

[0262] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XVIII):

[0263]

[0264] (XVIII)

[0265] wherein Rn is as defined herein.

[0266] In some embodiments, Rn is selected from -H or a Ci-C2salkyl, C2-C2salkenyl, C2-C2salkynyl, Ce-Cioaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, Ci-Csalkyl, C2-C5alkenyl, C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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"'.

[0267] In some embodiments, in a compound of formula (XI), Rs is -Ci-C2salkyl optionally substituted by at least one functionality selected from -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-ORio, 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)-Ci-C2salkyl and -C(=O)-ORw, wherein each of R', R", R'" and Rio is as defined above.

[0268] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XIX):

[0269] O

[0270]

[0271] wherein each of Ri, R2, n, m and Rio is as defined herein.

[0272] In some embodiments, R₁₀ 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, -Ci-Csalkyl, -C2-C5alkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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"';

[0273] 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.

[0274] In some embodiments, Ri and R2 are each a halide.

[0275] In some embodiments, each of Ri and R2 is a chloride atom.

[0276] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XX):

[0277]

[0278] wherein Rw is as defined herein.

[0279] In some embodiments, R₁₀ 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, -Ci-Csalkyl, -C2-Csalkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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"';

[0280] 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.

[0281] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (IV), wherein Rs is Ci-C2salkyl optionally substituted by at least one functionality selected from an hydroxyl, an amine, -OR10, and a halide.

[0282] 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 Rn is selected from -H, a -Ci-C2salkyl, -C2-C2salkenyl, -C2-C2salkynyl, -Ce-Cioaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, Ci-Csalkyl, C2-Csalkenyl, C2-Csalkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-Csalkyl, -S-Ci-Csalkenyl, -S-C1-C5alkynyl, -ONO2, -NO2, 2,2,6,6-tetramethylpiperidin-1-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.

[0283] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XXI):

[0284] NH-RU

[0285]

[0286] (XXI)

[0287] wherein each of Ri, R2, n, m and Rn is as defined herein.

[0288] In some embodiments, Rn is selected from -H or a Ci-C2salkyl, C2-C2salkenyl, C2-C2salkynyl, Ce-Cioaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, Ci-Csalkyl, C2-C5alkenyl, C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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"'.

[0289] In some embodiments, R’ is H, R” is absent and R’” is Rn, wherein Rn is -NHC(=O)CH2C(CH3)2-O-Aryl-Cl.

[0290] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XXII):

[0291]

[0292] wherein each of Ri, R2, n and m is as defined herein.

[0293] In some embodiments, n is 2 and m is 1.

[0294] In some embodiments, Ri and R2 are each a halide.

[0295] In some embodiments, each of Ri and R2 is a chloride atom.

[0296] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XXIII):

[0297]

[0298] Cl (XXIII)

[0299] wherein Rn is as defined herein.

[0300] In some embodiments, Rn is selected from -H or a Ci-C2salkyl, C2-C2salkenyl, C2-C2salkynyl, Ce-Cioaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, Ci-Csalkyl, C2-Csalkenyl, C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-ORio, -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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"'.

[0301] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXIV):

[0302]

[0303] (XXIV)

[0304] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (XI), wherein Rs is Ci-C2salkyl optionally substituted by at least one functionality selected from an hydroxyl, an amine, -ORio, and a halide.

[0305] In some embodiments, the at least one functionality is a hydroxyl, an amine or -ORio, wherein the amine having the structure NR'R" R"', wherein each of R', R", R'" and Rio is as defined above.

[0306] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XXV):

[0307]

[0308] wherein each of Ri, R2, n, m and Rio is as defined herein.

[0309] In some embodiments, R₁₀ 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, -Ci-Csalkyl, -C2-Csalkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-C1-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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"';

[0310] 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.

[0311] In some embodiments, n is 2 and m is 1.

[0312] In some embodiments, Ri and R2 are each a halide.

[0313] In some embodiments, each of Ri and R2 is a chloride atom.

[0314] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XXVI):

[0315] O-R10

[0316]

[0317] Cl (XXVI)

[0318] wherein Rw is as defined herein.

[0319] In some embodiments, R₁₀ 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, -Ci-Csalkyl, -C2-C5alkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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"';

[0320] 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.

[0321] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XXVII):R5

[0322] R9

[0323]

[0324] m(R2)— (XXVII)

[0325] wherein each of Ri, R2, n, m is as defined herein; R5 is absent or selected from H, -Ci-Csalkyl, -C(=O)-O-R8, -C(=O)-NR'-R8, halide, CN, and OH; and R9 is selected from -C(=O)-O-R8, -C(=O)-NR'-R8, -NH-C(=O)-O-R8, -NH-C(=O)-NR'-R8, -O-C(=O)-O-R8and -O-C(=O)-NR'-R8; R8is as defined herein.

[0326] In some embodiments, R5 is a -C1-C3 alkyl and R9 is selected from -C(=O)-Ci-C25alkyl, -C(=O)-O-R8, -C(=O)-NR'-R8, -NH-C(=O)-O-R8, -NH-C(=O)-NR'-R8, -O-C(=O)-O-R8and -O-C(=O)-NR'-R8; R8is as defined herein.

[0327] In some embodiments, R9 is -NH-C(=O)-O-R8, -NH-C(=O)-NR'-R8, -O-C(=O)-O-R8or -O-C(=O)-NR'-R8; R8is as defined herein.

[0328] In some embodiments, R9 is -NH-C(=O)-O-R8or -O-C(=O)-O-R8; R8is as defined herein.

[0329] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XXVIII):

[0330]

[0331] (XXVIII)

[0332] wherein each of Ri, R2, n, m and R8is as defined herein.

[0333] In some embodiments, R8is -Ci-C25alkyl.

[0334] In some embodiments, R8is -C2-C25alkenyl.In some embodiments, R₈ is -C₂-C₂₅alkynyl.

[0335] In some embodiments, R₈ is -C₆-C₁₀aryl.

[0336] In some embodiments, Rs is C3-Cioheteroaryl.

[0337] 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-Ci-Csalkyl, -S-Ci- Csalkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2- C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R”’, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2- C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, - NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2- C2salkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=0)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C6-Cioaryl, -NHC(=O)C2- C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3- Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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, Rs is -C2-C2salkenyl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0338] 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-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C25alkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci- C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH- C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH- C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl- NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci- C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R”’, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, - NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2- C2salkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, -NHC(=0)Ci-C25alkylene-C6-Cioaryl, -NHC(=O)C2- C25alkenylene-C6-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3- Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0339] In some embodiments, Rs is -Ce-Cioaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2,-NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2- C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C25alkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci- C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2- C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, - NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2- C2salkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2- C25alkenylene-C6-C10aryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3- Cioheteroaryl, --NHC(=O)C1-C25alkylene-C3-C10heteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0340] In some embodiments, Rs is C3-Cioheteroaryl substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-Csalkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-Csalkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"'.

[0341] In some embodiments, each of n and m is 1.

[0342] In some embodiments, Ri is CN and R2is a halide.

[0343] In some embodiments, R2is a chloride atom.

[0344] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXIX):

[0345]

[0346] (XXIX)

[0347] wherein Rs is as defined herein.

[0348] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (I), wherein each of Ri and R2, independently of the other is a group selected from H, a halide and -CN;

[0349] each of n and m, independently of the other, is an integer between 0 and 5, designating the number of substituents on the ring;

[0350] X is CH, CH2 or wherein the group C-R4 is C=R4;

[0351] R3 is H or a carbon containing group having between 1 and 3 carbon atoms, further optionally substituted;

[0352] 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;

[0353] 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.

[0354] In some embodiments, X-R4 is C=R4 and R4 is a nitrogen atom.

[0355] In some embodiments, R3 is a carbon containing group and R4 is a nitrogen containing group.

[0356] 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.

[0357] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (XXX):

[0358]

[0359] (XXX)

[0360] wherein

[0361] 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);

[0362] each of R5, Re and R7, independently of the other, may be absent or selected from -H, Ci-C3alkyl, -C(=O)-O-R8, -C(=O)-NR'-R8, halide, CN, OH, and NR'R";

[0363] 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.

[0364] In some embodiments, Li is nitrogen atom and L2 is a carbon atom.

[0365] 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.

[0366] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (XXXI):

[0367]

[0368] (XXXI)

[0369] wherein each of Ri, R2, n, m, Re and R7 are as defined herein.

[0370] In some embodiments, R7 is H and Rs is selected from -Ci-C3alkyl, -C(=O)-O-R8, -C(=O)-NR'-R8, a halide, -CN, -OH, and -NR'R"; and wherein R8is as defined above.In some embodiments, Re is a substituted -Ci-Csalkyl and R7 is H.

[0371] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXXII):

[0372]

[0373] wherein Rs is as defined herein.

[0374] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXXIII):

[0375]

[0376] ci (XXXIII)

[0377] wherein R9 is selected from -O-Rs and -NR’-Rs; Rs is as defined herein.

[0378] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXXIV):

[0379]

[0380] (XXXIV)

[0381] wherein R9 is selected from -O-Rs and -NR’ -Rs; wherein each of R’ and Rs is as defined herein.

[0382] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXXV):

[0383]

[0384] (XXXV)

[0385] wherein R9 is selected from -O-Rs and -NR’ -Rs; wherein each of R’ and Rs is as defined herein.

[0386] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXXVI):

[0387]

[0388] Cl (XXXVI)

[0389] wherein R9 is selected from -O-R8and -NR’-R8; wherein each of R’ and R8is as defined herein.

[0390] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the general formula (II), as defined herein:

[0391]

[0392] wherein

[0393] 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);

[0394] each of R5, RS and R7, independently of the other, may be selected from -H, -Ci-C3alkyl, -C(=O)-OH, -C(=O)-O-R8, -C(=O)-NR'R8, 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;

[0395] the 5-, 6-, 7- or 8-membered carbocyclic ring is further optionally substituted by at least one functionality B selected from -H, -Ci-C2salkyl, -C2-C2salkenyl, -C2-C2salkynyl, -Ce-Cioaryl, an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-C2-C5alkenyl, -S-C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-C2-C5alkenyl, -C(=O)-O-C2-C5alkynyl, -C(=O)-NR'R" R"', -C(=0)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-C2-C25alkenyl, -C(=O)-NR'-C(=O)-C2-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)-Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci- C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH- C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH- C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl- NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci- C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2- C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, - NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2- C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2- C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3- Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"';

[0396] 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):

[0397]

[0398] 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, -Ci-C2salkyl, -C2-C2salkenyl, -C2-C25alkynyl, -C(=0)-Ce-Cioaryl and -C(=0)-C3-Cioheteroaryl,

[0399] 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);

[0400] one of R5, Re and R7 may be absent;

[0401] Rs is selected from -H, -Ci-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -Ce-Cioaryl and Cs-Cioheteroaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-Ci-C25alkenyl, -C(=O)-NR'-C(=O)-Ci-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2,-NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R”’, -NH-C2-C25alkynyl-C(=O)-NR’R”R’”, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-Ce-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R’”, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C25alkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, --NHC(=O)C1-C25alkylene-C6-C10aryl, -NHC(=O)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=O)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=O)C2- C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"';

[0402] Rio is selected from -H, -Ci-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -Ce-Cioaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, -Ci-Csalkyl, -C -Csalkenyl, -C2-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-Ci-C5alkenyl, -C(=O)-O-Ci-C5alkynyl, -C(=O)-NR'R" R"', -O-Ci-C5alkyl, -O-Ci-C5alkenyl, -O-Ci-C5alkynyl, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-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, Ci-Csalkyl, C2- Csalkenyl, C2-Csalkynyl, -C(=O)-C2-C2salkyl, -C(=O)-C2-C25alkenyl and Cs-C2salkynyl; or wherein one of R', R" and R'" is absent; and wherein

[0403] each bond between N-L, L-L₁, L₁-L₂ and L₂-C (designated ---) is a single or double bond.

[0404] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (II), wherein L2 is a nitrogen atom and each of L and L is a carbon atom. In some embodiments, R7 is absent and R5 and Rs 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 moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXXVII):

[0405]

[0406] (XXXVII),

[0407] wherein each of Ri, R2, Rs, Rs, n and m is as defined above.

[0408] In some embodiments, Rs and Rs 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.

[0409] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (XXXVIII):

[0410]

[0411] (XXXVIII),

[0412] 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, -Ci-C2salkyl, -C2-C2salkynyl, -Ce-Cioaryl, an hydroxyl, an amine, a halide, -ONO2, -NO2, -S-, -S-Ci-C5alkyl, -S-Ci-C5alkenyl, -S-Ci-C5alkynyl, -C(=O)-, -C(=O)-Ci-C25alkyl, -C(=O)-O-Ci-C5alkyl, -C(=O)-O-C2-C5alkenyl, -C(=O)-O-C2-C5alkynyl, -C(=O)-NR'R" R"', -C(=O)-NR'-C(=O)-Ci-C25alkyl, -C(=O)-NR'-C(=O)-C2-C25alkenyl, -C(=O)-NR'-C(=O)-C2-C2salkynyl, -C(=0)-ORio, -O-Ci-Csalkyl, -O-Ci-Csalkenyl, -O-Ci-Csalkynyl, -NH-NH2, -NH-NH-C(=O)- Ci-C25alkyl, -NH-NH-C(=O)-C2-C25alkenyl, -NH-NH-C(=O)-C2-C25alkynyl, -NH-NH-C(=0)-C6-Cioaryl, -NH-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkyl-C(=O)-OH, -NH-C2-C25alkenyl-C(=O)-OH, -NH-C2-C25alkynyl-C(=O)-OH, -NH-Ci-C25alkyl-C(=O)-NR’R”R’”, -NH-C2-C25alkenyl-C(=O)-NR’R”R’”, -NH-C2-C25alkynyl-C(=O)-NR’R”R”’, -NH-Ci-C25alkyl-NH2, -NH-C2-C25alkenyl-NH2, -NH-C2-C25alkynyl-NH2, -NH-Ci-C25alkyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkenyl-NH-C(=O)-Ci-C25alkyl, -NH-C2-C25alkynyl-NH-C(=O)-Ci-C25alkyl, -NH-Ci-C25alkyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkenyl-NH-C(=0)-C6-Cioaryl, -NH-C2-C25alkynyl-NH-C(=0)-C6-Cioaryl, -NH-Ci-C25alkyl-NH-C(=0)-C3-Cioheteroaryl, -NH-C2-C2salkenyl-NH-C(=O)-C3-Cwheteroaryl, -NH-C2-C25alkynyl-NH-C(=0)-C3-Cioheteroaryl, -NH-Ci-C25alkylene-C(=O)-NR’R”R”’, -NH-C2-C25alkenylene-C(=O)-NR’R”R’”, -NH-C2-C25alkynylene-C(=O)-NR’R”R’”, -NH-Ci-C25alkylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkenylene-C(=O)-O-Ci-C25alkyl, -NH-C2-C25alkynylene-C(=O)-O-Ci-C25alkyl, -NHC(=O)Ci-C25alkyl, -NHC(=O)C2-C25alkenyl, -NHC(=O)C2-C25alkynyl, NHC(=O)Ci-C25alkylene-NR’R”R’”, -NHC(=O)C2-C25alkenylene-NR’R”R’”, NHC(=O)C2-C25alkynylene-NR’R”R’”, -NHC(=O)Ci-C25alkylene-OH, -NHC(=O)C2-C2salkenylene-OH, -NHC(=O)C2-C25alkynylene-OH, -NHC(=0)C6-Cioaryl, NHC(=O)C3-Cwheteroaryl, -NHC(=0)Ci-C25alkylene-C6-Cioaryl, -NHC(=0)C2-C25alkenylene-Ce-Cioaryl, -NHC(=0)C2-C25alkynylene-C6-Cioaryl, -NHC(=0)C3-Cioheteroaryl, -NHC(=0)Ci-C25alkylene-C3-Cioheteroaryl, -NHC(=0)C2-C25alkenylene-C3-Cwheteroaryl, -NHC(=0)C2-C25alkynylene-C3-Cioheteroaryl, 2, 2,6,6-tetramethylpiperi din- 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"';

[0413] 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):

[0414]

[0415] 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, -Ci-C25alkyl, -C2-C2salkenyl, -C2-C25alkynyl, -C(=0)-Ce-Cioaryl and -C(=0)-C3-Cioheteroaryl,

[0416] 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 thefunctionality is 1, 2 or 1, 3 or 1,4, wherein 1 designates the position of the existing group or the endocyclic N atom).

[0417] In some embodiments, ring A is a 5 -membered ring. In some embodiments, the ring is a heterocyclic ring comprising one or more heteroatom selected from N, O and S. In some embodiments, ring A is a 6-membered ring. In some embodiments, the ring is a heterocyclic ring comprising one or more heteroatom selected from N, O and S. in some embodiments, the ring is an aromatic ring or a heteroaryl ring.

[0418] In some embodiments, ring A is a 7-memebered ring. In some embodiments, the ring is a heterocyclic ring comprising one or more heteroatom selected from N, O and S.

[0419] In some embodiments, ring A comprises one or more double bonds.

[0420] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of the formula (XXXIX):

[0421]

[0422] wherein each of Ri, R2, n, m and B is as defined above.

[0423] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (XXXX):

[0424]

[0425] wherein each of Ri, R2, n, m and B is as defined above.

[0426] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (XXXXI):N^\

[0427] / N

[0428] N'-'X jj'

[0429] B

[0430]

[0431] m(R2)^C / (XXXXI),

[0432] wherein each of Ri, R2, n, m and B is as defined above.

[0433] In some embodiments, the moiety selectively interacting with the CB1R may be derived from a compound of formula (XXXXII):

[0434]

[0435] In some embodiments of compounds disclosed herein, 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, Ri and R2 are each a halide. In some embodiments, each of Ri and R2 is a chloride atom.

[0436] In some embodiments of compounds disclosed herein, n and m together represent 2 or 3 halide atoms. In some embodiments, the halide atoms are each a chloride atom.

[0437] In some embodiments, the CB1R recognizing moiety may be selected from:

[0438]

[0439]

[0440]

[0441] and others.

[0442] In some embodiments, compounds of the invention comprise an E3 ligase recruiter moiety selected as above, e.g., selected from a Hippel-Lindau (VHL) moiety, a pomalidomide-based moiety (CRBN), a DCAF15 moiety, a DCAF16 moiety, a MDM2 moiety and a variety of RING E3 ligase recruiter moi eties.

[0443] In some embodiments, in compounds of the invention, the E3 ubiquitin ligase recruiter moiety is any one of

[0444]

[0445] RBN-5,DCAF16-1, DCAF16-2, DCAF16-3, DCAF16-4,

[0446]

[0447] and RING 4, and the CB 1R recognizing and binding moiety is any one

[0448]

[0449]

[0450] and others. Each of the R groups, independently, may be a substituent selected from -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi-C6alkyl, -ON(Ci-C6alkyl)2, -N(Ci-C6alkyl)2, -N(C1-C6alkyl)3+, -NH(Ci-C6alkyl)2+, -NH2(Ci-C6alkyl)+, -NH3+, -N(OCi-C6alkyl)(Ci-C6alkyl), -N(OH)(Ci-C6alkyl), -NH(OH), -SH, -SCi-C6alkyl, -SS(Ci-C6alkyl), -C(=O)(Ci-C6alkyl), -CO2H, -CO2(Ci-C6alkyl), -OC(=O)(Ci-C6alkyl), -OCO2(Ci-C6alkyl), -C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -OC(=O)NH(Ci-C6alkyl), -NHC(=O)(Ci-C6alkyl), -N(Ci-C6alkyl)C(=O)(Ci-C6alkyl), -NHCO2(Ci-C6alkyl), -NHC(=O)N(Ci-C6alkyl)2, -NHC(=O)NH(Ci-C6alkyl), -NHC(=O)NH2, -C(=NH)O(Ci-C6alkyl), -OC(=NH)(Ci-C6alkyl), -OC(=NH)OCi-C6alkyl, -C(=NH)N(Ci-C6alkyl)2, -C(=NH)NH(Ci-C6alkyl), -C(=NH)NH2, -OC(=NH)N(Ci-C6alkyl)2, -OC(=NH)NH(Ci-C6alkyl), -OC(NH)NH2, -NHC(NH)N(Ci-C6alkyl)2, -NHC(=NH)NH2, -NHSO2(Ci-C6alkyl), -SO2N(Ci-C6alkyl)2, -SO2NH(Ci-C6alkyl), -SO2NH2, -SO2Ci-C6alkyl, -SO2OCi-C6alkyl, -OSO2Ci-C6alkyl, -SOCi-C6alkyl, -Si(Ci-C6alkyl)3, -OSi(Ci-C6alkyl)3-C(=S)N(Ci-C6alkyl)2, C(=S)NH(Ci-C6alkyl), -C(=S)NH2, -C(=O)S(Ci-C6alkyl), -C(=S)SCi-C6alkyl, -SC(=S)SCi-C6alkyl, -P(=O)(OCi-C6alkyl)2, -P(=O)(Ci-C6alkyl)2, -OP(=O)(Ci-C6alkyl)2, -OP(=O)(OCi-Cealkyl)2, -Ci-Cioalkyl, -Ci-Cioperhaloalkyl, -Ci-Cioalkenyl, -Ci-Cioalkynyl, heteroCi-Cioalkyl, heteroCi-Cioalkenyl, heteroCi-Cioalkynyl, -C3-Ciocarbocyclyl, -Ce-Cioaryl, 3-to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal substituents may be joined to form =0 or =S.

[0451] In each of the moi eties designated herein, the wavy line designates a bond of association to another moiety or a linker or bridging moiety as disclosed herein. It is to be understood that in some cases the actual point of connectivity between the moieties may vary. Therefore, the position indicated in the above structures for a bond of connectivity is not limiting. In each case, the connectivity may be through any atom ofthe moiety, as connectivity rules allow. For example, in a structure such as

[0452]

[0453] ci ci, the designated bond of connectivity may be that indicated or any atom of the ring structures.

[0454] In some embodiments, the E3 ubiquitin ligase recruiter moiety and the CB1R recognizing and binding moiety are associated with each other directly, without an intervening linker or bridging moiety. In such cases, for example, any of the E3 ubiquitin ligase recruiter moiety, e.g.,

[0455]

[0456]

[0457] 4, is directly bonded through an atom or a bond to a CB1R recognizing and binding

[0458]

[0459]

[0460] Direct association, generating a molecular glue, may be exemplified by compounds of the invention in which the E3 ubiquitin ligase recruiter moiety is any of the aforementioned moieties and the CB1R recognizing and binding moiety is

[0461]

[0462] In some embodiments, the E3 ubiquitin ligase recruiter moiety and the CB1R recognizing and binding moiety, each as defined and selected herein, are associated via a linker group. The linker group serves as a structural element that connects the two functional domains of the degrader molecule and provides the spatial orientation necessary to enable the formation of a productive ternary complex between the CB1receptor, the degrader molecule, and the recruited E3 ubiquitin ligase. In the context of heterobifunctional degrader molecules such as PROTACs, the linker may play an important role in determining the efficiency of target protein degradation by influencing the relative positioning, flexibility, and conformational dynamics of the two binding moieties. While the chemical composition and length of the linker may in some cases be crucial for enabling a PROTAC capacity to bridge the POI and the E3 ligase, the variety of linker groups in terms of composition and length is without any limitation.

[0463] In some embodiments, the chemical composition and length of the linker may be selected to facilitate effective bridging between the protein of interest (POI), here the CB 1 receptor, and the recruited E3 ligase. Proper spatial arrangement between the two binding domains may enhance the stability of the ternary complex and increase the efficiency with which ubiquitin molecules are transferred to the target protein.

[0464] Generally speaking, the linker group may be or may comprise any atom or group of atoms capable of covalently connecting the two functional domains of the degrader molecule of the invention. In some embodiments, the linker may be in a form of a chain comprising one or more heteroatoms, which may optionally include N, O and / or S. The linker may be selected amongst aliphatic groups, including linear or branched alkyl chains of variable length. In some cases, the aliphatic groups may be interrupted by one or more heteroatoms such as N, O and S (to yield such linker groups as as polyethyene glycol). In some cases, the linker may include functional groups such as alkyl or aryl ethers, amide groups, ester groups, arylenes, heteroarylenes, disulfides, heterocyclic groups, sulfonamides and ureas, hydrazones, alkyl or aryl esters, and others.

[0465] In some cases, the linker may also include heterocyclic groups or other cyclic structures that can provide structural rigidity or defined spatial orientation between the two functional domains. In some embodiments, the linker may further include disulfide bonds, which may confer redox-sensitive properties and allow cleavage of the linker under certain intracellular conditions.

[0466] In some embodiments, the linker may be selected from aliphatic chains, polyethylene glycol chains, alkyl or aryl ethers, amide-containing chains, arylenes, heteroarylenes, disulfides, heterocyclic linkers, sulfonamides, ureas, hydrazones, alkyl or aryl esters, or combinations thereof. The length of the linker may vary and may be selected to provide an appropriate spatial distance between the two functional domains of the degrader molecule.In some embodiments, the linker may further comprise at least one heteroaryl or heterocyclic group.

[0467] Each of the groups disclosed herein may be substituted by one or more substituents, selected from: -ORa, -ON(Rb)2, -N(Rb)2, -N(Rb)3+, -N(ORc)Rb, -S-, -SRa, -SSRc, -C(=O)Ra, -CO2-, -C=O-, -C(ORc)2, -CO2Ra, -OC(=O)Ra, -OCO2Ra, -C(=O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbCO2Ra, -NRbC(=O)N(Rb)2, -C(=NRb)Ra, -C(=NRb)ORa, -OC(=NRb)Ra, -OC(=NRb)ORa, -C(=NRb)N(Rb)2, -OC(=NRb)N(Rb)2, -NRbC(=NRb)N(Rb)2, -C(=O)NRbSO2Ra, -NRbSO2Ra, -SO2N(Rb)2, -SO2Ra, -SO2ORa, -OSO2Ra, -S(=O)Ra, -OS(=O)Ra, -Si(Ra)3, -OSi(Ra)3-C(=S)N(Rb)2, -C(=O)SRa, -C(=S)SRa, -SC(=S)SRa, -SC(=O)SRa, -OC(=O)SRa, -SC(=O)ORa, -SC(=O)Ra, -P(=O)(Ra)2, -P(=O)(ORc)2, -OP(=O)(Ra)2, -OP(=O)(ORc)2, -P(=O)(N(Rb)2)2, -OP(=O)(N(Rb)2)2, -NRbP(=O)(Ra)2, -NRbP(=O)(ORc)2, -NRbP(=O)(N(Rb)2)2, -P(Rc)2, -P(ORc)2, -P(Rc)3+, -P(ORc)3+, -P(Rc)4, -P(ORc)4, -OP(RC)2, -OP(RC)3+-, -OP(ORC)2, -OP(ORC)3+, -OP(RC)4, -OP(ORC)4, -Ci-C2oalkylene, -Ci-C2operhaloalkylene, -C2-C2oalkenylene, -C2-C2oalkynylene, heteroCi-C2oalkylene, heteroC2-C2oalkenylene, heteroC2-C2oalkynylene, -C3-Ciocarbocyclylene, heterocyclylene, -Ce-Cioarylene, -Ci-C2oalkylene-C6-Cioarylene, -Ci-C2oalkylyne-0-Ce-Cioarylene, -Ci-C2oalkylene-S-C6-Cioarylene, -Ci-C2oalkylene-NRb-C6-Cwarylene, wherein Ra is selected independently from -Ci-C2oalkyl, -Ci-C2operhaloalkyl, -Ci-C2oalkenyl, -Ci-C2oalkynyl, heteroCi-C2oalkyl, heteroCi-C2oalkenyl, heteroCi-C2oalkynyl, -C3-Ciocarbocyclyl, heterocyclyl, -Ce-Cioaryl, -Ci-C2oalkylene-Ce-Cioarylene, -Ci-C2oalkylyne-0-C6-Cioarylene, -Ci-C2oalkylene-S-C6-Cioarylene, -Ci-C2oalkylene-NRb-Ce-Cioarylene,

[0468] wherein Rb is selected independently from hydrogen, -OH, -ORa, -N(Rc)2, -CN, -C(=O)Ra, -C(=O)N(Rc)2, -CO2Ra, -SO2Ra, -C(=NRc)ORa, -C(=NRc)N(Rc)2, -SO2N(Rc)2, -SO2Rc, -SO2ORc, -SORa, -C(=S)N(Rc)2, -C(=O)SRc, -C(=S)SRc, -P(=O)(Ra)2, -P(=O)(ORC)2, -P(=O)(N(RC)2)2, -C1-C20alkyl, -C1-C20perhaloalkyl, -Ci-C2oalkenyl, -Ci-C2oalkynyl, heteroCi-C2oalkyl, heteroCi-C2oalkenyl, heteroCi-C2oalkynyl, -C3-Ciocarbocyclyl, heterocyclyl, -Ce-Cioaryl, -Ci-C2oalkylene-Ce-Cioarylene, -Ci-C2oalkylyne-0-C6-Cioarylene, -Ci-C2oalkylene-S-C6-Cioarylene, -Ci-C2oalkylene-NRb-Ce-Cioarylene,wherein Rc is selected independently from hydrogen, -Ci-C2oalkyl, -Ci-C2operhaloalkyl, -C2-C2oalkenyl, -C2-C2oalkynyl, heteroCi-C2oalkyl, heteroC2-C2oalkenyl, heteroC2-C2oalkynyl, -C3-C10carbocyclyl, heterocyclyl, -Ce-Cioaryl; and wherein each of the aforementioned functionalities, where chemically appropriate, may be substituted by one or more groups selected from -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi-C6alkyl, -ON(Ci-C6alkyl)2, -N(Ci-C6alkyl)2, -N(CI-C6alkyl)3+, -NH(Ci-C6alkyl)2+, -NH2(Ci-C6alkyl)+, -NH3+, -N(OCi-C6alkyl)(Ci-C6alkyl), -N(OH)(Ci-C6alkyl), -NH(OH), -SH, -SCi-C6alkyl, -SS(Ci-C6alkyl), -C(=O)(Ci-C6alkyl), -CO2H, -CO2(Ci-C6alkyl), -OC(=O)(Ci-C6alkyl), -OCO2(Ci-C6alkyl), -C(=O)NH2, -C(=O)N(Ci-C6alkyl)2, -OC(=O)NH(Ci-C6alkyl), -NHC(=O)(Ci-C6alkyl), -N(Ci-C6alkyl)C(=O)(Ci-C6alkyl), -NHCO2(Ci-C6alkyl), -NHC(=O)N(Ci-C6alkyl)2, -NHC(=O)NH(Ci-C6alkyl), -NHC(=O)NH2, -C(=NH)O(Ci-C6alkyl), -OC(=NH)(Ci-C6alkyl), -OC(=NH)OCi-C6alkyl, -C(=NH)N(Ci-C6alkyl)2, -C(=NH)NH(Ci-C6alkyl), -C(=NH)NH2, -OC(=NH)N(Ci-C6alkyl)2, -OC(=NH)NH(Ci-C6alkyl), -OC(NH)NH2, -NHC(NH)N(Ci-C6alkyl)2, -NHC(=NH)NH2, -NHSO2(Ci-C6alkyl), -SO2N(Ci-C6alkyl)2, -SO2NH(Ci-C6alkyl), -SO2NH2, -SO2Ci-C6alkyl, -SO2OCi-C6alkyl, -OSO2Ci-C6alkyl, -SOCi-C6alkyl, -Si(Ci-C6alkyl)3, -OSi(Ci-C6alkyl)3-C(=S)N(Ci-C6alkyl)2, C(=S)NH(Ci-C6alkyl), -C(=S)NH2, -C(=O)S(Ci-C6alkyl), -C(=S)SCi-C6alkyl, -SC(=S)SCi-C6alkyl, -P(=O)(OCi-C6alkyl)2, -P(=O)(Ci-C6alkyl)2, -OP(=O)(Ci-C6alkyl)2, -OP(=O)(OCi-Cealkyl)2, -Ci-Cioalkyl, -Ci-Cioperhaloalkyl, -Ci-Cioalkenyl, -Ci-Cioalkynyl, heteroCi-Cioalkyl, heteroCi-Cioalkenyl, heteroCi-Cioalkynyl, -C3-Ciocarbocyclyl, -Ce-Cioaryl, 3-to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal substituents may be joined to form =0 or =S.

[0469] In cases where a group, a functionality or a moiety is "substituted' or said to be “optionally substituted", substitution may be one or more atoms or groups of atoms selected from -CN, -N02, -N3, -SO2H, -SO3H, -OH, -OCi-C6alkyl, -0N(Ci-C6alkyl)2, -N(Ci-C6alkyl)2, -N(CI-C6alkyl)3+, -NH(Ci-C6alkyl)2+, -NH2(CI-C6alkyl)1+, -NH3+, -N(OCi-C6alkyl)(Ci-C6alkyl), -N(0H)(Ci-C6alkyl), -NH(OH), -SH, -SCi-C6alkyl, -SS(Ci-C6alkyl), -C(=O)(Ci-C6alkyl), -C02H, -CO2(Ci-C6alkyl), -OC(=O)(Ci-C6alkyl), -OCO2(Ci-C6alkyl), -C(=0)NH2, -C(=O)N(Ci-C6alkyl)2, -OC(=O)NH(Ci-C6alkyl), -NHC(=0)(Ci-C6alkyl), -N(Ci-C6alkyl)C(=O)(Ci-C6alkyl), -NHCO2(Ci-C6alkyl), -NHC(=0)N(Ci-C6alkyl)2, -NHC(=O)NH(Ci-C6alkyl), -NHC(=0)NH2, -C(=NH)0(Ci-C6alkyl), -OC(=NH)(Ci-C6alkyl), -OC(=NH)OCi-C6alkyl, -C(=NH)N(Ci- C6alkyl)2, -C(=NH)NH(Ci-C6alkyl), -C(=NH)NH2, -OC(=NH)N(Ci- C6alkyl)2, -OC(=NH)NH(Ci-C6alkyl), -OC(NH)NH2, -NHC(NH)N(Ci- C6alkyl)2, -NHC(=NH)NH2, -NHSO2(Ci-C6alkyl), -SO2N(Ci-C6alkyl)2, -SO2NH(CI- C6alkyl), -SO2NH2, -SO2Ci-C6alkyl, -SO2OCi-C6alkyl, -OSO2Ci-C6alkyl, -SOCi- C6alkyl, -Si(Ci-C6alkyl)3, -OSi(Ci-C6alkyl)3-C(=S)N(Ci-C6alkyl)2, -C(=S)NH(Ci-C6alkyl), -C(=S)NH2, -C(=O)S(Ci-C6alkyl), -C(=S)SCi-C6alkyl, -SC(=S)SCi-C6alkyl, -P(=O)(OCi-C6alkyl)2, -P(=O)(Ci-C6alkyl)2, -OP(=O)(Ci-C6alkyl)2, -OP(=O)(OCi-Cealkyl)2, -Ci-Cioalkyl, -Ci-Cioperhaloalkyl, -C2-Cioalkenyl, -C2-Cioalkynyl, heteroCi-Cioalkyl, heteroC1-C10alkenyl, heteroCi-Cioalkynyl, -C3-Ciocarbocyclyl, -Ce-Cioaryl, 3-to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal substituents may be joined to form =0 or =S.

[0470] In some embodiments, the linker connecting the E3 ubiquitin ligase recruiter moiety and the CB1R recognizing moiety may comprise one or more aromatic or heteroaromatic groups. The aromatic and heteroaromatic groups may be selected to introduce structural rigidity, defined spatial orientation, and favorable electronic properties within the degrader molecule, thereby facilitating proper positioning of the two functional domains required for effective ternary complex formation between the degrader, the E3 ligase, and the CB1R. Thus, according to some non-limiting examples aromatic and heteroaromatic groups may include benzene groups, pyridine groups, pyrazole groups, imidazole groups, thiazole groups, oxadiazole groups, triazole groups, isoquinoline groups, quinoline groups, indole groups, pyrimidine groups, tetrazole groups and other related ring systems.

[0471] In some embodiments, the linker comprises one or more carbocyclic or heterocyclic ring structures. The incorporation of such cyclic structural elements may be selected or designed to at least partially impart rigidity, conformational control, or steric orientation to the degrader molecule, which may assist in optimizing the spatial relationship between the CBlR-binding moiety and the E3 ligase recruiter moiety. Accordingly, such cyclic structures may include, without limitation, 4-, 5-, 6-, 7- or 8-membered carbocyclyl groups, as well as heterocyclic rings containing one or more heteroatoms such as N, O, and S. Representative examples of suitable heterocyclic linkers include pyrrolidine groups, imidazolidine groups, oxazolidine groups, thiazolidinegroups, piperidine groups, morpholine groups, piperazine groups, aziridine groups, oxetane groups, and other related systems.

[0472] In some embodiments, the linker comprises a plurality of functional groups connected sequentially, forming a chain-like structure in which adjacent units are linked through carbonyl moieties, amine linkages, amide bonds, or heteroatom bridges. For example, functional groups may be connected via amide bonds, carbamate linkages, urea groups, ether linkages, or thioether bridges, each of which can influence the flexibility, polarity, and conformational behavior of the linker.

[0473] In some embodiments, the linker comprises a plurality of functional groups, each being associated to another via a carbonyl moiety, an amine moiety, an amide moiety, a heteroatom (such as N, O and S), and others.

[0474] In some embodiments, the linker comprises groups or moieties capable of forming hydrogen bonds, either as hydrogen bond donors or hydrogen bond acceptors. Such groups may enhance interactions with surrounding amino acid residues in the protein binding interfaces or may contribute to stabilizing the ternary complex formed between the CB1 receptor, the degrader molecule, and the recruited E3 ligase. Such functional groups may include, without limitation, amines, amides, hydroxyl groups, carbonyl groups, sulfonamides, ureas, and heteroaromatic rings containing nitrogen or oxygen atoms.

[0475] In some embodiments, the linker comprises a triazole group or other heterocyclic groups, which may be introduced, for example, through click-chemistry-based synthetic methods such as azide-alkyne cycloaddition. Triazole-containing linkers are particularly useful because they provide chemical stability, moderate rigidity, and the ability to participate in hydrogen bonding and dipolar interactions. Accordingly, the linker may comprise one or more triazole rings, optionally substituted by one or more substituent groups.

[0476] In some embodiments, the linker may comprise a triazole moiety having a structure such as 1,2, 3 -triazole or related substituted triazole systems, wherein the substituent group R may represent any suitable substituent, including alkyl, aryl, heteroaryl, haloalkyl, amino-substituted groups, or other functional groups capable of modifying the physicochemical or structural properties of the degrader molecule. In someembodiments, the linker comprises a triazole having a structure:

[0477]

[0478] or, wherein R is any substituting group. In some embodiments, the linker comprises a triazole having the structure

[0479]

[0480] In some embodiments, the linker may comprise a heterocycle selected from aziridinylene, oxetanylene, thietanylene, indolylene, quinolinylene, isoquinolinylene, benzimidazolylene, benzothiazolylene, pyridinylene, pyrimidinylene, pyrazinylene, morpholinylene, piperidinylene, thiomorpholinylene, pyrrolylene, furanylene, thiophenylene, imidazolylene, triazolylene, oxazolylene, thiazolylene and others.

[0481]

[0482] Non-limiting examples of linkers include

[0483]

[0484] others.

[0485] In some embodiments, compounds of the invention comprise a E3 ubiquitin ligase recruiter moiety selected from Hippel-Lindau (VHL) moiety, a pomalidomide-based moiety (CRBN), a DCAF15 moiety, a DCAF16 moiety, a MDM2 moiety and a variety of RING E3 ligase recruiter moi eties and a CB 1R recognizing and binding moiety selected as herein; wherein the E3 ubiquitin ligase recruiter moiety and the CB1R recognizing and binding moiety are bonded through a linker selected from aliphatic groups, aliphatic groups interrupted by one or more heteroatoms (such as polyethyeneglycol), alkyl or aryl ethers, amide groups, arylenes, heteroarylenes, disulfides, heterocyclic groups, sulfonamides and ureas, hydrazones, alkyl or aryl esters, and others.

[0486] In some embodiments, in compounds of the invention comprising a linker groups, the E3 ubiquitin ligase recruiter moiety is any one of

[0487] 'N > k k P ■, o'

[0488]

[0489] DCAF16-1, DCAF16-2,

[0490]

[0491] In some embodiments, in compounds of the invention comprising a linker group, the CB1R recognizing and binding moiety is any one o

[0492]

[0493] f

[0494]

[0495]

[0496] hereinabove.In some cases, for example, any of the E3 ubiquitin ligase recruiter moiety, e.g.,

[0497]

[0498]

[0499] 4, is bonded through a linker group to a CB1R recognizing and binding moiety selected

[0500]

[0501]

[0502] wherein each R is as defined herein, and wherein the linker group is selected amongst aliphatic groups, aliphatic groups interrupted by one or more heteroatoms (such as polyethyene glycol), alkyl or aryl ethers, amide groups, arylenes, heteroarylenes, disulfides, heterocyclic groups, sulfonamides and ureas, hydrazones, alkyl or aryl esters, and others.

[0503] PROTAC compounds of the invention may be exemplified by compounds of the

[0504] invention in which the E3 ubiquitin ligase recruiter moiety i

[0505]

[0506] s

[0507] CB1R recognizing and binding moiety is any one o

[0508]

[0509] f Cl Cl,C

[0510]

[0511] Cl, Cl, and wherein the linker group is selected amongst aliphatic groups, aliphatic groups interrupted by one or more heteroatoms (such as polyethyene glycol), alkyl or aryl ethers, amide groups, arylenes, heteroarylenes, disulfides, heterocyclic groups, sulfonamides and ureas, hydrazones, alkyl or aryl esters, and others.

[0512] In some embodiments of a PROTAC degrader molecule of the invention, the linker group is selected amongst aliphatic groups, aliphatic groups interrupted by one or more heteroatoms (such as polyethyene glycol), alkyl or aryl ethers, amide groups, arylenes, heteroarylenes, disulfides, heterocyclic groups, sulfonamides and ureas, hydrazones, alkyl or aryl esters, and others.

[0513] Non-limiting examples of degrader molecules of the invention include

[0514]

[0515]

[0516] The invention further provides a compound or a degrader molecule selected from:

[0517]

[0518]

[0519] Each of the degrader molecules of the invention constitutes an independent embodiment of the invention.

[0520] The invention further provides a composition comprising a degrader molecule as disclosed and exemplified herein, including any carrier.

[0521] Further provided are pharmaceutical compositions comprising at least one compound or degrader molecule, as disclosed herein, or a pharmaceutically acceptable form thereof. Such compositions may comprise pharmaceutically acceptable carriers, diluents, excipients, stabilizers, buffers, preservatives, or other formulation components suitable for administration to cells, tissues, or subjects. In some embodiments, the- Ill -compositions may be formulated for systemic or local administration, including but not limited to oral, intravenous, subcutaneous, intramuscular, intraperitoneal, topical, transdermal, intranasal, inhalational, or targeted tissue delivery routes. The compositions may be provided in a variety of dosage forms, including solutions, suspensions, emulsions, tablets, capsules, powders, lyophilized preparations, controlled-release formulations, nanoparticles, liposomal formulations, or other delivery systems designed to enhance stability, bioavailability, or tissue targeting.

[0522] The invention further provides a degrader molecule as disclose herein for use as a degrader of CB1 receptor. In some embodiments, the degrader molecule is capable of inducing degradation of CB1R through recruitment of the cellular ubiquitin-proteasome system, thereby reducing or eliminating the abundance of the receptor within cells. Degradation of the CB1R may be achieved in vitro, in vivo or in situ, depending on the experimental or therapeutic context. In vitro degradation may occur, for example, in cultured cells, isolated tissue samples, or biochemical assay systems. In vivo degradation may occur following administration of the compound to a subject, wherein the degrader molecule promotes CB1R ubiquitination and subsequent proteasomal degradation within target tissues. In situ degradation may occur in localized biological environments such as specific tissues, organs, or pathological sites.

[0523] The invention further provides a proteasome-targeting compound, namely a degrader molecule as disclosed herein.

[0524] Also, the invention provides a CBlR-targeted therapeutic strategy, wherein degradation of the CBIR is induced through administration of a degrader molecule of the invention. In some embodiments, the therapy involves administering a degrader molecule of the invention to a subject or delivering the compound to a target tissue in order to achieve degradation of the CBIR. The degradation of the receptor may result in or bring about lowering, reducing, diminishing, modulating or eliminating the receptor mediated signaling activity. By reducing the functional presence of the CBIR, compounds of the invention may modulate physiological and pathological pathways associated with CB1 receptor signaling.

[0525] Further provided are composition and methods of therapeutic treatment for preventing or treating a disease or disorder associated with CBIR activity or dysregulation. Because CBIR signaling is implicated in numerous biological processes, targeted degradation of CBIR may provide therapeutic benefit across a wide range ofdisease indications. Such diseases or disorders include, without limitation, cancer, neuromuscular diseases, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases, metabolic disorders, infectious diseases, age-related conditions, and fibrotic diseases.

[0526] Examples of neurodegenerative diseases that may be treated or prevented using compositions of the invention include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington’s disease (HD), and related neurodegenerative disorders. In some embodiments, compounds of the invention may also be used to treat inflammatory or autoimmune diseases, including but not limited to inflammatory bowel disease (IBD), asthma, rheumatoid arthritis, and related inflammatory conditions.

[0527] In some embodiments, degrader molecules of the invention may also be used in the treatment of cardiovascular diseases, including conditions such as heart failure, vascular dysfunction, and related disorders. In further embodiments, the degrader molecules may be used in the treatment of metabolic disorders, including diabetes, obesity, metabolic syndrome, and related metabolic diseases. Additionally, the compositions described herein may be useful in treating infectious diseases, including viral infections, as well as conditions associated with aging, tissue fibrosis, or pathological tissue remodeling.

[0528] In some embodiments, the invention further provides therapeutic compositions for the treatment of cancer. Cancers treatable by compositions of the invention may include all known cancers, noting for example, prostate cancer, breast cancer, sarcoma, melanoma, carcinoma, leukemia, glioblastoma, melanoma, glioblastoma, pancreatic cancer, ovarian cancer, colorectal cancer, lung cancer and other malignancies.

[0529] The invention further provides methods of therapeutic treatment of a subject suffering or expected to suffer from or at risk of developing a CBlR-driven disease or disorder. These methods include administering to the subject a therapeutically effective amount of a degrader molecule or according to the invention. Administration of the degrader molecule results in recruitment of an E3 ubiquitin ligase to the CB1R, leading to ubiquitination and proteasomal degradation of the receptor. As a result, CB1R-mediated signaling pathways are reduced or eliminated.

[0530] In some embodiments, the method comprises administering to a subject an amount of a degrader molecule of the invention sufficient to cause degradation of the CB1Rwithin one or more tissues of the subject. The amount administered may depend on factors including the subject’s condition, the route of administration, the pharmacokinetic properties of the compound, and the severity of the disease being treated.

[0531] The invention further concerns a method of degrading or inactivating CB1R in a tissue or a biological sample, the method comprising contacting said tissue or sample with a degrader molecule of the invention, thereby inducing receptor degradation in the tissue or sample.

[0532] In some embodiments, the protein degradation may be achieved in vitro, for example in cultured cells or biological samples treated with a compound of the invention.

[0533] In some embodiments, the protein degradation may be achieved in vivo by administering to a subject said degrader molecule such that the molecule induces ubiquitin-mediated degradation of CB1R within target tissues of the subject.

[0534] Compounds, degrader molecules and compositions of the invention designed to induce degradation of the CB1R may be administered via any suitable route of administration known in the art. Suitable routes include, without limitation, oral, parenteral, intravenous, subcutaneous, intramuscular, intraperitoneal, intrathecal, inhalational, transdermal, topical, intranasal, ocular, or localized delivery to a specific tissue or organ. The route of administration may be selected based on factors including the nature of the disease being treated, the location of the affected tissue, the desired pharmacokinetic profile, and the physicochemical properties of the degrader compound. In some embodiments, localized delivery to a particular tissue, organ, or pathological site may be advantageous for achieving higher local concentrations of the compound while minimizing systemic exposure.

[0535] Dosing regimens may vary depending on a number of factors, including the specific degrader molecule employed, the route of administration, the pharmacodynamic and pharmacokinetic properties of the degrader molecule, the condition being treated, and the physiological characteristics of the subject. In some embodiments, a degrader molecule of the invention may be administered once daily, twice daily, periodically, or intermittently according to a predetermined treatment protocol. In other embodiments, the degrader molecule may be administered in a dosage range sufficient to achieve effective and sustained degradation of the CB1 receptor while minimizing undesirable side effects or off-target interactions. The dosage and administration schedule may beadjusted over time based on therapeutic response, tolerability, or clinical parameters observed in the treated subject.

[0536] As used herein, the terms “treat,” “treating,” and “treatment” refer to any intervention in a subject or biological system that produces a beneficial or desired biological, medical, or clinical effect with respect to a disease, disorder, or pathological condition associated with CB1R activity. Such beneficial effects may include, without limitation, delaying the onset of a disease or disorder, reducing the severity of one or more symptoms, alleviating symptoms, slowing, halting, or reversing disease progression, stabilizing the disease state, inducing partial or complete remission, improving quality of life, prolonging survival, or any combination thereof. Treatment does not necessarily require complete elimination of the disease or disorder, and includes circumstances in which the disease is controlled, mitigated, or managed without being fully cured.

[0537] As used herein, the term “treatable,” and any linguistic variation thereof, refers to a disease, disorder, or condition for which administration of a compound or composition of the invention is expected to produce one or more beneficial effects as described herein. A disease or disorder may be considered treatable even if only a subset of subjects responds to treatment, even if the treatment provides symptomatic improvement rather than a cure, or even if the benefit is temporary or partial. Treatable conditions may include diseases in which CB1R signaling contributes to disease progression or pathology. In some embodiments, compounds of the invention may be used as a monotherapy or in combination with other therapeutic agents, including pharmacological treatments, biological agents, or medical interventions.

[0538] Similarly, the terms “preventing,” “prevention,” or any linguistic variation thereof refer to interventions that reduce the likelihood, risk, or probability that a subject will develop a disease, disorder, or pathological condition associated with CB1R activity, or that delay the onset of such a condition. Prevention may include primary prevention, in which a disease is prevented from occurring in a subject at risk, as well as secondary prevention, in which early or subclinical disease progression is slowed or halted. Preventive interventions may also involve reducing the severity of a disease once it manifests, lowering the frequency of disease recurrence, or preventing progression from an early-stage condition to a more severe or advanced disease state.Compounds or degrader molecules of the invention may be administered in an “effective amount,” meaning an amount sufficient to achieve a desired biological, therapeutic, or prophylactic effect. The effective amount may vary depending on factors including the specific degrader molecule used, the route of administration, the frequency and duration of treatment, the disease or disorder being treated or prevented, the severity of the condition, and characteristics of the subject such as age, body weight, genetic background, metabolic status, and overall health. In certain embodiments, the effective amount may be an amount sufficient to induce degradation of the CB 1R, thereby reducing or eliminating CBlR-mediated signaling pathways associated with disease. The effective amount need not correspond to the maximum tolerated dose and may be lower than a dose that produces measurable effects in every treated subject, provided that a beneficial therapeutic or prophylactic effect is achieved in at least a portion of the treated population. Determination of an appropriate effective amount is within the ordinary skill of the art and may be established through routine experimentation, dose-ranging studies, and clinical optimization.

[0539] As used herein, the term “degradation,” and any linguistic variation thereof, refers to the breakdown and removal of the CB1R protein through activation of the ubiquitin-proteasome pathway. In this process, the degrader molecule recruits an E3 ubiquitin ligase to the CB 1R, resulting in ubiquitination of the receptor and subsequent recognition by the cellular proteasome. The proteasome then degrades the ubiquitinated receptor into peptide fragments, thereby eliminating the receptor from the cellular environment. This degradation results in reduction or elimination of the functional activity of CB1R, including pathological activities associated with CB1R signaling, such as oncogenic, inflammatory, metabolic, or neurodegenerative processes.

[0540] BRIEF DESCRIPTION OF THE DRAWINGS

[0541] 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:

[0542] Figs. 1A-D: CB1R in diabetic kidney disease. Different pathways where CB1R can cause DKD: (A) In a healthy kidney, CB 1R plays a regulator ’ role in the expression of SGLT2 and GLUT2. SGLT2 facilitates the transport of glucose from the proximaltubule lumen into the interstitial space, coupled with sodium. Once glucose is in the interstitial space, GLUT2 enables its transfer into the bloodstream through passive diffusion. This coordinated mechanism ensures efficient glucose reabsorption and homeostasis. (B) In DKD, overactivation of CB1R leads to upregulation of GLUT2, by activating rapamycin complex (mTORCl) which enhances glucose reabsorption into the bloodstream, contributing to inflammation and kidney damage. (C) CB1R causes glomerulosclerosis by decreasing miR-29a (D) Overactivation of CB1R leads to translocation of GLUT2 from basal membrane to apical membrane resulting in increased glucose reabsorption and kidney injury.

[0543] Fig. 2: CB1R targeting small molecules, utilized small molecules targeting CB1R, including Rimonabant and its derivatives.

[0544] Figs. 3A-B. (A). CB1R signaling pathway in breast cancer and its role in disease progression. (B). PROTAC strategy utilized in this study for CB1R degradation.

[0545] Figs. 4A-B. GLuc-CBlR reporter assay. (A). Schematic representation of the GLuc-tagged CB1 reporter. (B). Single dose experiment of all designed PROTACs at 10 pM for 24 h. Data are presented as the mean ± SD (n = 3). * Represents p < 0.1, ** represents p < 0.01 and *** represents p < 0.001 as determined by Student t-test compared to vehicle.

[0546] Figs. 5A-D. Evaluation of CB1R protein degradation. (A). CB1R degradation efficacy with three different degraders. MCF-7 cells were incubated with 10 pM of the degraders for 48 h. Western blot analysis was performed and compared to the housekeeping protein vinculin. (B). Time-dependent treatment for Pro-CB8 in MCF-7, 10 pM dose. (C). Dose-dependent treatment for Pro-CB8 in MCF-7 for 48 h. (D). Mechanistic study of CB1R degradation using Pro-CB8 Treatment was done in the presence of the proteasome inhibitor MG132 at 0.2 pM for 48 h.

[0547] Figs. 6A-D. Evaluation of CB1R oncogenic downstream pathway. (A). p-ERK, p-AKT and CB1 expression in MCF7 cells treated with Pro-CB8, 10 pM dose for 48 h. B). Abundance of MCM5 in MCF-7 cells treated dose-dependently with Pro-CB8 and Rimonabant for 24 h, measured by RTqPCR. (C). Abundance of BCL2 in MCF-7 cells treated dose-dependently with Pro-CB8 and Rimonabant for 24 h, measured by RTqPCR. (D). BCL2 expression in MCF7 cells treated in a time-dependent manner with Pro-CB8, 10 pM dose. Data is presented as the mean ± SD (n = 9), *represents p < 0.05,** represents p < 0.01 as determined by a one-way ANOVA comparison relative to untreated (UT).

[0548] Figs. 7A-D. Evaluation of cancer-associated cellular behaviors. (A). Viability assay of MCF-7 cells treated with a single dose (10 pM) of Pro-CB8 and Rimonabant, measured using crystal violet. (B). Quantification of cell viability across treatment with three different concentrations. (C). Proliferation assay of MCF-7 cells treated with two different concentrations of Pro-CB8 and Rimonabant for 48 h. Data is presented as the mean ± SD (n = 3), **** represents p < 0.0001 as determined by a one-way ANOVA comparison relative to 0. (D). Apoptosis assay of MCF-7 cells treated with Pro-CB8 and Rimonabant for 48 h at 10 pM. Data is presented as the mean ± SD (n = 3), *** represents p < 0.001, **** represents p < 0.0001 as determined by a one-way ANOVA comparison relative to 0.

[0549] Figs. 8A-E. Anticancer effect of Pro-CB8 on 3D breast cancer models. (A). Schematic representation of morphological changes in 3D tumor spheroid following ProCBS treatment. (B). Morphological changes in MDA-MB-231 spheroid after 10 pM doses of Rimonabant and Pro-CB8. (C). Time course evaluation of spheroid area using image view software. (D). Morphological changes in MCF-7 spheroid after 10 pM doses of Rimonabant and Pro-CB8. (E). Time-course evaluation of spheroid area using image view software. Data is presented as the mean ± SD (n = 2), *** represents p < 0.001, **** represents p < 0.0001 as determined by a one-way ANOVA comparison relative to untreated.

[0550] Figs. 9A-B. (A) CB1R signaling pathway in cancer and its role in disease progression. (B) Proposed molecular glue-mediated mechanism for CB1R degradation.

[0551] Fig. 10. Chemical structures of the designed CB1R molecular glue degraders. The left panel displays the individual binding moieties used for construction of the final compounds, while the right panel presents the corresponding final molecules. Compounds containing the RNF126 ligase recruiters are highlighted in green, and compounds bearing the vinylsulfonyl piperazine moiety are highlighted in blue. Negative control analogues are indicated with an orange background.

[0552] Figs. 11A-D. Evaluation of CB1R protein degradation. (A) CB1R degradation efficacy with various degraders. MCF-7 cells were incubated with degraders (lOpM) for 24h. Western blot analysis was performed and compared to the housekeeping protein vinculin. (B) Time-dependent treatment for MG-CB2 in MCF-7, 10 pM dose. (C) MCF-7 cells were treated with increasing concentrations of MG-CB2 for 24 h, demonstrating a dose-dependent effect, as shown by the DC50curve. (D) HepG2 cells were treated with increasing concentrations of MG-CB2 for 24 h,

[0553] Figs. 12A-B. Mechanistic analysis of CB1R degradation and evaluation of downstream oncogenic signaling pathway. (A) Mechanistic study of CB1R degradation using MG-CB2. Treatment was done in the presence of the proteasome inhibitor MG132 at 0.2 pM for 24 h. (B) p-ERK, p-mTOR, BCL2, CB2 and CB1 expression in MCF7 cells treated with MG-CB2, 20 pM dose for 24 h.

[0554] Figs. 13A-D. Evaluation of cancer associated phenotypes in MCF-7 cells. (A) Viability assay of MCF-7 cells treated for 24 h with single dose (lOpM) of MG-CB2 and Rimonabant, measured using crystal violet. Data is presented as the mean ± SD (n = 3), *** represents p < 0.0001 as determined by Student t-test compared to the vehicle. (B) Proliferation assay of MCF-7 cells treated with 4 different concentrations of MG-CB2 for 24hr. Data is presented as the mean ± SD (n = 3), *** represents p < 0.001, **** represents p < 0.0001 as determined by a one-way ANOVA comparison relative to the vehicle. (C) Wound healing assay was used to assess the migratory ability of MCF-7 cells treated with 20pM of MG-CB2, each data point represents the mean of 12 replicates. Error bars indicate standard deviation. Data are presented as the mean ± SD (n = 12). *** represents p < 0.001 as determined by Student t-test compared to “vehicle”. (D) Transwell assay was used to assess the cell motility of MCF-7 cells treated with 20pM of MG-CB2. Data is presented as the mean ± SD (n = 3), **** represents p < 0.0001 as determined by Student t-test compared to the vehicle.

[0555] DETAILED DESCRIPTION OF EMBODIMENTS

[0556] Cannabinoid receptor type 1 (CB1R) functions as a major regulatory element within the endocannabinoid system (ECS) and exhibits pronounced expression throughout the central nervous system (CNS), particularly within neuronal tissues of the brain and spinal cord. Beyond the CNS, CB1R is broadly distributed across peripheral organs and endocrine tissues, including the liver, skeletal muscle, and components of the cardiovascular system. Structurally, CB1R belongs to the G-protein-coupled receptor (GPCR) superfamily and contains seven membrane-spanning regions that support intracellular signaling events following cannabinoid engagement. The activity of CB1R is regulated by chemically distinct classes of cannabinoid ligands. Endocannabinoids arebiosynthesized in situ from arachidonic acid derivatives, with 2-arachidonoylglycerol and anandamide representing the primary endogenous mediators. Through activation of CB1R and related receptors such as cannabinoid receptor type 2 (CB2R), these lipid messengers coordinate a wide range of physiological responses. In addition, CB1R can be activated by exogenous compounds, including phytocannabinoids such as Δ9-tetrahydrocannabinol (THC) derived from Cannabis sativa, which are capable of altering receptor-dependent signaling cascades.

[0557] Over the last several decades, extensive investigation of the ECS has established CB1R as a key regulatory component involved in controlling numerous neurophysiological functions, including mood regulation, cognitive processes, appetite, motor activity, and coordination. Beyond its essential role in normal physiology, aberrant CB1R signaling has been linked to a range of pathological conditions, including chronic liver disease, cancer, and neurological disorders, and mounting evidence further implicates CB1R in the regulation of metabolic homeostasis. Persistent upregulation of CB1R signaling has been observed in multiple cancer types, including breast cancer and hepatocellular carcinoma, and is associated with increased tumor aggressiveness and disease progression. Mechanistically, aberrant CB1R activation engages downstream signaling pathways that promote cancer cell survival, proliferation, migration, and invasion, while simultaneously suppressing apoptotic responses.

[0558] We recently reported the development of a CB IR-targeting PROTAC that enabled efficient and selective degradation of CB1R, resulting in a marked attenuation of malignant cellular phenotypes in both two-dimensional cultures and three-dimensional cancer models. These findings establish targeted CB1R degradation as a viable and innovative therapeutic strategy in oncology, with the potential to overcome key limitations associated with conventional CB1R inhibitors. Building on this proof of concept, we sought to advance toward a second generation of CB1R degraders based on a molecular glue strategy. Molecular glues offer distinct advantages over PROTACs, including improved drug-like properties. In this article, we report the design and synthesis of a series of bivalent CBlR-targeting molecular glue degraders and evaluate their activity in cancer cell -based models. Collectively, this new generation of CB 1R degraders represents a step forward toward drugging and degrading CB1R for the treatment of CBlR-associated diseases.Methods and materials

[0559] General chemistry methods and instruments

[0560] Reagents and solvents were sourced from commercial suppliers and used as obtained without additional purification unless stated otherwise. Reactions were conducted under an argon atmosphere using anhydrous solvents, with exceptions noted. Reactions were stirred magnetically and monitored by thin layer chromatography (TLC) carried out on Merck glass silica gel plates (60 F254) using UV light (254 nm / 365 nm), iodine, and ninhydrin stain as visualizing agents. All chemicals were obtained from commercial sources unless otherwise stated. Compounds were purified using silica gel chromatography (Silica gel, Bio Lab, 60 Å). Another purification was conducted with Ultimate 3000 semi -preparative HPLC instrument (Thermo Scientific), the system composed of VWD-3400rs Detector, HPG-3200BX Pump, and Fraction Collector F. The system was equipped with an HPLC Column Luna C18250x21.2 mm. Purifications were conducted with a flow rate of 10 mL / min with a gradient of 10-90% MeOH or MeCN (+ 0.1% FA) in water (+ 0.1% FA) over 55 min followed by 5 min at 90% MeOH or MeCN (+ 0.1% FA). Purities of products were analyzed by analytical HPLC by Shimadzu Nexera UHPLC (LC-40). Analyses were conducted with a flow rate of 0.3 mL / min with a gradient of 2-70% MeOH in water. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was performed on a BRUKER microflex LRF MALDI-TOF / TOF instrument using dihydroxy benzoic acid as a matrix. Spectra were acquired using the Bruker Daltonics Flex Control 3.4 and analyzed using Bruker Daltonics Flex Analysis 3.4. High-resolution mass spectra (HR-MS) was measured on a Sciex X500R QToF instrument. NMR measurements were conducted using either 80, 300 or 500 MHz as stated for each spectrum, and analysis was done via MestReNova 10.0 software.

[0561] MALDI Bruker Microflex: MALDI instrument was used for the detection of the molecular weight of the synthesized compounds. l,6-Diphenyl-l,3,5-hexatriene (DHP) matrix was prepared with MS grade or HPLC grade solvents, (acetonitrile, methanol, nanopure water). 0.5ul samples were mixed with 0.5ul matrix (1: 1 ratio) and applied to a MSP anchorchip 96 BC target.Nuclear Magnetic Resonance (NMR) were recorded on Bruker Fourier 80 spectrometer in deuterated solvent. Proton chemical shifts are reported in ppm (5). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration and coupling constants (Hz). Mestrenova 10.0 version was used to analyze the Hl NMR spectrum.

[0562] Abbreviations

[0563] Ac2O: acetic anhydride, AcOK: potassium acetate, DCM: dichloromethane, DDW: double distilled water, DIPEA: N, N-Diisopropyl ethylamine, DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, DTT: dithiothreitol, EDCI: l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDTA: ethylenediaminetetraacetic acid, EtAOc: ethyl acetate, EtsN: tri ethylamine, EtOH: ethanol, FA: formic acid, HATU: l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate, HOBt: 1 -hydroxybenzotriazole, HPLC: high-performance liquid chromatography, HRMS: high-resolution mass spectrometry, K2CO3: potassium carbonate, KI: potassium iodide, K3PO4: tri potassium phosphate, MALDI-TOF: Matrix-assisted laser desorption ionization time-of-flight, MeCN: acetonitrile, MeOH: methanol, MgSO4: magnesium sulfate, MgCl2: magnesium chloride, MS: mass spectrometry, NaCl: sodium chloride, NaH: sodium hydride, NaHCO3: sodium bicarbonate, Na2HPO4: disodium phosphate, NMR: nuclear magnetic resonance, NaN3: sodium azide, NaOH: sodium hydroxide, p-TsCl: 4-Toluenesulfonyl chloride, PBS: phosphate buffered saline, PDL: poly-D-lysine, PE: petroleum ether, PF A: paraformaldehyde, PVDF: polyvinylidene fluoride, SDS-PAGE: sodium dodecyl sulphate-polyacrylamide gel electrophoresis, THF: tetrahydrofuran, TLC: Thin layer chromatography, TBS: tris buffered saline, TBST: tris buffered saline with 0.05% (v / v) Tween-20, TFA: trifluoroacetic acid, UT: Untreated, UV: Ultraviolet.

[0564] Results and Discussion

[0565] Synthesis of CB1R PROTAC Degraders

[0566] As a first step, we selected Rimonabant, the CB1R antagonist, as our CB1R binder. Rimonabant was originally developed for the treatment of obesity but was later withdrawn from the market due to severe psychiatric side effects. To conjugate Rimonabant with the E3 ligase recruiter we modified its piperidine ring by converting itinto a carboxylic acid functional group. Thalidomide was chosen for its high efficiency in recruiting CRBN, which serves as the substrate receptor within the CRL4-CRBN E3 ubiquitin ligase complex. It was purposefully selected due to its lower molecular weight compared to other E3 ligase recruiters, providing a significant advantage in drug development by enhancing the design of CB1R degraders. The optimization process involved modifying both the type and length of the linker connecting the CB1R binder to the CRBN recruiting moiety to achieve optimal efficacy. Aliphatic chains ranging from 2 to 8 carbons were synthesized to identify the optimal length to direct CB1R ubiquitination (Pro-CBl to Pro-CB4; Table 1). To introduce rigidity and restrict linker flexibility, we designed and synthesized linkers incorporating heterocyclic rings, such as piperidine and piperazine (Pro-CB5 to Pro-CB7; Table 1). Finally, to diversify the type of heterocyclic linker, we utilized a click reaction instead of amide formation, incorporating a triazole ring between the CB1R binder and the CRBN recruiter (Pro-CB8 to Pro-CBIO; Table 1). The attachment to thalidomide was achieved through an aniline moiety. Another type of E3 ligase recruiter, an amine-functionalized VHL032 ligand was synthesized to recruit the Von Hippel -Lindau (VHL) protein into the E3 ligase complex for coupling purposes with the CB1R binder. VHL is more effective and selective for certain protein families, such as hypoxia-inducible factor (HIF-la). Additionally, the VHL-recruiting ligand is larger than the previously synthesized thalidomide-based recruiter, which may limit molecular penetration, hinder ternary complex formation required for ubiquitination, and ultimately reduce the efficiency of CB1R targeting and degradation a central goal in our E3 ligase comparison. We synthesized two CB1R degraders using the VHL recruiter. In the first degrader, the VHL recruiter is directly coupled to the CB1R binder (Pro-CBl 1; Table 1), while in the second, the E3 ligase recruiter and CB1R binder are connected via a linker containing a triazole ring (Pro-CB12; Table 1). In both cases, the VHL binder was attached via an amid bond.

[0567] Drug-like Properties.

[0568] The physicochemical characteristics of druglikeness of all synthesized compounds were assessed using the SWISSADME platform. This tool provides a graphical representation for each compound, evaluating six essential parameters: lipophilicity, size, polarity, solubility, flexibility, and saturation (Table 1). The shaded region on each plot indicates the ideal range for drug-like compounds, as established bythe criteria of Lovering et al. and Ritchie et al. However, none of the synthesized PROTAC derivatives fell within this defined range. This aligns with the common challenge that PROTACs face in meeting Lipinski’s criteria due to their large size and bifunctional design. To further assess druglikeness, we utilized the ADMETLab3.0 web server. Interestingly, despite not fitting traditional druglikeness parameters, all synthesized PROTAC derivatives were classified as drug like according to Pfizer’s expanded criteria (Table 1), which accommodate the unique properties of hybrid drugs advancing into clinical development. Moreover, according to both SWISSADME and ADMETLab3.0, none of the PROTAC derivatives exhibited BBB permeability (Table 1). These findings highlight that the PROTAC derivatives are potentially peripherally restricted and should not penetrate the CNS. This characteristic provides a significant therapeutic advantage, as it reduces the risk of psychotropic side effects commonly associated with CB1R modulation in the CNS.

[0569] GLuc-CBlR Reporter Assay.

[0570] To evaluate the effects of CB1R degraders in cells using a high-throughput approach, a GLuc-FLAG-CB 1 reporter assay was employed. In this assay, the CB1R was fused with Gaussia Luciferase (GLuc), allowing for real-time monitoring of its expression through luminescence intensity. A decrease in GLuc luminescence indicates CB1R degradation (Fig. 4A). HEK293 (Human Embryonic Kidney) cells were transfected with the GLuc-FLAG-CB 1 plasmid, enabling expression of the fusion protein. The CB1R degraders were then administered at a single concentration of 10 μM for 24 h. We observed a decrease in luminescence intensity upon the addition of several tested compounds, indicating CB1R degradation to varying degrees. Among them, Pro-CB8 exhibited the most significant reduction in luminescence intensity (~60%), suggesting it was the most effective CB1R degrader (Fig. 4B). In contrast, Rimonabant, the CB1R antagonist, showed minimal luminescence reduction, indicating a negligible effect on CB1R expression. Based on these results, Pro-CB8 was selected for further evaluation due to its superior CB1R degradation activity compared to the other tested compounds.

[0571] Protein Expression.

[0572] Following the initial cellular screening, we proceeded to evaluate our approach and derivative compounds using the MCF-7 (Michigan Cancer Foundation-7) breastcancer cell line, which is known to overexpress CB1R, a feature associated with its oncogenic characteristics. This makes MCF-7 an ideal model for evaluating the efficacy of our CBlR-targeting PROTACs. First, to confirm cellular uptake of the compound in this cell line and ensure that ubiquitination occurs intracellularly, we exploited the molecule’s intrinsic fluorescence. Using fluorescence microscopy at 3, 8, 24, and 48h post-treatment, we tracked its accumulation. Intracellular fluorescence became detectable after 3 h, peaked at 8 h, and remained robust through 48 h, demonstrating efficient and sustained cellular penetration. We assessed the most promising compounds from our initial screen in an endogenous cellular assay, focusing on their ability to reduce CB1R protein levels. MCF-7 cells were treated with the selected degraders at 10 pM for 48 h, and CB1R expression was measured by Western blot. Consistent with the reporter assay results, Pro-CB8 significantly reduced CB1R levels by approximately 80% (Fig. 5A).

[0573] Interestingly, the most potent PROTAC, Pro-CB8, contained a linker featuring a triazole ring, suggesting that increased linker rigidity and the triazole ring contribute to ternary complex formation and inducing more potent degradation. To investigate degradation kinetics, Pro-CB8 was tested in a time-dependent assay at 10 pM, demonstrating a progressive, time-dependent reduction in CB1R levels with the most potent effect observed after 48 h of treatment (Fig. 5B). Based on these findings, Pro-CB8 was further tested in MCF-7 cells for 48 h, in a dose response manner across a concentration range of 1 pM to 20 pM. Pro-CB8 significantly reduced CB1R protein levels, achieving approximately 75% degradation at the highest concentrations with a calculated degradation concentration (DC50) of 3.37pM (Fig. 5C). We next aimed to determine whether CB1R degradation was cell line dependent. To do this, we utilized MDA-MB-231 cells (Metastatic Differentiated Adenocarcinoma of the Breast), which are also known to overexpress CB1R. We selected Pro-CB8, the most effective PROTAC in MCF-7 cells, and performed a dose-dependent treatment over 48 h using three concentrations ranging from 1 pM to 10 pM. Pro-CB8 induced a significant reduction in CB1R levels, with a maximum decrease of approximately 90% at 10 pM. These results suggest that CB1R degradation by Pro-CB8 is not limited to a specific cell line, supporting the broader applicability of our approach. To confirm that CB1R degradation was mediated via the ubiquitin-proteasome system (Ups), MCF-7 cells were treated with 0.2 pM MG132, a proteasome inhibitor. Cotreatment of MG132 with Pro-CB8 prevented CB1R degradation, confirming that proteasome inhibition blocked the effect, and that theobserved CB 1R reduction relied mainly on E3 ligase recruitment and proteasomal activity (Fig. 5D) To further validate the mechanism of action, siRNA targeting the E3 ligase CRBN was used in MCF-7 cells. Notably, cotreatment with siRNA and Pro-CB8 in MCF7 cells showed no diminution in CB1R protein levels, confirming that CB1R degradation is specifically mediated through the E3 ligase subunit CRBN. As further validation, MCF-7 cells were treated individually with the parental CB1R binder and the CRBN E3 ligase-recruiting moiety. Neither treatment led to a significant decrease in CB1R levels, reinforcing that receptor degradation was not due to inhibition, but rather to targeted proteasomal degradation driven by PROTAC-mediated ternary complex formation. As part of the specificity validation, the effect of Pro-CB8 on CB2R was assessed. Although CB2R protein levels are challenging to detect reliably using antibodybased methods, we employed a recombinant rabbit monoclonal antibody against CB2R from Invitrogen, which detected a band at the expected molecular weight. The results showed no impact on CB2R expression, supporting the selective degradation of CB 1R by Pro-CB8.

[0574] Effect on Downstream Pathways.

[0575] To investigate the downstream effects of our most potent degrader, Pro-CB8, we first assessed CB 1R signaling by measuring phosphorylation of AKT and ERK (Fig.3A).

[0576] Consistent with CBlR’s known coupling to the PI3K / AKT and MAPK / ERK cascades, Pro-CB8 treatment markedly decreased levels of pAKT and pERK by approximately 70% (Fig. 6A). Phosphorylated AKT drives both transcriptional upregulation and stabilization of the antiapoptotic protein BCL-2, thereby blocking apoptotic pathways, while activated ERK promotes oncogenic signaling enhancing cell survival, suppressing apoptosis, and inducing expression of key proliferation factors such as MCM5, which is essential for cancer cell growth and viability. Accordingly, we measured BCL2 and MCM5 mRNA levels in MCF-7 cells following treatment with Pro-CB8 or the parental CB1R ligand, Rimonabant. Our results revealed a reduction in the expression of both genes at 10 pM Pro-CB8, withBCL2 also showing decreased expression at IpM. In contrast, Rimonabant treatment did not cause noticeable change in the mRNA levels of either gene at the tested concentrations, emphasizing the enhanced efficacy of targeted protein degradation over mere antagonism (Figs. 6B, C). In addition, BCL2 protein levels were evaluated in MCF-7 cells treated with 10 pM Pro-CB8 in a time-dependent manner, revealing a 56%reduction after 48 h (Fig. 6D). Moreover, we assessed the downstream effect of Pro-CB8 in MDA-MB-231, where it also significantly reduced BCL2 and MCM5 expression by approximately 50%. Again, Rimonabant showed no notable impact. These findings highlight the superior efficacy of Pro-CB8 in downregulating key cancer-related genes and proteins, underscoring its potential as a promising therapeutic candidate for breast cancer treatment.

[0577] Inhibition of Cancer-Associated Cellular Behaviors.

[0578] To further evaluate the cellular functional consequences of Pro-CB8 on cancer-associated cellular behaviors, we conducted proliferation, cytotoxicity, and apoptosis assays in two breast cancer cell lines. Cell viability was first assessed following treatment with Pro-CB8 and Rimonabant at three concentrations (0.1 pM, 1 pM, and 10 pM). To assess cytotoxicity, crystal violet staining was performed to label DNA in adherent viable cells, enabling measurement of their total biomass without altering protein levels in the surviving cells. The CB1R degrader, Pro-CB8, demonstrated clear cytotoxic activity across all tested concentrations in MCF-7 cells, in contrast to Rimonabant, which exhibited a comparatively weaker effect (Figs. 7A, B)- To further validate the viability assay, healthy fibroblast cells were treated with both Rimonabant and Pro-CB8, and no significant decrease in cell viability was observed. These findings emphasize the advantage of targeted degradation in reducing cancer cell viability. Furthermore, a significant reduction in cell proliferation was observed following Pro-CB8 treatment compared to Rimonabant (Fig. 7C). To explore whether the observed decrease in cell viability was associated with apoptosis, we employed the Caspase-Gio 3 / 7 assay, which measures caspase activity through the luminescent detection of aminoluciferin following substrate cleavage. Consistent with the downregulation of the antiapoptotic protein BCL2, treatment with Pro-CB8 resulted in a robust increase in apoptosis at 10 pM, indicating that the CB1R degrader Pro-CB8 actively induces apoptotic cell death (Fig.

[0579] 7D). These findings were further validated in the MDA-MB-231 cell line. In alignment with the MCF-7 results, Pro-CB8 significantly reduced proliferation at IpM and 10 pM, while also inducing a dose dependent marked increase in apoptosis. Notably, the inhibition of cancer-associated cellular behaviors was more evident at the 48 h mark, consistent with the catalytic degradation of the CB1R. This sustained degradation likely disrupts the expression of key survival proteins, inducing cumulative cellular stress,decreased proliferation, and increased cytotoxicity. Overall, at 1 pM and 10 pM, Pro-CB8 consistently suppressed multiple cancer-associated cellular behaviors proliferation, viability, and apoptosis demonstrating a significantly enhanced effect compared to the CB1R antagonist Rimonabant. This superior activity is likely attributed to the catalytic mechanism of the PROTAC degrader, supporting its promise as a potential therapeutic strategy in breast cancer treatment.

[0580] Anticancer Activity in 3D Cell Models.

[0581] For further validation, we developed 3D cancer spheroid cultures using two breast cancer cell lines, MCF-7 and MDA-MB-231. Spheroids provide a more physiologically relevant model for anticancer drug screening by mimicking the 3D architecture, cell-cell interactions, and microenvironmental gradients found in solid tumors. Importantly, they enable the evaluation of drug penetration and resistance mechanisms, thereby providing more predictive insights into therapeutic efficacy. Following spheroid formation and treatment administration with Pro-CB8, we observed signs of tumor cell death, evidenced by the accumulation of dead cells and disrupted spheroid morphology. Continued cell death overtime led to a decrease in spheroid size and compromised cell-cell adhesion. This progressive loss of structural integrity ultimately caused the disintegration of the spheroids into smaller cellular fragments (Fig. 8A). Notably, treatment with the CB1R degrader Pro-CB8 resulted in pronounced and sustained disintegration of both MCF-7 and MDA-MB-231 spheroids, beginning as early as day three and persisting throughout the observation period (Figs. 8B, D). In contrast, untreated spheroids and those treated with the control compound Rimonabant displayed only an inhibition of the tumor growth in MCF-7 spheroids and no significant observable effect in MDA-MB-231 spheroids (Figs. 8C, E). These findings underscore the robust and consistent anticancer activity of Pro-CB8 across both 2D and 3D experimental models, reinforcing its therapeutic potential. In conclusion, the ability of Pro-CB8 to induce spheroid disintegration highlights its efficacy in a more physiologically relevant system that closely mimics the in vivo tumor microenvironment. These promising results support translational potential of this approach.In Vivo Blood-Brain Barrier Penetration.

[0582] To experimentally evaluate the blood-brain barrier permeability of the CB1R-targeting PROTAC Pro-CB8, we performed an in vivo brain penetration assay in mice. Mice were administered an intraperitoneal (IP) injection of Pro-CB8 at a dose of 5 mg / kg. One hour post-treatment, the animals were sacrificed, and their brains were dissected, extracted, and analyzed using LC / MS to quantify compound levels. The experiment was performed in triplicate. In all three samples, the brain concentrations were below 10 ng / g, respectively levels considered indicative of minimal CNS exposure. The average brain concentration of the degrader Pro-CB8 was 6.43 ng / g, with a standard deviation of ±3.6 ng / g. These experimental results are consistent with our earlier in silico predictions using the SWISSADME and ADMETLab 3.0 platforms, which also indicated that Pro-CB8 is unlikely to cross the blood-brain barrier. These findings not only demonstrate that Pro-CB8 achieves significant degradation of CB1R, but also highlight its favorable pharmacokinetic profile, showing poor brain penetration and confirming its peripheral restriction. This dual profile potent, selective target degradation combined with limited CNS exposure, positions Pro-CB8 as a promising therapeutic candidate with a potentially improved safety profile compared to traditional CB1R inhibitors.

[0583] CONCLUSION

[0584] The CB1 Receptor is increasingly recognized as a compelling therapeutic target in oncology due to its role in promoting tumor progression and resistance to apoptosis. Despite the potential of CB 1R antagonists, their clinical utility has been limited by central nervous system (CNS) side effects and the emergence of resistance mechanisms. In this study, we addressed these challenges by designing and synthesizing a novel series of CBlR-targeting PROTACs that offer a dual advantage: selective degradation of CB1R and minimized CNS penetration. Using Rimonabant as the CBlR-binding moiety and thalidomide- or VHL-based ligands as E3 ligase recruiters, we generated a diverse library of bifunctional molecules with varied linker compositions and architectures. Several PROTACs effectively induced CB1R degradation, with the most promising candidates demonstrating potent antiproliferative and pro-apoptotic effects in cancer models, including 3D spheroids. Importantly, druglikeness and ADMET profiling confirmed favorable properties for further development, despite the inherent physicochemical complexity of PROTACs. To complement these in silico predictions, in vivo assessmentof blood-brain barrier permeability demonstrated that our lead compound, Pro-CB8, exhibits no significant CNS exposure. These experimental results confirm the peripheral restriction of Pro-CB8, reinforcing its potential as a safer and more selective therapeutic approach for CBlR-driven cancers. Together, these findings establish targeted CB1R degradation as a viable and innovative strategy for cancer therapy, potentially overcoming the limitations of traditional inhibitors and paving the way for the next generation of cannabinoid-based therapeutics.

[0585] PROTAC scaffold: E3 ligase recruiter: A. Cereblon (CRBN) B. Von Hippel-Lindau (VHL) "Four families of PROTACs were synthesized, differing in both linker type and E3 ligase recruiter. The linkers include aliphatic chains (highlighted in green), heterocyclic linkers (highlighted in pink), and triazole linkers (highlighted in blue). PROTACs containing the VHL recruiter are highlighted with a gray background.

[0586]

[0587] ighlighted wilts a gray hachgos ansiTable 1

[0588] Molecular Glues.

[0589] One of the major signaling routes downstream of CB 1R involves activation of the extracellular signal-regulated kinase (ERK) pathway (Fig. 9A). Stimulation of CB1R promotes ERK phosphorylation (pERK), which in turn enhances oncogenic signaling by supporting cancer cell survival and inhibiting apoptotic responses. In tumors characterized by CB1R overexpression, this pathway may become hyperactivated, thereby amplifying pro-survival signaling and contributing to tumor progression. In addition to ERK signaling, CB1R activation has been linked to modulation of the mammalian target of rapamycin (mTOR) pathway. mTOR is a central regulator of cellular growth, proliferation, differentiation, and survival, and its phosphorylationdependent activation plays a critical role in cancer biology. Accumulating evidence indicates that aberrant mTOR signaling also governs tumor cell motility, invasion, and metastatic potential. Furthermore, CBlR-associated signaling can influence the expression of anti-apoptotic proteins such as BCL2, which promotes tumor cell survival by preventing programmed cell death. Together, activation of the ERK and mTOR pathways, along with upregulation of BCL2, forms a coordinated pro-survival signaling network that supports cancer progression (Fig. 9A).

[0590] Owing to its broad impact on fundamental physiological functions, CB1R has emerged as an important pharmacological target, driving the development of therapeutic agents aimed at modulating its signaling. Pharmacological modulators of CB1R are generally classified into two groups: receptor agonists, such as THC and dronabinol, which stimulate CB1R activity, and antagonists or inverse agonists, including rimonabant and taranabant, which suppress receptor signaling.

[0591] Selective elimination of disease-associated proteins has emerged as a powerful therapeutic strategy that offers distinct advantages over conventional inhibitor-based approaches. This paradigm, termed targeted protein degradation (TPD), leverages the cell’s endogenous protein quality-control machinery to induce the complete removal of pathogenic proteins rather than merely suppressing their activity. In the context of CB 1R-targeted therapeutics, TPD strategies commonly exploit the ubiquitin-proteasome system (UPS), the principal intracellular pathway responsible for regulated protein turnover. The UPS operates through a highly coordinated enzymatic cascade involving El ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases, which collectively label target proteins with ubiquitin chains and direct them to the 26S proteasome for selective degradation.

[0592] Among TPD modalities, proteolysis-targeting chimeras (PROTACs) have emerged as a leading technology. PROTACs are heterobifunctional molecules composed of a ligand that binds the protein of interest, a second ligand that recruits an E3 ubiquitin ligase, and a linker connecting the two. Formation of a ternary complex between the target protein, PROTAC, and E3 ligase enables selective ubiquitination and subsequent proteasomal degradation of the target. An alternative TPD strategy employs molecular glues, a class of small molecules that promote or stabilize interactions between a target protein and an E3 ubiquitin ligase without requiring a linker. By inducing protein-protein interactions and facilitating E3 ligase-substrate complex formation, molecular glues enable selective degradation of target proteins while remaining within traditional druglike chemical space. Their compact size distinguishes them from heterobifunctional PROTACs and contributes to more favorable physicochemical and pharmacokinetic properties. Based on their mode of action, molecular glues can be classified into two main subclasses. Monovalent molecular glues bind a single protein and remodel its surface to recruit a neo- substrate, as exemplified by thalidomide derivatives acting through cereblon (CRBN). In contrast, bivalent molecular glues simultaneously engage both the E3 ligase and the target protein through distinct binding sites on a compact, linker-less scaffold. Recent studies, including work from the Nomura and Ciulli laboratories, have demonstrated that such bivalent molecular glues can efficiently induce targeted protein degradation without reliance on conventional linker based PROTAC architectures. The dual-engagement capability of bivalent molecular glues, combined with the inherently small size shared by this degrader class, enhances cellular uptake and expands the accessible chemical space for degrader design. Compared with bulky, linker-containing PROTACs (often -800-1200 Da), molecular glues exhibit superior druggability, improved cell permeability, oral bioavailability, and more favorable ADME profiles, while avoiding the solubility and tissue-penetration limitations associated with larger degraders. Collectively, these features position molecular glues as a versatile and translationally attractive platform for targeted protein degradation.

[0593] These strategies provide notable advantages over conventional small-molecule inhibitors, particularly for difficult therapeutic targets such as CB1R, which is aberrantlyoverexpressed in multiple cancer types. Although several CB1R antagonists have demonstrated therapeutic potential, their clinical utility is often constrained by the development of resistance mechanisms, including receptor upregulation and activation of compensatory signaling pathways, as well as the requirement for sustained receptor occupancy through continuous dosing. In contrast, targeted protein degradation enables a selective removal of the target protein, offering a powerful approach for addressing proteins that are traditionally considered undruggable. Degrader molecules operate through a catalytic mode of action, whereby a single molecule can induce degradation of multiple target protein copies, allowing efficacy at lower concentrations and potentially reducing treatment frequency. By eliminating the protein rather than transiently blocking its activity, TPD strategies may circumvent resistance mechanisms and provide more durable therapeutic responses, making them particularly attractive for targeting CB1R in cancer and other disease contexts. Importantly, recent advances in GPCR-targeted PROTAC development have demonstrated that membrane receptors are amenable to degradation-based strategies. In this context, CB1R emerges as a highly attractive and previously underexplored candidate for degradation-based intervention.

[0594] Synthesis of CB1R Molecular Glue Degraders.

[0595] As an initial step, rimonabant, a well-characterized CB 1R antagonist, was selected as the CBlR-binding moiety. Rimonabant was subsequently functionalized with a series of distinct covalent chemical handles designed to convert the CB1R ligand into covalent molecular degraders of the receptor. The first class of covalent handles incorporated either a trifluoromethylphenyl cinnamamide moiety (MG-CB1 & MG-CB2) or a fumarate warhead (MG-CB3 & MG-CB4), both of which are capable of covalently engaging RNF126, a RING-family E3 ubiquitin ligase. These electrophilic warheads react with nucleophilic residues, most commonly cysteine residues, within the E3 ligase, forming a covalent bond. Formation of this covalent linkage stabilizes the degrader-ligase interaction and promotes assembly of a highly stable ternary complex. This covalent “tagging” of the E3 ligase enhances recruitment of otherwise weakly interacting target proteins, thereby facilitating efficient ubiquitination and subsequent proteasomal degradation.36 As a second class of covalent handles, a vinylsulfonyl piperazine moiety (MG-CB5 & MG-CB6) was employed to selectively engage a different E3 ligase named DCAF16 through cysteine-directed covalent modification.38 A key distinguishingfeature of this series is its relatively lower molecular weight (approximately 500 Da), compared to the other degrader series engage the RNF126 E3 ligase protein, which are closer to 600 Da. This reduction in molecular weight may confer advantageous physicochemical properties and improved drug-like characteristics relative to the higher-molecular-weight analogues. Notably, all the covalent warheads rely on the presence of a reactive double bond to enable covalent bond formation with their respective E3 ligase.

[0596] To validate the requirement for covalent engagement, negative control analogs (MG-CB7 & MG-CB8, Fig. 10 were generated in which CB1R binder moiety was conjugated to structurally related molecules lacking the reactive double bond. These controls were specifically designed for the subset of molecules incorporating the RNF132-recruiting moiety, enabling direct evaluation of the necessity of covalent E3 ligase engagement for productive target degradation. In the absence of the electrophilic double bond, these analogues can interact with the E3 ligase only through reversible, noncovalent interactions, resulting in weak and transient binding that is insufficient to stabilize the ternary complex required for efficient ubiquitination.

[0597] CB1R Molecular glue degraders druglike molecules. The physicochemical properties and drug-likeness of all synthesized compounds were evaluated using the ADMETLab 3.0 platform. Overall, the bioavailability profiles indicate a broadly balanced, drug-like physicochemical space, with favorable lipophilicity, size, solubility, and saturation trends across the series. In line with these results, most compounds satisfy standard drug-likeness filters (Lipinski) and the expanded Pfizer criteria, and four candidates meet the GSK drug-likeness guidelines. Compared with our previously reported CB1R PROTAC derivatives, these molecular glue degraders occupy a more compact, drug-like physicochemical space, supporting improved developability. Collectively, these in silico data support good developability and highlight the translational potential of the molecular glue degraders as compact, drug-like therapeutic candidates.

[0598] Effect of the molecular glue degraders on CB1R in cancer cells. To evaluate the efficacy of our newly synthesized compounds and overall strategy, we employed the MCF-7 (Michigan Cancer Foundation-7) breast cancer cell line, which is known to overexpress CB1R; a characteristic linked to its oncogenic phenotype. This property makes MCF-7 cells a suitable model for assessing the activity of CBlR-targeting molecular glues. All synthesized compounds were initially screened for their ability toreduce CB1R protein levels (Fig. 11A). MCF-7 cells were treated with each candidate degrader at a concentration of 10 μM for 24 h, and CB1R expression was analyzed by Western blotting. Among the compounds tested, MG-CB2 produced a pronounced reduction in CB1R protein levels, achieving approximately 90% degradation, indicating superior efficacy relative to the other derivatives. In contrast, rimonabant, the parental CB1R antagonist, did not alter CB1R protein abundance, confirming that receptor antagonism alone is insufficient to reduce CB1R expression (Fig. 11 A). Notably, MG-CB2 contains a piperazine ring linked to a trifluoromethylphenyl cinnamamide moiety, suggesting that this structural combination may enhance ternary complex formation and thereby promote more efficient CB1R degradation. In comparison, MG-CB6, which incorporates a fumarate warhead moiety, exhibited cytotoxicity at higher concentrations (10 and 20 pM). However, at lower concentrations, MG-CB6 demonstrated a clear dosedependent degradation profile, achieving approximately 90% CB1R reduction, indicating potent degradation despite its concentration-dependent toxicity. The observed toxicity at elevated doses may reflect increased electrophilicity of the fumarate moiety, potentially leading to off-target cysteine engagement. In contrast, treatment with molecular glue compounds incorporating the vinylsulfonyl piperazine moiety (MG-CB5& MG-CB6), designed to recruit the DCAF16 E3 ligase, did not result in detectable CB1R degradation or changes in receptor expression levels (Fig. 11 A). Given their lack of measurable degradation activity, these DCAF16-recruiting analogues were not advanced for further evaluation in this study. Importantly, the negative control molecules (MG-CB7& MG-CB8), which lack the double bond required to induce covalent bond formation with RNF126, had no effect on CB1R expression, similar to the parent binders. To further characterize degradation kinetics, MG-CB2 was evaluated in a time-dependent manner at 10 μM. Treatment resulted in a progressive decrease in CB1R protein levels, with maximal degradation observed after 24 and 48 h (Fig. 11B). No significant differences were observed between 24 and 48h. Based on these findings, MG-CB2 was subsequently examined in a dose-response study in MCF-7 cells over a concentration range of 0.01 to 20 μM for 24 h (Fig. 11C). MG-CB2 induced a concentration-dependent reduction in CB1R expression, achieving approximately 90.2 ± 8.1% degradation at the highest concentrations, with a calculated degradation half-maximal concentration (DC50) of 4.1 μM (Fig. 11C). To determine whether CB1R degradation by MG-CB2 was cell-line specific, we extended our analysis to HepG2 (hepatocellular carcinoma) cells, which alsoexhibit elevated CB1R expression. HepG2 cells were treated with MG-CB2 for 24 h across a concentration range from 1 to 20 μM. Consistent with the results obtained in MCF-7 cells, MG-CB2 induced a robust and dose-dependent decrease in CB1R protein levels, with a maximal degradation of approximately 95% at 20 pM, with a calculated DC50 of 6μM (Fig. 11D). Collectively, these data demonstrate that MG-CB2 mediated CB1R degradation is not restricted to a single cancer cell line, supporting the broader applicability of this molecular glue-based degradation strategy.

[0599] Degradation Mechanistic study.

[0600] To verify that CB1R degradation occurred through the UPS, MCF-7 cells were treated with MG132, a well-established proteasome inhibitor. Co-treatment with MG132 effectively abolished MG-CB2 induced CB1R degradation, demonstrating that proteasomal inhibition blocks this effect and confirming that CB1R reduction is dependent on E3 ligase recruitment and proteasome activity (Fig. 12A). As an additional control, MCF-7 cells were treated separately with either the parental CBlR-binding ligand or the trifluoromethylphenyl cinnamamide E3 ligase-recruiting moiety alone. Neither compound produced a measurable decrease in CB1R protein levels, indicating that receptor loss was not a consequence of CB1R antagonism or nonspecific effects, but rather required molecular glue mediated ternary complex formation and targeted proteasomal degradation. To further assess selectivity, the impact of MG-CB2 on CB2R expression was examined. No change in CB2R protein levels was observed, supporting the selective degradation of CB1R by MG-CB2 (Fig. 12B).

[0601] Effect on Downstream Pathways.

[0602] To evaluate the downstream consequences of CB1R degradation by our most potent compound, MG-CB2, we examined key signaling pathways associated with CB1R activity by assessing phosphorylation of mTOR and ERK, as well as expression of the anti-apoptotic protein BCL2. Consistent with the established coupling of CB1R to the mTOR and MAPK / ERK signaling cascades, treatment with MG-CB2 resulted in a substantial reduction in pathway activation, decreasing phosphorylated mTOR (p-mTOR) levels by approximately 60% and phosphorylated ERK (p-ERK) levels by approximately 80% in MCF-7 cells (Fig. 12B). Given that ERK activation supports oncogenic signaling by promoting cell survival, suppressing apoptosis, and that mTOR phosphorylation is acentral regulator of cellular growth, survival, migration, and metastatic potential, these results indicate effective disruption of pro-tumorigenic signaling.

[0603] In parallel, we evaluated the impact of MG-CB2 on BCL2 expression, a key anti-apoptotic protein regulated downstream of CB1R signaling. MG-CB2 treatment led to a marked decrease in BCL2 protein levels in MCF-7 cells at a concentration of 20 μM (Fig.

[0604] 12B). Notably, similar effects were observed in HepG2 cells, where MG-CB2 reduced BCL2 expression by approximately 80% and phosphorylated mTOR levels by approximately 40%. Collectively, these findings demonstrate that MG-CB2 effectively suppresses multiple CBlR-dependent oncogenic pathways across distinct cancer cell lines, highlighting its strong potential as a therapeutic candidate for breast cancer and other CBlR-driven malignancies.

[0605] Inhibition of Cancer-Associated Cellular Behaviors.

[0606] To further investigate the functional cellular effects of MG-CB2 on cancer-associated phenotypes, we performed a series of cell viability, cytotoxicity, proliferation, migration, and invasion assays in two cancer cell lines. Cell viability was initially evaluated following treatment with MG-CB2 or the CB1R antagonist rimonabant. Cytotoxicity was assessed using crystal violet staining, which labels DNA in adherent viable cells and allows quantification of total cellular biomass without altering protein levels in surviving cells. In MCF-7 cells, MG-CB2 exhibited pronounced cytotoxic activity across all tested concentrations, whereas rimonabant produced a weaker and statistically insignificant effect (Fig. 13A). To assess selectivity, healthy cells were treated with MG-CB2, and no significant reduction in cell viability was observed, indicating that the potent glue degrader preferentially affects cancer cells. These results underscore the advantage of targeted CB1R degradation over conventional receptor antagonism in reducing cancer cell viability. Consistent with these findings, MG-CB2 treatment also resulted in a significant suppression of cell proliferation in MCF-7 cancer cells compared with rimonabant (Fig. 13B), while exhibiting no measurable effect on the proliferation of healthy cells, underscoring its selective anti -proliferative activity. The antiproliferative and cytotoxic effects of MG-CB2 were further confirmed in HepG2 cells, where treatment led to a dose-dependent reduction in proliferation, accompanied by a measurable decrease in cell viability at 10 μM. Together, these data demonstrate thatMG-CB2 effectively impairs multiple cancer-associated cellular behaviors across distinct tumor cell lines.

[0607] To evaluate the impact of CB1R degradation on cancer cell motility, we examined the ability of the best degrader, MG-CB2, to suppress migratory behavior in MCF-7 cells. Cell migration was first assessed using a wound-healing assay, in which a scratch is introduced into a confluent monolayer to generate a defined gap and collective two-dimensional migration is monitored over time. This assay reflects coordinated cell movement driven by edge sensing and cell-cell interactions and is closely associated with the oncogenic phenotype of breast cancer cells. Following treatment, wound closure was monitored at 2 h intervals. Notably, MG-CB2 induced a pronounced and sustained inhibition of cell migration, as reflected by an approximately 80% reduction in wound density compared to untreated controls, even after 72 h of treatment. This indicates a markedly lower number of cells repopulating the wound area, demonstrating the strong anti-migratory activity of the degrader (Fig. 13C). To further validate these findings in a model that more closely recapitulates metastatic behavior, we performed an invasion assay, which measures individual cell chemotaxis through a three-dimensional porous membrane in response to a chemoattractant gradient. This assay better mimics metastatic dissemination, as cells must detach, traverse a physical barrier, and survive in suspension. MCF-7 cells were treated with MG-CB2, and invasion was monitored over a 5-day period. Strikingly, MG-CB2 almost completely abolished cell invasion, achieving close to 100% inhibition (Fig. 13D). Notably, the suppression of cancer-associated migratory and invasive behaviors became most evident at later time points (3-5 days), consistent with the catalytic and sustained nature of CB1R degradation. Collectively, these results highlight the superior efficacy of the molecular glue-based degrader and support its potential as a promising therapeutic strategy for limiting cancer cell migration and invasion.

[0608] CONCLUSION CB1R is increasingly recognized as an attractive therapeutic target in oncology due to its involvement in tumor progression and resistance to apoptotic cell death. In this study, we addressed this challenge by designing and synthesizing a series of CB1R-targeting molecular glues capable of selectively inducing CB1R degradation. Using rimonabant as the CBlR-binding ligand and incorporating cinnamamide or fumaratebased warheads to recruit E3 ubiquitin ligases, we generated a diverse library of bivalent molecular glue degraders with improved drug-like properties relative to PROTACs, which often require higher molecular weight architectures. Among these, the lead compound MG-CB2 efficiently promoted CB1R degradation. Mechanistic investigations and downstream pathway analyses demonstrated that MG-CB2 effectively disrupts CB1R signaling across its associated oncogenic pathways. Moreover, MG-CB2 exhibited robust antiproliferative and antimetastatic activity in cancer models and significantly suppressed cancer cell motility and migration. Collectively, these findings establish targeted degradation of CB1R as a viable and innovative therapeutic strategy in cancer, with the potential to overcome key limitations associated with conventional CB1R inhibitors. This work lays the foundation for the development of next-generation cannabinoid-based therapeutics that leverage targeted protein degradation to achieve enhanced efficacy and durability.

[0609] CHEMICAL SYNTHESIS PROCEDURES

[0610]

[0611] Scheme 1Compounds KT1-02, KT1-34, KT1-36 and KT1-08 were synthesized according to previously reported methods.

[0612] 1: 3 -fluorophthalic anhydride (1.5 g, 9 mmol, 1 eq) and 3- aminopiperidine-2, 6-dione hydrochloride salt (1.6 g, 9.75 mmol, 1.1

[0613]

[0614] equiv.) were dissolved in AcOH (20 mL) followed by potassium acetate (2.65 g, 27 mmol, 3 eq). The mixture was heated to 90 °C. The reaction time was 18 hours, the mixture was diluted with 50 mL water and cooled over ice. The precipitate was then centrifuged (2500 rpm, 10 minutes, 4 °C) and decanted. The remaining solid was then resuspended in water, centrifuged and decanted again. The grey crude solid was adsorbed to silica and column chromatography was performed with gradient from 5 to 70% Ethyl Acetate in Petroleum Ether to obtain white solid 1 (3.5g, 76%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C13H9FN2O4[M+H]+276: found 277, [M+Na]+found 299, [M+K]+found 314.

[0615] KT1-02: 1 (50 mg, 0.181 mmol, 1 equiv.) was dissolved in DMF (30 mL) and DIPEA (95 μL, 0.543 mmol, 3 equiv.) was added. N-Boc-Ethylenediamine (32 mg, 0.199 mmol, 1.1 eq) was

[0616]

[0617] separately dissolved in DMF (2 mL) and added to the reaction. Reaction mixture was heated to 60 °C for 3 hours. Reaction was cooled to room temprature, diluted with EtOAC (40 mL) and water (20 mL). After separation, the aqueous layer was extracted twice with EtOAc (40 mL). The combined organic layers were washed once with brine (40 mL), dried over MgSO4 and evaporated under reduced pressure. KT1-02 crude was dissolved in 50% TFA solution in DCM (10 mL) and reacted 1 hours at room temperature. After completion, volatiles were evaporated using nitrogen stream and purified using column chromatography from 0 to 5% MeOH in DCM to obtain KT1-02 as yellow solid (40 mg, 80%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C15H16N4O4[M+H]+316: found 317, [M+Na]+found 339, [M+K]+found 375.KT1-34: 1 (50 mg, 0.181 mmol, 1 equiv.) was dissolved in DMF (30 mL) and DIPEA (95 μL, 0.543 mmol, 3 equiv.) was added. N-Boc-l,4-diaminobutane ( 37.5 mg, 0.199 mmol, 1.1 eq) was separately dissolved in DMF (2 mL) and added to the reaction.

[0618]

[0619] Reaction mixture was heated to 60 °C for 3 hours. Reaction was cooled to room temprature, diluted with EtOAC (40 mL) and water (20 mL). After separation, the aqueous layer was extracted twice with EtOAc (40 mL). The combined organic layers were washed once with brine (40 mL), dried over MgSO4 and evaporated under reduced pressure. KT1-34 crude was dissolved in 50% TFA solution in DCM (10 mL) and reacted 1 hours at room temperature. After completion, volatiles were evaporated using nitrogen stream and purified using column chromatography from 0 to 5% MeOH in DCM to obtain KT1-34 as yellow solid (60 mg, 98%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C17H20N4O4[M+H]+344: found 345, [M+Na]+found 367.

[0620] KT1-36: 1 (50 mg, 0.181 mmol, 1 equiv.) was dissolved in DMF (30 mL) and DIPEA (95 μL, 0.543 mmol, 3 equiv.) was added. N-Boc-l,8-octanediamine ( 48.6 mg, 0.199 mmol, 1.1 eq) was separately dissolved in DMF (2 mL) and added to the reaction. Reaction mixture was heated to 60 °C for 3 hours. Reaction was

[0621]

[0622] cooled to room temprature, diluted with EtOAC (40 mL) and water (20 mL). After separation, the aqueous layer was extracted twice with EtOAc (40 mL). The combined organic layers were washed once with brine (40 mL), dried over MgSO4 and evaporated under reduced pressure. KT1-36 crude was dissolved in 50% TFA solution in DCM (10 mL) and reacted 1 hours at room temperature. After completion, volatiles were evaporated using nitrogen stream and purified using column chromatography from 0 to 5% MeOH in DCM to obtain KT1-36 as yellow solid (50 mg, 70%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C21H28N4O4[M+H]+400: found 401, [M+Na]+found 421, [M+K]+found 443.KT1-08: 1 (50 mg, 0.181 mmol, 1 equiv.) was dissolved in DMF (30 mL) and DIPEA (95 pL, 0.543 mmol, 3 equiv.) was added. N-Boc-Piperazine ( 37 mg, 0.199mmol, 1.1 eq) was separately dissolved in DMF (2 mL) and added to the reaction.

[0623]

[0624] Reaction mixture was heated to 60 °C for 3 hours. Reaction was cooled to room temprature, diluted with EtOAC (40 mL) and water (20 mL). After separation, the aqueous layer was extracted twice with EtOAc (40 mL). The combined organic layers were washed once with brine (40 mL), dried over MgSO4 and evaporated under reduced pressure. KT1-08 crude was dissolved in 50% TFA solution in DCM (10 mL) and reacted 1 hours at room temperature. After completion, volatiles were evaporated using nitrogen stream and purified using column chromatography from 0 to 5% MeOH in DCM to obtain KT1-08 as yellow solid (39 mg, 63%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C17H18N4O4[M+H]+342: found 343, [M+Na]+found 363, [M+K]+found 385.

[0625] KT3-06

[0626]

[0627] KT3-19

[0628] Scheme 2Compounds KT3-06, KT3-17, KT3-18, and KT3-19 were synthesized according to previously reported methods.

[0629] KT3-06: To a solution of 5-(4-chlorophenyl)- l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid (20 mg, 0.052 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (45 pl, 0.26 mmol, 5 equiv.),

[0630]

[0631] HATU (40 mg, 0.104 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then KT1-34 (18 mg, 0.052 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 4% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-06 (35 mg, 95%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C34H29Cl3N6O5[M+H]+707.99: found 709, [M+Na]+found 731, [M+K]+found 747. Analytical HPLC result showed 100% purity at 9.962 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) 58.01 (s, 1H), 7.52 - 7.46 (m, 1H), 7.46 - 7.41 (m, 1H), 7.34 - 7.27 (m, 4H), 7.09 (d, J= 7.4 Hz, 2H), 7.03 (d, J= 6.8 Hz, 2H), 6.90 (d, J= 8.5 Hz, 1H), 6.25 (t, J= 5.8 Hz, 1H), 5.01 - 4.74 (m, 1H), 3.41 (dd, J= 46.8, 6.1 Hz, 4H), 2.97 -2.56 (m, 3H), 2.37 (s, 3H), 2.18 -2.04 (m, 1H), 1.82 - 1.66 (m, 4H).

[0632] KT3-17: To a solution of 5-(4- chlorophenyl)- 1 -(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-carboxylic acid (20 mg, 0.043 mmol, 1 equiv.) in dry DMF (2 mL)

[0633]

[0634] DIPEA (45 pl, 0.215 mmol, 5 equiv.), HATU (34 mg, 0.086 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then KT1-36 (15 mg, 0.043 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). Thecombined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 4% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-17 (8 mg, 25%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C38H37Cl3N6O5[M+H]+764: found 765, [M+Na]+found 787, [M+K]+found 803. Analytical HPLC result showed the 95% purity at 9.278 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) 58.17 (s, 1H), 7.59 - 7.38 (m, 2H), 7.27 (dd, J= 5.0, 1.4 Hz, 5H), 7.14 - 7.00 (m, 3H), 6.98 (t, J= 6.0 Hz, 1H), 6.88 (d, J= 8.5 Hz, 1H), 6.23 (t, J= 5.5 Hz, 1H), 4.91 (dd, J= 11.8, 5.4 Hz, 1H), 3.41 (q, J= 6.8 Hz, 2H), 3.25 (q, J = 6.6 Hz, 2H), 3.03 - 2.54 (m, 3H), 2.37 (d, J= 1.1 Hz, 3H), 2.14 (dd, J= 9.7, 4.0 Hz, 1H), 1.31 (d, J = 32.6 Hz, 10H).

[0635] KT3-18: To a solution of 5-(4-chlorophenyl)-l- (2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid (20 mg, 0.056 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (47 pl, 0.28 mmol, 5 equiv.), HATU

[0636]

[0637] (44 mg, 0.112 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then KT1-02 (18 mg, 0.056 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 4% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-18 (11 mg, 30%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C32H25Cl3N6O5[M+H]+679.9: found 680, [M+Na]+found 703, [M+K]+found 719. Analytical HPLC result showed 100% purity at 7.027 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.60-7.37 (m, 2H), 7.35 -7.26 (m, 5H), 7.12 - 7.01 (m, 4H), 6.48 (t, J= 6.0 Hz, 1H), 5.01 - 4.77 (m, 1H), 3.62 (dt, J= 21.1, 6.2 Hz, 4H), 2.99 -2.62 (m, 3H), 2.38 (s, 3H), 2.15 (d, J= 35.5 Hz, 1H).KT3-19: To a solution of 5-(4-chlorophenyl)-l- (2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid (16 mg, 0.043 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (36 pl, 0.215 mmol, 5 equiv.), HATU (34 mg, 0.086 mmol, 2 equiv.) was added and

[0638]

[0639] stirred for 10 minutes at room temperature. Then KT1- 08 (15 mg, 0.043 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 4% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-19 (11 mg, 37%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C34H27Cl3N6O5[M+H]+705.98: found 706, [M+Na]+found 739, [M+K]+found 755. Analytical HPLC result showed the 100% purity at 6.963 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) 5 8.06 (s, 1H), 7.62 (dd, J = 8.3, 7.2 Hz, 1H), 7.45 (dd, J = 4.8, 2.5 Hz, 2H), 7.30 (td, J = 5.9, 5.4, 2.0 Hz, 2H), 7.22 - 7.15 (m, 2H), 7.08 (d, J= 8.5 Hz, 2H), 4.97 (dd, J = 12.1, 5.3 Hz, 1H), 4.08 (t, J= 9.7 Hz, 4H), 3.41 (q, J = 10.0, 7.5 Hz, 4H), 3.06 - 2.54 (m, 3H), 2.23 (s, 3H), 2.18 - 1.90 (m, 1H).

[0640]

[0641] KT3-25Scheme 3

[0642] Compounds KT3-24 and KT3-25 were synthesized according to previously reported methods.

[0643] KT3-24: To a solution of l-Boc-azetidine-3 -carboxylic acid (18 mg, 0.087 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (73 pl, 0.435 mmol, 5 equiv.), HATU (66 mg, 0.174 mmol, 2 equiv.) was added and stirred for 10 minutes at room

[0644]

[0645] temperature. Then KT1-34 (30 mg, 0.087 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 25% MeOH in DCM, to obtain KT3-26 (30 mg, 81%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C21H25N5O5[M+H]+427.46: found 428, [M+Na]+found 450, [M+K]+found 466.

[0646] KT3-25: To a solution of N-Boc-piperidine-4- carboxylic acid (17 mg, 0.07 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (60 pl, 0.360 mmol, 5 equiv.), HATU (55 mg, 0.144 mmol, 2 equiv.) was added and stirred for 10 minutes

[0647]

[0648] at room temperature. Then KT1-34 (25 mg, 0.072 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 25% MeOH in DCM, to obtain KT3-25 (30 mg, 93.7%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C23H29N5O5[M+H]+455: found 456, [M+Na]+found 478, [M+K]+found 594.

[0649]

[0650] Scheme 4

[0651] KT3-30: To a solution of 5-(4-chlorophenyl)- l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid (17 mg, 0.043 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (55 pl, 0.215 mmol, 5 equiv.), HATU (50 mg, 0.086 mmol, 2 equiv.) was added and

[0652]

[0653] stirred for 10 minutes at room temperature. Then KT3-25 (20 mg, 0.043 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 5% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-30 (4 mg, 8%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C40H38Cl3N7O6[M+H]+819: found 820, [M+Na]+found 843, [M+K]+found 859. Analytical HPLC result showed 99.87% purity at 8.804 minutes of retention time.1H NMR (300 MHz, Chloroform-d) δ 7.46 (dd, J= 17.0, 1.8 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.26 - 7.21 (m, 1H), 7.18 (s, 1H), 7.08 (s, 3H), 6.88 (d, J= 8.5 Hz, 1H), 5.67 (s, 1H), 5.01 - 4.59 (m, 2H), 4.42 (d, J= 13.5 Hz, 1H), 3.30 (d, J= 6.2 Hz, 4H), 2.82 (d, J= 30.7 Hz, 4H), 2.39 (s, 1H), 2.18 (s, 3H), 2.00 - 1.57 (m, 12H).KT3-31: To a solution of 5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3-carboxylic acid (27 mg, 0.07 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (59 pl, 0.35 mmol, 5 equiv.), HATU (53 mg, 0.14 mmol, 2

[0654]

[0655] equiv.) was added and stirred for 10 minutes at room temperature. Then KT3-24 (20 mg, 0.043 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 5% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-31 (8 mg, 15%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C34H27Cl3N6O5[M+H]+791: found 792, [M+Na]+found 814, [M+K]+found 830. Analytical HPLC result showed the 99% purity at 8.952 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) δ 8.46 (d, J= 10.8 Hz, 1H), 7.55 - 7.37 (m, 2H), 7.34 - 7.27 (m, 2H), 7.16 (d, J= 8.5 Hz, 1H), 7.06 (dd, J= 14.4, 7.8 Hz, 3H), 6.87 (d, J= 8.6 Hz, 1H), 6.21 (s, 1H), 5.91 (d, J= 6.2 Hz, 1H), 4.92 (dd, J= 10.8, 5.7 Hz, 1H), 4.68 (d, J = 7.4 Hz, 2H), 4.30 (d, J= 7.5 Hz, 2H), 3.29 (q, J= 7.0, 6.6 Hz, 4H), 2.82 (dt, J= 30.4, 11.2 Hz, 3H), 2.31 (s, 3H).Cl

[0656]

[0657] Scheme 5

[0658] KT3-41: To a solution of 5-Hexynoic acid (7 mg, 0.059 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (50 pl, 0.295 mmol, 5 equiv.), HATU (90 mg, 0.118

[0659]

[0660] mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then lH-Pyrazole-3-carboxamide, N-(2-aminoethyl)-5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- (ACI) (25 mg, 0.059 mmol, 1 equiv.) was added and stirred at room temperature for 2 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column

[0661]

[0662] chromatography from 0 to 20% MeOH in DCM to obtain KT3-41 (20 mg, 65%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C25H23Cl3N4O2[M+H]+517.84: found 518, [M+Na]+found 540, [M+K]+found 556.

[0663] KT3-42: To a solution of 4-Ethynylbenzoic acid (17 mg, 0.118 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (99 pl, 0.59 mmol, 5 equiv.), HATU (90 mg, 0.236 mmol, 2equiv.) was added and stirred for 10 minutes at room temperature. Then lH-Pyrazole-3- carboxamide, N-(2-aminoethyl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- (ACI) (50 mg, 0.118 mmol, 1 equiv.) was added and stirred at room temperature for 2 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 20% MeOH in DCM to obtain KT3-42 (54 mg, 84%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C28H21Cl3N4O2[M+H]+551.85: found 552, [M+Na]+found 574, [M+K]+

[0664]

[0665] KT1-04 Scheme 6

[0666] KT3-23: To a solution of 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (30 y— mg, 0.078 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (66 pl, ci— CJ / V'MX / 'N

[0667]

[0668] 0.39 mmol, 5 equiv.), HATU (60mg, 0.156 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then KT3-21(7 mg, 0.078 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layerswere washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 40% MeOH in DCM to obtain white solid KT3-23 (29 mg, 82%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C19H15Cl3N6O [M+H]+449: found 450, [M+Na]+found 473, [M+K]+found 489.

[0669] KT1-04: 1 (50 mg, 0.181 mmol, 1 equiv.) and Propargylamine (23 mg, 0.181 mmol, 1 equiv.) were mixed with DIPEA (82.72 μmL, 0.905mmol, 5 equiv.) in 2 mL DMF and stirred

[0670]

[0671] at 90°C temperature for 2 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 2% MeOH in DCM to obtain KT 1-04 (60 mg, 80%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C16H13N3O4[M+H]+310: found 311, [M+Na]+found 333.

[0672]

[0673] KT3-27

[0674] Scheme 7KT3-22: 1 (50 mg, 0.181 mmol, 1 equiv.) and KT3-21 (16 mg, 0.181 mmol, 1 equiv.) were mixed with DIPEA (82.72 μmL, 0.905mmol, 5 equiv.) in 2 mL DMF and stirred at 90°C temperature for 6 hours. After completion, the reaction was

[0675]

[0676] diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 2% MeOH in DCM to obtain KT3-21 (60 mg, 96%). The molecule was characterized by MALDI.

[0677] KT3-27: KT3-23 (16 mg, 0.047 mmol, 1 equiv.) and KT1-04 (20 mg, 0.047 mmol, 1 equiv.) were mixed with copper sulfate pentahydrate (3 mg, 0.047 mmol, 40%) and sodium ascorbate (3 mg,

[0678]

[0679] 0.047 mmol, 40%) in 2 mL DMF and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 2% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-27 (9 mg, 26The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C34H27Cl3N6O5[M+H]+791: found 792, [M+Na]+found 814, [M+K]+found 830. Analytical HPLC result showed the 97% purity at 8.952 minutes of retention time.

[0680] KT3-28: KT3-21 (9 mg, 0.027 mmol, 1 equiv.) and KT3-42 (20 mg, 0.027 mmol, 1 equiv.) were mixed with copper sulfate

[0681]

[0682] pentahydrate (3 mg, 0.027 mmol, 40%) and sodium ascorbate (2.5 mg, 0.027 mmol, 40%) in 2 mL DMF and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 2.5% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-27 (5 mg, 21%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C43H35Cl3N10O6[M+H]+894: found 895, [M+Na]+found 914, [M+K]+found 933. Analytical HPLC result showed the 99.2% purity at 8.77 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) δ 9.02 (s, 1H), 7.89 (d, J= 8.2 Hz, 2H), 7.85 - 7.77 (m, 3H), 7.71 (s, 1H), 7.49 (t, J= 7.8 Hz, 2H), 7.41 (d, J= 2.0 Hz, 1H), 7.30 (d, J= 2.4 Hz, 1H), 7.24 (d, J= 8.4 Hz, 1H), 7.14 (d, J= 7.1 Hz, 1H), 7.03 (d, J= 8.3 Hz, 2H), 6.85 (d, J= 8.5 Hz, 1H), 6.45 (t, J= 6.6 Hz, 1H), 4.89 (dd, J= 11.8, 5.5 Hz, 1H), 4.64 (q, J= 6.2 Hz, 2H), 4.02 - 3.48 (m, 6H), 3.00 - 2.54 (m, 3H), 2.35 (s, 3H), 2.17 - 2.02 (m, 1H).

[0683] KT3-29: KT3-21 (10 mg, 0.028 mmol, 1 equiv.) and KT3-42 (15 mg, 0.028 mmol, 1 equiv.) were mixed with

[0684]

[0685] copper sulfate pentahydrate (3 mg, 0.028 mmol, 40%) and sodium ascorbate (3 mg, 0.028 mmol, 40%) in 2 mL DMF and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 2% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-29 (2 mg, 8.3%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C40H37Cl3N10O6[M+H]+860: found 861, [M+Na]+found 883, [M+K]+found 899. Analytical HPLC result showed the 100% purity at 8.22 minutes of retention time.

[0686] 1H NMR (300 MHz, Chloroform-d) δ 9.30 (s, 1H), 7.47 (t, J= 7.8 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.29 (q, J= 2.8 Hz, 4H), 7.09 (dd, J= 25.2, 7.7 Hz, 3H), 6.76 (d, J= 8.5 Hz, 1H), 6.62 (s, 1H), 6.35 (t, J= 6.6 Hz, 1H), 4.99 - 4.83 (m, 1H), 4.54 (q, J= 5.8 Hz, 2H), 3.83 (d, J= 6.1 Hz, 2H), 3.50 (dt, J = 27.3, 6.0 Hz, 4H), 2.88 (d, J= 11.0 Hz, 1H), 2.84 - 2.71 (m, 2H), 2.68 (t, J= 13 Hz, 2H), 2.34 (s, 3H), 2.12 (t, J= 7.4 Hz, 3H), 1.93 - 1.82 (m, 3H).-

[0687] KT1.36

[0688] Scheme 8

[0689] KT3-35: To a solution of KT3-11 (30 mg, 0.049 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (41 pl, 0.245 mmol, 5 equiv.), HATU (37 mg, 0.098 mmol, 2

[0690]

[0691] equiv.) was added and stirred for 10 minutes at room temperature. Then KT1-36 (26 mg, 0.049 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 5% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-35 (3 mg, 6.7%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C44H47Cl3N8O7[M+H]+906: found 907, [M+Na]+found 929, [M+K]+found 935. Analytical HPLC result showed the 99.79% purity at 9.37 minutes of retention time.

[0692]

[0693] Scheme 9ck KT3-36: To a solution of 5-(4- y ft chlorophenyl)-l-(2,4-dichlorophenyl)-4- H methyl-lH-pyrazole-3-carboxylic acid (39

[0694]

[0695] o2 m& 0 102 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (66 pl, 0.39 mmol, 5 equiv.), HATU (60mg, 0.156 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then N-Boc-l,8-octanediamine (25 mg, 0.102 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 40% MeOH in DCM to obtain white solid KT3-10 (35 mg, 68%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C25H29Cl3N4O [M+H]+507.8: found 508, [M+Na]+found 530, [M+K]+found 516.

[0696] KT3-37: Solution of 1 (15 mg, 0.054 mmol, 1 equiv.) and KT3-36 (27 mg, 0.054 mmol, 1 equiv.) in was stirred 2 mL of DMF, at 60°C. DIPEA (27 pl, 0.162

[0697]

[0698] mmol, 3 equiv.) was added and stirred for 18 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 5% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-37 (2 mg, 5%). The molecule was characterized by MALDI, m / z: calculated for C38H37Cl3N6O5[M+H]+764: found 765, [M+Na]+found 787, [M+K]+found 803. Analytical HPLC result showed the 100% purity at 8.5 minutes of retention time.

[0699]

[0700] Scheme 10

[0701] KT3-44: To a solution of 5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3-carboxylic acid (20 mg, 0.052 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (36 pl,

[0702]

[0703] 0.262 mmol, 5 equiv.), HATU (40 mg, 0.104 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then KT5-07 VHL (22 mg, 0.052 mmol, 1 equiv.) was added and stirred at room temperature for 2 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 20% MeOH in DCM to obtain KT3-44 (10 mg, 24%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C39H39Cl3N6O4S [M+H]+794.19: found 795, [M+Na]+found 817, [M+K]+found 833.KT3-45: To a solution of 4-Ethynylbenzoic acid (10 mg, 0.069 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (48 pl, 0.348 mmol, 5 equiv.), HATU (52 mg, 0.139 mmol, 2 equiv.) was added and stirred for 10 minutes at room

[0704]

[0705] temperature. Then KT5-07 VHL (30 mg, 0.069 mmol, 1 equiv.) was added and stirred at room temperature for 2 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 20% MeOH in DCM to obtain KT3-45 (25 mg, 64%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C31H34N4O4S [M+H]+558.7: found 559, [M+Na]+found 582, [M+K]+found 598.

[0706] KT3-46: KT3-45 (25 mg, 0.044 mmol, 1 equiv.) and KT3-23 (20 mg, 0.044 mmol, 1 equiv.) were mixed with copper sulfate pentahydrate (5

[0707]

[0708] mg, 0.044 mmol, 40%) and sodium ascorbate (4 mg, 0.044 mmol, 40%) in 2 mL DMF and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 10% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3- 27 (10 mg, 22%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C50H49Cl3N10O5S [M+H]+1008.4: found 1009, [M+Na]+found 1031, [M+K]+found 1047. 'H NMR (300 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.88 (s, 1H), 7.75 (s, 2H), 7.69 (s, 2H), 7.36 (d, J= 3.6 Hz, 5H), 7.30 (s, 1H), 7.19 (d, J= 4.4 Hz, 2H), 7.03 (d, J= 8.2 Hz, 2H), 6.82 (d, J= 8.6 Hz, 1H), 4.83 - 4.70 (m, 2H), 4.70 - 4.63 (m, 2H), 4.62 - 4.54 (m, 2H), 4.36 (dd, J= 15.0, 5.3 Hz, 1H), 4.21 (d, J= 11.5 Hz, 1H), 3.99 (d, J= 6.3 Hz, 2H), 3.67 (d, J= 9.5 Hz, 1H), 2.53 (s, 3H), 2.36 (s, 3H), 2.17 (dd, J= 13.5, 8.2 Hz, 2H).Development of Molecular Glue Degraders Targeting CB1R

[0709] Chemical synthesis procedures

[0710] KT3-39

[0711] KT3-B3 Ct

[0712]

[0713] KT3-40

[0714] Scheme 11

[0715] KT3-02: To a solution of 3-[4- (Trifluoromethyl)phenyl]-2-propenoic acid (5 mg, 0.023 mmol, 1 equiv.) in dry DMF (2 mL)

[0716]

[0717] DIPEA (20 pl, 0.115 mmol, 5 equiv.), HATU (17 mg, 0.046 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then lH-Pyrazole-3 -carboxamide, N-(2-aminoethyl)-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl- (ACI) (10 mg, 0.023 mmol, 1 equiv.) was added and stirred at room temperature for 2 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 2% MeOH in DCM.Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-02 (10 mg, 71%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C29H22Cl3F3N4O2[M+H]+621.87: found 622, [M+Na]+found 643, [M+K]+found 660. Analytical HPLC result showed the 98.8% purity at 10.412 minutes of retention time.1H NMR (300 MHz, Chloroform-d) δ 7.59 (d, J= 4.1 Hz, 4H), 7.45 - 7.33 (m, 2H), 7.30 (dd, J = 8.6, 1.9 Hz, 3H), 7.15 - 6.89 (m, 3H), 6.51 (d, J = 15.7 Hz, 1H), 3.65 (h, J= 5.9, 4.8 Hz, 4H), 2.37 (s, 3H).

[0718] c\ KT3-03: To a solution of 3 -(4- AL Me o Methoxybenzoyl)acrylic acid (7.3 mg, 0.035 mmol,

[0719] 1equiv.) in dry DMF (2 mL) DIPEA (30 pl, 0.175

[0720]

[0721] mmol, 5 equiv.), HATU (13 mg, 0.07 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then lH-Pyrazole-3- carboxamide, N-(2-aminoethyl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- (ACI) (15 mg, 0.035 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 15% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-14 (2.2 mg, 5.6%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C30H25Cl3N4O4[M+H]+611.9: found 613, [M+Na]+found 635, [M+K]+found 651. Analytical HPLC result showed the 98% purity at 10.894 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) δ 8.09 - 7.89 (m, 3H), 7.44 - 7.34 (m, 2H), 7.30 (d, J= 8.2 Hz, 4H), 7.09 - 7.00 (m, 2H), 7.00 - 6.92 (m, 2H), 3.88 (s, 3H), 3.76 - 3.45 (m, 4H), 2.36 (s, 3H).

[0722] KT3-39: To a solution of 4- (Trifluoromethyl)hydrocinnamic acid (5 mg, 0.023 mmol, 1 equiv.) in dry DMF (2 mL)

[0723]

[0724] DIPEA (20 pl, 0.115 mmol, 5 equiv.), HATU (17 mg, 0.046 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then lH-Pyrazole-3 -carboxamide, N-(2-aminoethyl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- (ACI) (10 mg, 0.023 mmol, 1 equiv.) was added and stirred at room temperature for 2 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 2% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-39 (10 mg, 71%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C29H24Cl3F3N4O2[M+H]+623.88: found 624, [M+Na]+found 646, [M+K]+found 662. Analytical HPLC result showed the 100% purity at 10.147 minutes of retention time.1H NMR (300 MHz, Chloroform-d) δ 7.58 - 7.35 (m, 3H), 7.34 - 7.27 (m, 5H), 7.24 (d, J = 2.8 Hz, 1H), 7.10 - 7.00 (m, 2H), 3.60 - 3.35 (m, 4H), 3.01 (t, J= 7.7 Hz, 2H), 2.51 (dd, J= 8.6, 6.9 Hz, 2H), 2.35 (s, 3H).

[0725] Cl\ KT3-40: To a solution of 3-(4- A.y lf,!sT'0MeMethoxyphenyl)propanoic acid(5 mg, 0.023 \.MeH H J mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (20Cl\= < 'N^ Tf

[0726]

[0727] ci oHpl, 0.115 mmol, 5 equiv.), HATU (17 mg, 0.046 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then 1H-Pyrazole-3 -carboxamide, N-(2-aminoethyl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)- 4-methyl- (ACI) (10 mg, 0.023 mmol, 1 equiv.) was added and stirred at room temperature for 2 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 2% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-40 (10 mg, 71%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C30H27Cl3N4O4[M+H]+613.92: found 614, [M+Na]+found 636. Analytical HPLC result showed the 100% purity at 9.445 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) δ 7.43 (d, J= 2.0 Hz, 1H), 7.34 - 7.19 (m, 6H), 7.18 - 6.94 (m, 4H), 6.94 - 6.58 (m, 2H), 6.37 (s, 1H), 3.75 (s, 3H), 3.63 - 3.23 (m, 4H), 2.88 (dd, J= 8.8, 6.8 Hz, 2H), 2.46

[0728]

[0729] KT3-32: To a solution of 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (100 mg, 0.268 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (226 pl, 1.34 mmol, 5 equiv.), HATU (203 mg, 0.536 mmol,

[0730]

[0731] 2 equiv.) was added and stirred for 10 minutes at room temperature. Then N-Boc-piperazine (50 mg, 0.268 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was deprotected with 50% TFA / DCM for 1 hour. Then the crude was evaporated and purified using column chromatography from 0 to 25% MeOH in DCM, to obtain KT3-32 (110 mg, 92%). The molecule was characterized by MALDI.

[0732] KT3-33: To a solution of 3-[4- (Trifluoromethyl)phenyl]-2-propenoic acid (23 mg, 0.111 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (93 pl, 0.555 mmol, 5 equiv.),

[0733]

[0734] HATU (85 mg, 0.222 mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then KT3-32 (50 mg, 0.111 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated andpurified using column chromatography from 0 to 25% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-33 (12 mg, 17%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C31H24CI3F3N4O2 [M+H]+647.9: found 649, [M+Na]+found 671, [M+K]+found 687. Analytical HPLC result showed the 99.7% purity at 10.652 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) δ 7.77 – 7.57 (m, 5H), 7.47 (d, J= 2.2 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.25 (d, J = 2.2 Hz, 1H), 7.20 - 6.80 (m, 4H), 3.86 (q, J = 23.8, 22.4 Hz, 8H), 2.23 (s, 3H).

[0735] KT3-34: To a solution of 3-(4- Methoxybenzoyl)acrylic acid (22 mg, 0.111 mmol, 1 equiv.) in dry DMF (2 mL) DIPEA (93 pl, 0.555 mmol, 5 equiv.), HATU (84 mg, 0.222

[0736]

[0737] mmol, 2 equiv.) was added and stirred for 10 minutes at room temperature. Then KT3- 32 (50 mg, 0.111 mmol, 1 equiv.) was added and stirred at room temperature for 6 hours. After completion, the reaction was diluted with EtOAC (20 mL) and water (10 mL) for extraction. The aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were washed once with brine (10 mL), dried over MgSO4, and evaporated under reduced pressure. The crude product was evaporated and purified using column chromatography from 0 to 25% MeOH in DCM. Additional purification was done with HPLC 10-90% acetonitrile to obtain KT3-34 (12 mg, 17%). The molecule was characterized by MALDI, m / z: calculated for Chemical Formula: C32H27CI3N4O4 [M+H]+637.9: found 639, [M+Na]+found 661, [M+K]+found 677. Analytical HPLC result showed the 99.6% purity at 9.685 minutes of retention time. 'H NMR (300 MHz, Chloroform-d) δ 8.14 – 7.91 (m, 3H), 7.67 - 7.41 (m, 2H), 7.38 - 7.29 (m, 2H), 7.24 (d, J= 2.1 Hz, 1H), 7.21 - 6.85 (m, 5H), 3.88 (d, J= 8.3 Hz, 11H), 2.23 (s, 3H).RESULTS

[0738] Biological protocols

[0739] Cell Lines

[0740] The compounds were tested in the MCF7 human breast cancer cell line (ERpositive) and the MDA-MB-231 triple-negative breast cancer (TNBC) cell line.

[0741] Cell culture

[0742] All cells were maintained at 37 °C in an atmosphere of 5% CO2. MCF7 cells were cultured in a medium containing Earle's salts and L-glutamine, supplemented with 10% (v / v) fetal bovine serum (FBS; Sigma-Aldrich; F9665) and 1% penicillin / streptomycin solution (Diagnovum; D910). MDA-MB-231 cells were grown in a medium with L-glutamine, supplemented with 10 mM HEPES (Capricorn Scientific; HEP-B), 10% (v / v) FBS, and 1% penicillin / streptomycin solution.

[0743] Resazurin cell viability assay

[0744] MCF7 cells at 80% confluence in 96 well plates were treated with different synthesized compounds for 24 hr. The resazurin assay kit (Abeam, ab 129732) was used to analyze cell viability by incubating each sample with 20X cell viability solution for 4 hr prior to fluorometric analysis. The fluorescence resulting from reduction of resazurin to resorufin was measured with excitation and emission wavelengths of 530 and 570 nm, respectively using the Synergy Hl Hybrid Multi-Mode Microplate Reader (Biotek, Agilent). Cell viability was calculated as the percent increase in fluorescence of treated cells compared to fluorescence in untreated cells.

[0745] Proliferation assay

[0746] The WST-1 Assay Kit ab65475, also known as the Quick Cell Proliferation Assay Kit II, is designed for efficient cell proliferation studies. It includes WST Reagent (lyophilized; provided as 1 vial for 500 assays or 5 vials for 2500 assays), Electro Coupling Solution (ECS; 5 ml for 500 assays or 25 ml for 2500 assays), and Stop Solution (5 ml for 500 assays or 25 ml for 2500 assays). The kit should be stored at -20°C. To prepare the WST Solution, the lyophilized reagent was dissolved in ECS (5 ml for 500 assays or 25 ml for 2500 assays), aliquoted (1 ml per 96-well plate assay), and stored at -20°C. The prepared solution was stable for one year at -20°C or up to six months at +4°Cwhen protected from light and avoiding repeated freeze-thaw cycles, which may increase background. For the assay, cells were cultured at densities of 0.1 × 104to 5 x io4cells per well in a 96-well microtiter plate, with a final volume of 100 pl per well of culture medium. Cells are incubated for 24-96 hours in the absence or presence of test factors. After incubation, 10 pl of WST Solution was added to each well, avoiding bubbles, followed by an additional 0.5-4 hours of incubation under standard conditions. The absorbance of treated and untreated samples was measured at 420-480 nm using a microtiter plate reader, with a reference wavelength of -650 nm. Blank wells containing only culture medium and WST Solution were used to establish a baseline. The plate can be read multiple times until the optical density (OD) reaches 1.8. If needed, the reaction can be stopped by adding 10 pl of Stop Solution to each well and mixing thoroughly, with readings taken within 48 hours. Plates should be protected from light and evaporation.

[0747] Apoptosis assay

[0748] To perform the Caspase-Gio® 3 / 7 Assay, equilibrate the Caspase-Gio® 3 / 7 Buffer and lyophilized Substrate to room temperature. For the assay, we used a 1: 1 ratio of Caspase-Gio® 3 / 7 Reagent to sample volume. We mixed 100 pl of reagent with 100 pl of sample in a 96-well plate or 25 pl of each in a 384-well plate. Included blank reactions (reagent, vehicle, and medium without cells) to measure background luminescence, negative controls (vehicle-treated cells and reagent), and experimental assays (treated cells and reagent). Subtracted blank values from experimental results to account for background luminescence. Prepared controls to evaluate basal and induced caspase activity, as background caspase activity may arise from serum or untreated cells.

[0749] Gaussian luciferase reporter assay

[0750] The Secrete-Pair™ Gaussia Luciferase Assay Kit was utilized for the sensitive and stable measurement of GLuc activity. Initially, a plasmid containing the GLuc gene alongside the CB1R sequence was transfected into HEK293 cells. After 24-48 hours of incubation, the cells were treated with the degrader molecules for an additional 24 hours. Following treatment, 10-20 pl of culture medium containing secreted GLuc was collected into appropriate plates or tubes. The 10x GLuc Assay Buffer was thawed to room temperature and diluted to a 1× concentration using ddH₂O, preparing 50-100 pl per reaction. The GLuc working solution was prepared by mixing the GLuc substrate withthe 1× GLuc Assay Buffer immediately before use. This solution was protected from light and incubated at room temperature for 25 minutes. Subsequently, 50 pl of the working solution was added to each sample, gently mixed, and luminescence was measured using a luminometer set to a 1-2 second integration time.

[0751] To ensure accurate and reliable results, reagents were handled carefully to avoid contamination, and assay solutions were protected from light. Additionally, all samples and reagents were brought to room temperature before starting the assay. Duplicates or triplicates were used for each reaction to enhance result reliability.

[0752] General protocol for western blotting

[0753] MCF7 cells were grown in 6-well plates at about 60% confluency...

Claims

CLAIMS:

1. A compound comprising an E3 ubiquitin ligase recruiter moiety and a CB1R recognizing moiety, wherein said E3 ubiquitin ligase recruiter moiety and said CB1R recognizing moiety are associated directly or via a linker moiety.

2. The compound according to claim 1, for degrading of a CB1 receptor in vivo or in vitro.

3. The compound according to claim 1 or 2, wherein the E3 ubiquitin ligase recruiter moiety is selected from Hippel-Lindau (VHL) moiety, a pomalidomide-based recruiter (CRBN) moiety, a DC AF 15 moiety, a DC AF 16 moiety, a MDM2 moiety and a RING E3 ligase moiety.

4. The compound according to claim 2, wherein the E3 ligase recruiter moiety isCRBN-3, CRBN-4,DCAF15-2, cDCAF16-2,!RING 3, and RING 4, wherein each of the moi eties may be substituted.

5. The compound according to any one of the preceding claims, wherein the CB1R recognizing moiety is an optionally substituted aromatic, heteroaromatic, fused aromatic system, multicyclic aromatic or heteroaromatic, or heterocyclic ring system having optionally a substitution selected from amine, hydroxy, amide, carboxylic acid, ester, and ether.

6. The compound according to any one of the preceding claims, wherein the CB1R recognizing moiety comprises a heterocyclic or a heteroaryl ring system being an optionally substituted -Cs-Cioheterocyclic or an optionally substituted -Cs-Cioheteroaryl, wherein substitution is by a group selected from amine, hydroxy, amide, carboxylic acid, ester, ether, aryl, heteroaryl, and carbocyclic.

7. The compound according to claim 6, wherein the -Cs-Cioheterocyclic or -C3-Cioheteroaryl comprises one or more ring heteroatoms selected from N, O and / or S.

8. The compound according to claim 5 or 6, wherein the -Cs-Cioheterocyclic or -C3-Cioheteroaryl is selected amongst monocyclic, bicyclic or fused ring systems.

9. The compound according to claim 8, wherein monocyclic, bicyclic or fused ring systems are selected amongst substituted or unsubstituted indoles, substituted or unsubstituted pyrroles, substituted or unsubstituted imidazoles, substituted or a substituted pyrrolopyrdines, substituted or unsubstituted benzothiophenes, substituted or unsubstituted thieno pyridines, substituted or unsubstituted pyridines, substituted or unsubstituted piperidines, substituted or unsubscribed pyrazines, substituted or unsubstituted pyrazoles, substituted or unsubstituted triazoles.

10. The compound according to any one of the preceding claims, wherein the CB1R recognizing moiety is a substituted or an unsubstituted nitrogen-containing heterocycle or heteroaromatic ring structure.

11. The compound according to claim 10, wherein the CB1R recognizing moiety is a substituted or an unsubstituted nitrogen-containing heterocycle or heteroaromatic ring structure that is substituted by a -C₆-C₁₀aryl, a -C₃-C₁₀heteroaryl, a -C₁-C₅alkylene-C₆-C₁₀aryl, a -C₁-C₅alkylene-C₃-C₁₀heteroaryl and / or by a -C₃-C₁₀carbocyclic ring structure.

12. The compound according to claim 11, wherein the moiety selectively interactingsubstituted or unsubstituted, and wherein each R, independently, is a substitution on any carbon atom of the ring structure.

13. The compound according to any one of the preceding claims, wherein the CB1Rrecognizing moiety is selected from:o14. The compound according to any one of the preceding claims, wherein the E3 ubiquitin ligase recruiter moiety is any oneO' DCAF16-1,and RING 4, and the CB1R recognizing moiety is any one of15. The compound according to claim 13, wherein the E3 ubiquitin ligase recruiter moiety and the CB1R recognizing moiety are associated directly.

16. A compound selected from:

17. The compound according to any one of claims 1 to 15, wherein the E3 ubiquitin ligase recruiter moiety and the CB 1R recognizing and binding moiety are associated via a linker group.

18. The compound according to claim 17, wherein the linker group is an atom or group of atoms, optionally comprising one or more heteroatoms.

19. The compound according to claim 18, wherein the linker group is selected from aliphatic groups, aliphatic groups interrupted by one or more heteroatoms, alkyl or aryl ethers, amide groups, arylenes, heteroarylenes, disulfides, heterocyclic groups, sulfonamides and ureas, hydrazones, alkyl or aryl esters.

20. The compound according to claim 17 or 18, wherein the linker groups comprises at least one heteroaryl or heterocyclyl group.

21. The compound according to claim 20, wherein the linker group comprises one or more functionality selected from -ORa, -ON(Rb)2, -N(Rb)2, -N(Rb)3+, -N(ORc)Rb, -S-, -SRa, -SSRc, -C(=O)Ra, -CO2-, -C=O-, -C(ORc)2, -CO2Ra, -OC(=O)Ra, -OCO2Ra, -C(=O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbCO2Ra, -NRbC(=O)N(Rb)2, -C(=NRb)Ra, -C(=NRb)ORa, -OC(=NRb)Ra, -OC(=NRb)ORa, -C(=NRb)N(Rb)2, -OC(=NRb)N(Rb)2, -NRbC(=NRb)N(Rb)2, -C(=O)NRbSO2Ra, -NRbSO2Ra, -SO2N(Rb)2, -SO2Ra, -SO2ORa, -OSO2Ra, -S(=O)Ra, -OS(=O)Ra, -Si(Ra)3, -OSi(Ra)3 -C(=S)N(Rb)2, -C(=O)SRa, -C(=S)SRa, -SC(=S)SRa, -SC(=O)SRa, -OC(=O)SRa, -SC(=O)ORa, -SC(=O)Ra, -P(=O)(Ra)2, -P(=O)(ORc)2, -OP(=O)(Ra)2, -OP(=O)(ORc)2, -P(=O)(N(Rb)2)2, -OP(=O)(N(Rb)2)2, -NRbP(=O)(Ra)2, -NRbP(=O)(ORc)2, -NRbP(=O)(N(Rb)2)2, -P(Rc)2, -P(ORc)2, -P(Rc)3+, -P(ORc)3+, -P(Rc)4, -P(ORc)4, -OP(Rc)2, -OP(Rc)3+-, -OP(ORc)2, -OP(ORc)3+, -OP(Rc)4, -OP(ORc)4, -Cl-C20alkylene, Cl-C20perhaloalkylene, C2-C20alkenylene, C2-C20alkynylene,heteroCi -C20alkylene, heteroC2-C20alkenylene, heteroC2-C20alkynylene, C3-ClOcarbocyclylene, heterocyclylene, C6-C10arylene, -Cl-C20alkylene-C6-C10arylene, -Cl-C20alkylyne-0-C6-C10arylene, -Cl-C20alkylene-S-C6-C10arylene, -Cl-C20alkylene-NRb-C6-C 1 Oarylenewherein Ra is selected independently from Cl-C20alkyl, Cl-C20perhaloalkyl, Cl-C20alkenyl, Cl-C20alkynyl, heteroCi -C20alkyl, heteroCl-C20alkenyl, heteroCl-C20alkynyl, C3-C10carbocyclyl, heterocyclyl, C6-C10aryl, -Cl-C20alkylene-C6-C1 Oarylene, -Cl-C20alkylyne-O-C6-Cl Oarylene, -Cl-C20alkylene-S-C6-Cl Oarylene, -C l-C20alkylene-NRb-C6-C 1 Oarylene,wherein Rb is selected independently from hydrogen, -OH, -ORa, -N(Rc)2, -CN, -C(=O)Ra, -C(=O)N(Rc)2, -CO2Ra, -SO2Ra, -C(=NRc)ORa, -C(=NRc)N(Rc)2, -SO2N(Rc)2, -SO2Rc, -SO2ORc, -SORa, -C(=S)N(Rc)2, -C(=O)SRc, -C(=S)SRc, -P(=O)(Ra)2, -P(=O)(ORc)2, -P(=O)(N(Rc)2)2, Cl-C20alkyl, Cl-C20perhaloalkyl, Cl-C20alkenyl, Cl-C20alkynyl, heteroCl-C20alkyl, heteroCl-C20alkenyl, heteroCl-C20alkynyl, C3-C10carbocyclyl, heterocyclyl, C6-C10aryl, -Cl-C20alkylene-C6-C1 Oarylene, -Cl-C20alkylyne-O-C6-Cl Oarylene, -Cl-C20alkylene-S-C6-Cl Oarylene, -C l-C20alkylene-NRb-C6-C 1 Oarylene,wherein Rc is selected independently from hydrogen, Cl-C20alkyl, Cl-C20perhaloalkyl, C2-C20alkenyl, C2-C20alkynyl, heteroCl-C20alkyl, heteroC2-C20alkenyl, heteroC2-C20alkynyl, C3-C10carbocyclyl, heterocyclyl, C6-C10aryl; and wherein each of the aforementioned functionalities, where chemically appropriate, may be substituted by one or more groups selected from -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCl-C6alkyl, -ON(C1-C6alkyl)2, -N(Cl-C6alkyl)2, -N(C1-C6 alkyl)3+, -NH(C1-C6alkyl)2+, -NH2(C1-C6alkyl)+, -NH3+, -N(OCl-C6alkyl)(Cl-C6 alkyl), -N(OH)(C1-C6alkyl), -NH(OH), -SH, -SCl-C6alkyl, -SS(Cl-C6alkyl), -C(=O)(Cl-C6alkyl), -CO2H, -CO2(Cl-C6alkyl), -OC(=O)(Cl-C6alkyl), -OCO2(C1-C6alkyl), -C(=0)NH2, -C(=O)N(C1-C6alkyl)2, -OC(=O)NH(C1-C6alkyl), - NHC(=O)(C1-C6alkyl), -N(Cl-C6alkyl)C(=O)(Cl-C6alkyl), -NHCO2(C1-C6alkyl), -NHC(=O)N(C1-C6alkyl)2, -NHC(=O)NH(C1-C6alkyl), -NHC(=0)NH2, C(=NH)O(C1-C6alkyl), -OC(=NH)(C1-C6alkyl), -OC(=NH)OC1-C6alkyl, C(=NH)N(C1-C6alkyl)2, -C(=NH)NH(C1-C6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-C6alkyl)2, -OC(NH)NH(C1-C6alkyl), -0C(NH)NH2, -NHC(NH)N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -SO2NH(C1-C6alkyl),-SO2NH2, -SO2Cl-C6alkyl, -SO2OCl-C6alkyl, -OSO2Cl-C6alkyl, -S0Cl-C6alkyl, -Si(Cl-C6alkyl)3, -OSi(Cl-C6alkyl)3 -C(=S)N(C1-C6alkyl)2, C(=S)NH(C1-C6alkyl), C(=S)NH2, -C(=0)S(Cl-C6alkyl), -C(=S)SCl-C6alkyl, -SC(=S)SCl-C6alkyl, -P(=O)(OCl-C6alkyl)2, -P(=O)(Cl-C6alkyl)2, -OP(=O)(C1-C6 alkyl)2, -OP(=O)(OC1-C6alkyl)2, Cl-ClOalkyl, Cl-ClOperhaloalkyl, Cl-ClOalkenyl, Cl-ClOalkynyl, heteroCl-ClOalkyl, heteroCi -ClOalkenyl, heteroCl-ClOalkynyl, C3-C10carbocyclyl, C6-C10aryl, 3 to 10-membered heterocyclyl, or 5 to 10-membered heteroaryl; or two geminal substituents are joined to form =0 or =S.

22. The compound according to any one of claims 17 to 21, wherein the linker comprises one or more aromatic or a heteroaromatic group.

23. The compound according to claim 22, wherein the linker comprises a benzene group, a pyridine group, a pyrazole group, an imidazole group, a thiazole group, an oxadiazole group, a triazole group, an isoquinoline group, a quinoline group, an indole group, a pyrimidine group, and / or a tetrazole group.

24. The compound according to any one of claims 17 to 21, wherein the linker comprises one or more carbocyclic or heterocyclic ring structures.

25. The compound according to claim 24, wherein the ring structure is selected from 4-, 5-, 6-, 7- or 8-member carbocyclyl groups, pyrrolidine groups, imidazolidine groups, oxazolidine groups, thiazolidine groups, piperidine groups, morpholine groups, piperazine groups, aziridine groups, and oxetane groups.

26. The compound according to claim 23, wherein the linker comprises a group selected from triazoles and heterocyclic groups.

27. The compound according to any one of claims 17 to 21, wherein the linker comprises a heterocycle selected from aziridinylene, oxetanylene, thietanylene, indolylene, quinolinylene, isoquinolinylene, benzimidazolylene, benzothiazolylene, pyridinylene, pyrimidinylene, pyrazinylene, morpholinylene, piperidinylene, thiomorpholinylene, pyrrolylene, furanylene, thiophenylene, imidazolylene, triazolylene, oxazolylene, and thiazolylene.

28. The compound according to any one of the claims 17 to 27, wherein the linker isor comprises a group selected from29. The compound according to any one of the claims 17 to 28, wherein the E3 ubiquitin ligase recruiter moiety selected from Hippel-Lindau (VHL) recruiter moiety, a pomalidomide-based recruiter (CRBN) moiety, a DCAF15 recruiter moiety, a DCAF16 recruiter moiety, a MDM2 recruiter moiety and a RINGE3 ligase recruiter moiety; and a CB1R recognizing and binding moiety selected as herein; wherein the E3 ubiquitin ligase recruiter moiety and the CB1R recognizing moiety are bonded through a linker selected from aliphatic groups, aliphatic groups interrupted by one or more heteroatoms (such as polyethyene glycol), alkyl or aryl ethers, amide groups, arylenes, heteroarylenes, disulfides, heterocyclic groups, sulfonamides and ureas, hydrazones, alkyl or aryl esters.

30. The compound according to any one of claims 17 to 28, wherein the E3 ubiquitinligase recruiter moiety is selected from[f >:o Y”NHCRBN-2, ° ° CRBN-3,MDM2, DCAF15-1, DCAF15-2,RING 4, and is bonded through a linkergroup to a CB1R recognizing moiety selectedamongst aliphatic groups, aliphatic groups interrupted by one or more heteroatoms, alkyl or aryl ethers, amide groups, arylenes, heteroarylenes, disulfides, heterocyclic groups, sulfonamides and ureas, hydrazones, alkyl or aryl esters.

32. A compound according to any one of the preceding claims, for use in a method of degrading a CB 1 receptor.

33. The compound accoridng to claim 32, wherein the degradation comprises CB1R ubiquitination and subsequent proteasomal degradation within target tissues.

34. The compound according to claim 32 or 33, wherein the CB1R is degraded in vitro, in vivo or in situ.

35. A composition comprising a compound according to any one of claims 1 to 34.

36. The composition according to claim 35, being a pharmaceutical composition comprising further a pharmaceutically acceptable carrier.

37. A CB1R-targeted therapy, the therapy comprising administering a compound according to any one of claims 1 to 34 to a subject or to a target tissue to achieve degradation of the CB1R; wherein said degradation modulates physiological and pathological pathways associated with CB1 receptor signaling.

38. A composition for preventing or treating a disease or disorder affected by or driven by a CB1 receptor activity, the composition comprising a compound according to any one of claims 1 to 34.

39. The composition according to claim 38, wherein the disease or disorder is cancer, neuromuscular diseases, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases, metabolic disorders, infectious diseases, age-related conditions, and fibrotic diseases.

40. The composition according to claim 39, wherein the disease or disorder is cancer.

41. A method of therapeutic treatment of a subject suffering or expected to suffer from or at risk of developing a CB1R-driven disease or disorder, the method comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 34.

42. The method according to claim 41, wherein the disease or disorder is selected from cancer, neuromuscular diseases, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases, metabolic disorders, infectious diseases, age-related conditions, and fibrotic diseases.

43. The method accoridng to claim 42, wherein the disease or disorder is cancer.

44. The method according to claim 41, wherein the effective amount is sufficient to cause degradation of the CB1R in one or more tissues of the subject.

45. The method according to any one of claims 41 to 44, wherein the compound or a pharmaceutical composition comprising same is administered via an administration route selected from oral, parenteral, intravenous, subcutaneous, intramuscular, intraperitoneal, intrathecal, inhalational, transdermal, topical, intranasal, ocular, or localized delivery to a target tissue or organ.

46. A method of degrading or inactivating a CB 1 receptor in a tissue or a sample, the method comprising contacting said tissue or sample with a compound according to any one of claims 1 to 34, thereby inducing degradation.

47. The method according to claim 46, wherein the degradation is achieved in vitro.

48. The method according to claim 46, wherein the protein degradation is achieved in vivo by administering to a subject said compound.

49. A method of therapeutic treatment of a subject suffering or expected to suffer from or at risk of developing a CB1R-driven disease or disorder, the method comprising administering to said subject an effective amount of a compound selected from:

50. A method of degrading or inactivating a CB 1 receptor in a tissue or a sample, the method comprising contacting said tissue or sample with a compound selected from:

51. A compound for use in a method of degrading a CB1 receptor in vivo or in a biological sample, the compound selected from:

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