Cannabinoid conjugate molecules

Abstract

To provide multifunctional conjugate molecules in which at least one therapeutic agent is covalently attached to a cannabinoid by means of a linker.SOLUTION: The disclosed conjugate molecules are designed to deliver therapeutically beneficial conjugate molecule components and can be used to treat cancer and other disorders. The conjugate molecules comprise at least one therapeutic agent component covalently linked, directly or via a linker, to at least one cannabinoid component. In some embodiments, the conjugate molecules can contain an additional cannabinoid component.SELECTED DRAWING: None

Description

[Technical field]

[0001] Each document cited in this disclosure is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure relates generally to multifunctional therapeutic agents. [Background technology]

[0003] Detailed Description The present disclosure describes multifunctional conjugate molecules comprising at least one therapeutic agent moiety and at least one cannabinoid moiety covalently linked by a linker: [ka]

[0004] In contrast to traditional prodrugs, the disclosed conjugate molecule embodiments are designed to provide more than one therapeutic benefit through more than one mechanism of action; this therapeutic benefit is provided when the therapeutic component is covalently linked to its target, allowing the cannabinoid to be released at or near the therapeutic site of action, and then a second therapeutic benefit can be provided. That is, these conjugate molecules are designed to provide the therapeutic benefit of each of these components. In other embodiments, the therapeutic component and the cannabinoid component are released to provide their respective therapeutic benefit through the functionality of the linker.

[0005] For example, the formation of reactive oxygen species (ROS) is a by-product of normal respiratory processes in oxygen-rich environments (Storz & Imlay, Curr. Opin. Microbiol. 2, 188-94, 1999). There is valuable evidence in the literature regarding the role that endogenous ROS play in mutagenesis and their contribution to microbial mutation accumulation during oxidative stress (reviewed in Dwyer et al., Curr. Opin. Microbiol. 12, 482-89, 2009). Indeed, bacteria have evolved several enzymatic mechanisms to combat toxic ROS (Imlay, Ann. Rev. Biochem. 77, 755-76, 2008).

[0006] ROS are generated within cells and are converted into superoxide (O2· - ), hydrogen peroxide (H2O2), and the highly destructive hydroxyl radical (OH·). - and H2O2 can be enzymatically eradicated by the action of superoxide dismutase and catalase / peroxidase, respectively.

[0007] Excessive intracellular levels of ROS can damage proteins, nucleic acids, lipids, membranes, and organelles, thereby activating cell death processes such as apoptosis. Apoptosis is a tightly controlled and highly conserved cell death process during which cells undergo self-destruction (Kerr et al., Br. J. Cancer 26, 239-57, 1972). Apoptosis can be induced by a variety of exogenous and endogenous signals, including ROS (reviewed in Redza-Dutordoir & Averill-Bates, Biochem. Biophys. Acta 1863, 2977-92, 2016). Apoptosis can also be induced by exposure to xenobiotics such as antibiotics and chemotherapeutic drugs, and apoptosis is often mediated by ROS.

[0008] Cannabinoids have demonstrated the ability to promote ROS production. Cannabidiol (CBD), a non-toxic, non-psychotropic cannabinoid, has been shown to have antitumor activity in multiple cancer types (Massi et al., J. Pharmacol. Exp. Ther. 308, 838-45, e-pub 2003). Activation of endogenous cannabinoid type 1 (CB1) and type 2 (CB2) receptors has been shown to inhibit tumor progression (Velasco et al., Nat. Rev. Cancer 12, 436-44, 2012). CBD has been reported to inhibit the viability of human GBM in culture (an effect opposite to that in the presence of the ROS scavenger α-tocopherol / vitamin E) (Velasco et al., 2012).

[0009] It has been shown that CBD-dependent ROS production is accompanied by a decrease in glutathione, an important antioxidant that prevents damage to cellular components by ROS (Massi et al., Cell. Mol. Sci. 63, 2057-66, 2006). Part of the CBD-dependent stress originated from mitochondria and activated multiple caspases involved in the intrinsic and extrinsic apoptosis pathways. Further studies analyzing GBM tumor tissues treated with CBD revealed that inhibition of lipoxygenase signaling plays a role in the antitumor activity of CBD (McAllister et al., J. Neuroimmune Pharmacol. 10, 255-67, 2015). Furthermore, indirect modulation of the endocannabinoid system by CBD may contribute to the observed antitumor activity. Cannabigerol (CBG) is another non-psychotropic cannabinoid that interacts with specific targets involved in carcinogenesis and has shown potent antitumor activity (Guindon & Hohmann, Br. J. Pharmacol. 163, 1447-63, 2011). CBG appears to be mechanistically similar to CBD, influencing the inflammatory microenvironment important for carcinogenesis and cancer progression (Mantovani et al., Nature 454, 436-44, 2008; Solinas et al., Cancer Metastasis Rev. 29, 243-48, 2010). Furthermore, CBG could exert a proapoptotic effect by selectively increasing ROS production in colorectal cancer cells but not in healthy colon cells (Borrelli et al., Carcinogenesis 35, 2787-97, 2014). [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Storz&Imlay,Curr.Opin.Microbiol.2,188-94,1999 [Non-Patent Document 2] Dwyer et al.,Curr.Opin.Microbiol.12,482-89,2009 [Non-Patent Document 3] Imlay,Ann.Rev.Biochem.77,755-76,2008 [Non-Patent Document 4] Kerr et al.,Br.J.Cancer 26,239-57,1972 [Non-Patent Document 5] Redza-Dutordoir&Averill-Bates,Biochem.Biophys.Acta 1863,2977-92,2016 [Non-Patent Document 6] Massi et al.,J.Pharmacol.Exp.Ther.308,838-45,e-pub 2003 [Non-Patent Document 7] Velasco et al.,Nat.Rev.Cancer 12,436-44,2012 [Non-Patent Document 8] Massi et al.,Cell.Mol.Sci.63,2057-66,2006 [Non-Patent Document 9] McAllister et al.,J.Neuroimmune Pharmacol.10,255-67,2015 [Non-Patent Document 10] Guindon & Hohmann,Br.J.Pharmacol.163,1447-63,2011 [Non-Patent Document 11] Mantovani et al.,Nature 454,436-44,2008 [Non-Patent Document 12] Solinas et al.,Cancer Metastasis Rev.29,243-48,2010 [Non-Patent Document 13] Borrelli et al.,Carcinogenesis 35,2787-97,2014 Summary of the Invention [Means for solving the problem]

[0011] conjugated molecule The conjugate molecule comprises at least one therapeutic moiety covalently attached, either directly or via a linker, to at least one cannabinoid moiety.

[0012] In some embodiments, the therapeutic component is directly covalently attached to a hydroxy or carboxylic acid group of the cannabinoid component. In some embodiments, the cannabinoid conjugate component comprises a therapeutic component and a cannabinoid component linked by a linker, the linker being covalently attached at one end to the therapeutic component and at the other end to a hydroxy or carboxylic acid group of the cannabinoid component. In some embodiments, the hydroxy group is an "aromatic hydroxy group" (i.e., a hydroxy group directly attached to an aromatic hydrocarbon). In some embodiments, the hydroxy group is an "aliphatic hydroxy group" (i.e., a hydroxy group attached to a carbon that is not part of an aromatic ring).

[0013] In some embodiments, the conjugate molecule contains only one therapeutic moiety. In other embodiments, the conjugate molecule can contain two or more therapeutic moieties (which can be the same or different), for example, when the cannabinoid moiety has at least two hydroxy groups, or at least one hydroxy group and at least one carboxylic acid group, or at least two carboxylic acid groups.

[0014] In some embodiments where the therapeutic moiety is linked via a linker, the two or more linkers may be the same or different, and independently, the two or more therapeutic moieties may be the same or different. Also, independently, when the cannabinoid moiety contains two or more hydroxy groups, these two or more hydroxy groups may be aliphatic, or these two or more hydroxy groups may be aromatic, or, for example, a first hydroxy group may be aliphatic and a second hydroxy group may be aromatic.

[0015] In some embodiments, using certain types of linkers described below, the conjugate molecule can include two therapeutic moieties, both attached to a single linker. The two therapeutic moieties can be the same or different.

[0016] In some embodiments, the conjugated molecule may include an additional cannabinoid component.

[0017] The conjugate molecules can have one or more asymmetric centers and thus can be prepared as mixtures of isomers (e.g., racemic or diasteromeric mixtures) or in enantiomerically or diastereomerically pure form. Such forms include, but are not limited to, diastereomers, enantiomers, and atropisomers. The conjugate molecules can also contain alkenes and thus can be prepared as mixtures of double bond isomers or, independently, as either the E or Z form. Isotopic variants of the conjugate molecules can also be prepared.

[0018] The conjugated molecules can form salts. A "pharmaceutically acceptable salt" is a salt that retains at least some biological activity of the free (non-salt) compound and that can be administered to an individual as a drug or pharmaceutical. Such salts include, for example: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, and tartaric acid; (2) salts formed when any of the acidic protons present in the parent compound are replaced with a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharma- ceutical acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 Jan;66(1):1-19. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] definition The following definitions apply to the descriptions of "therapeutic moiety(s)" and "Linker", as well as the descriptions of "Group 1 Substituents" and "Group 2 Substituents" in the sections below.

[0020] "C1-C3 straight or branched alkyl" means "methyl, ethyl, propyl, and isopropyl."

[0021] "C1-C8 straight chain or branched alkyl" means "methyl, ethyl, C3, C4, C5, C6, C7, and C8 straight chain alkyls and C3, C4, C5, C6, C7, and C8 branched alkyls."

[0022] "C1-C3 straight or branched chain heteroalkyl" means "a straight or branched chain heteroalkyl containing 1, 2, or 3 carbon atoms."

[0023] "C1-C8 straight chain or branched heteroalkyl" means "each of C1, C2, C3, C4, C5, C6, C7, and C8 straight chain heteroalkyl and C1, C2, C3, C4, C5, C6, C7, and C8 branched heteroalkyl."

[0024] "C1-C12 straight chain or branched heteroalkyl" means each of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 straight chain heteroalkyl and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 branched heteroalkyl.

[0025] "C1-C24 straight chain or branched heteroalkyl" means each of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, and C24 straight chain heteroalkyl and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, and C24 branched heteroalkyl.

[0026] "C1-C6 straight or branched alkoxyl" means "straight or branched alkoxyl containing 1, 2, 3, 4, 5, or C carbon atoms."

[0027] "C1-C6 straight chain or branched alkylamino" means "straight chain or branched alkylamino containing 1, 2, 3, 4, 5, or 6 carbon atoms."

[0028] "C1-C6 straight-chain or branched dialkylamino" means "each straight-chain or branched dialkylamino in which each alkyl independently contains 1, 2, 3, 4, 5, or 6 carbon atoms."

[0029] The term "6- to 10-membered aromatic" means "each of 6-, 7-, 8-, 9-, and 10-membered aromatics."

[0030] "5- to 10-membered heteroaromatic" means "each of 6-, 7-, 8-, 9-, and 10-membered heteroaromatic."

[0031] "3- to 9-membered cycloheteroalkyl" means "respectively 3-, 4-, 5-, 6-, 7-, 8-, and 9-membered cycloheteroalkyl."

[0032] "C3-C6 cycloalkyl" means "C3, C4, C5, and C6 cycloalkyl."

[0033] "Halide" means "Cl, Br, and I."

[0034] "Group 1 Substituents" is the group of substituents consisting of: (a) -OH; (b)-NH2; (c)=O; (d)=S; (e) = NR7, where R7 is H or C1-C3 straight or branched alkyl, or C1-C3 straight or branched heteroalkyl containing O, N, or S atoms; (f) -C(O)OR4, where R4 is H or a C1-C3 straight chain or branched alkyl; (g) -C(O)NR5R6, where R5 and R6 are independently H or C1-C6 straight chain or branched alkyl; (h) halide; (i) C1-C6 linear or branched alkoxyl; (j) C1-C6 linear or branched alkylamino; (k) C1-C6 linear or branched dialkylamino; (l) a 6- to 10-membered aromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (i) phenyl; (ii) Halides; (iii) cyano; (iv) C1-C6 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (v) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; (m) a 5-10 membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (i) phenyl; (ii) Halides; (iii) cyano; (iv) C1-C6 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (v) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; (n) 3-9 membered cycloheteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, 3, or 4 substituents independently selected from: (i) phenyl; (ii) Halides; (iii) cyano; (iv) C1-C6 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (v) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (o) C3-C6 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (i) phenyl; (ii) Halides; (iii) cyano; (iv) C1-C6 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (v) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) 1, 2, or 3 substituents independently selected from Group 2 substituents.

[0035] "Group 2 Substituents" is the group of substituents consisting of: (a) -OH; (b)-NH2; (c)=O; (d)=S; (e) = NR7, where R7 is H or C1-C3 straight or branched alkyl, or C1-C3 straight or branched heteroalkyl containing O, N, or S atoms; (f) -C(O)OR4, where R4 is H or a C1-C3 straight chain or branched alkyl; (g) -C(O)NR5R6, where R5 and R6 are independently H or C1-C6 straight chain or branched alkyl; (h) halide; (i) Cyano; (j) trifluoromethyl; (k) C1-C6 linear or branched alkoxyl; (l) C1-C6 linear or branched alkylamino; (m) C1-C6 linear or branched dialkylamino; (n) 6- to 10-membered aromatic; and (o) 5-10 membered heteroaromatic groups containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S.

[0036] The above definitions apply to the following descriptions: For example, the phrase "R4 is H, or C1-C3 straight or branched alkyl" should be read to describe each of the five embodiments, respectively: R4 is H, R4 is methyl, R4 is ethyl, R4 is propyl, and R4 is isopropyl.

[0037] Therapeutic component(s) As used in this disclosure, a "therapeutic agent moiety" is a therapeutic portion or therapeutic segment of a therapeutic agent present in a conjugate molecule and covalently attached to a linker. Several therapeutic agents can be used to provide the therapeutic agent moiety of a conjugate molecule.

[0038] Epoxides In some embodiments, the therapeutic moiety is an epoxide.The following is an example of how cannabinoids can be released from conjugated molecules when epoxides are bound to targets.It is understood that the molecular structure of the target contains nucleophilic groups such as NH, OH and SH that can react with epoxide agents. [ka]

[0039] The epoxide component of the conjugated molecule has the following structure: [ka] Here, R a is absent or is a C1-C3 straight chain or branched alkyl, or a C1-C3 straight chain or branched heteroalkyl containing an O, N, or S atom. Carfilzomib is an example of an epoxide.

[0040] Aziridine In some embodiments, the therapeutic moiety is an aziridine. An example of how cannabinoids can be released from conjugated molecules upon binding of the aziridine to a target is shown below. It is understood that the molecular structure of the target contains nucleophilic groups such as NH, OH, and SH that can react with the aziridine agent. [ka]

[0041] The aziridine component of the conjugated molecule has the following structure: [ka]

[0042] Here, R a is absent or is a C1-C3 straight-chain or branched alkyl, or a C1-C3 straight-chain or branched heteroalkyl containing an O, N, or S atom; R b is R or -PS(NR c1 R c2 ) and R c1 and R c2 is independently a C1-C6 straight chain or branched alkyl, or a C1-C6 cycloalkyl, and R is selected from the group consisting of: (a) H; (b) C1-C8 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 1 substituents; (c) C1-C8 straight chain or branched heteroalkyl containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 1 substituents; (d) Phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: (1) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and / or (ii) one or two substituents independently selected from Group 2 substituents; and (2) C1-C6 straight or branched heteroalkyl containing 1 or 2 heteroatoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and / or (ii) one or two substituents independently selected from Group 1 substituents; (e) a 6- to 10-membered aromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (1) Phenyl; (2) Halides; (3) Cyano; (4) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents, and (5) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (f) 5-10 membered heteroaromatic rings containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (1) Phenyl; (2) Halides; (3) Cyano; (4) trifluoromethyl; (5) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents; and (6) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (g) optionally substituted with one, two, or three substituents independently selected from the group consisting of: [ka] (1) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (h) 3-9 membered cycloheteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: (1) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (2) C1-C6 straight or branched heteroalkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (3) phenyl optionally substituted with 1, 2, or 3 substituents independently selected from Group 2 substituents, and (4) a 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, or 3 substituents independently selected from Group 2 substituents; and (i) C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from: (1) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (2) C1-C6 straight or branched heteroalkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (3) phenyl optionally substituted with 1, 2, or 3 substituents independently selected from Group 2 substituents; and (4) A 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, or 3 substituents independently selected from Group 2 substituents.

[0043] In some embodiments, R is selected from the group consisting of: (a) H; (b) C1-C6 straight or branched alkyl optionally substituted with: (i) up to nine fluorine atoms (i.e., 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms); and / or (ii) up to three substituents selected from Group 1 substituents (i.e., 1, 2, or 3); (c) C1-C6 straight chain or branched heteroalkyl containing 1-3 heteroatoms (1, 2, or 3) independently selected from O, N, and S, optionally substituted with: (i) up to nine fluorine atoms; and / or (ii) up to three substituents selected from Group 1 substituents; (d) phenyl optionally substituted with 1 to 3 (i.e., 1, 2, or 3) substituents independently selected from the group consisting of: (i) C1-C6 straight or branched alkyl; and (ii) C1-C6 straight chain or branched heteroalkyl containing 1 or 2 heteroatoms independently selected from O, N, and S, and optionally substituted with 1-6 fluorine atoms (i.e., 1, 2, 3, 4, 5, or 6 fluorine atoms) and / or 1 or 2 substituents selected from Group 1 substituents and halides; and (e) optionally substituted with 1 to 3 substituents independently selected from the following: [ka] (i) C1-C6 straight or branched alkyl; and (ii) C1-C6 straight chain or branched heteroalkyl containing 1 or 2 heteroatoms independently selected from O, N, and S, and optionally substituted with 1-6 fluorine atoms and / or 1 or 2 substituents selected from Group 1 substituents. Sulfonate

[0044] In some embodiments, the therapeutic moiety is a sulfonate.An example of how cannabinoids can be released from conjugated molecules upon binding of sulfonate to target is shown below.It is understood that the molecular structure of the target contains nucleophilic groups such as NH, OH, and SH that can react with sulfonate agent.Although these examples utilize NH2 groups such as from lysine residues in both steps 1 and 2, it is understood that a completely different nucleophilic group on the target can be used to attack the linkage and release the cannabinoid in the second step. [ka]

[0045] The sulfonate component of the conjugate molecule has the following structure: [ka] Here, R d is either (a) a C1-C8 straight chain or branched alkyl optionally substituted with: (i) up to 9 fluorine atoms; and / or (ii) up to 3 substituents independently selected from Group 1 substituents; or (b) a phenyl optionally substituted with up to 3 substituents independently selected from the group consisting of C1-C6 straight chain or branched alkyl and (i) up to 6 fluorine atoms and / or 1 or 2 substituents independently selected from Group 2 substituents.

[0046] Halide In some embodiments, the therapeutic moiety is a halide.The following is an example of how cannabinoids can be released from conjugated molecules upon binding of halide to target.It is understood that the molecular structure of the target contains nucleophilic groups such as NH, OH and SH that can react with halide agents.Although these examples utilize NH2 groups such as from lysine residues in both steps 1 and 2, it is understood that a completely different nucleophilic group on the target can be used to attack the linkage and release the cannabinoid in the second step. [ka]

[0047] The halide component of the conjugate molecule has the structure [ka] where X is Cl, Br, or I.

[0048] Temozolomide and temozolomide analogs In some embodiments, the therapeutic moiety is temozolomide or an analog of temozolomide, which is a DNA methylating / alkylating agent: [ka]

[0049] An example of how cannabinoids can be released from conjugated molecules upon binding of temozolomide analogue moieties to targets is shown below.It is understood that the molecular structure of the target contains nucleophilic groups such as NH, OH and SH that can react with alkylating agents.In this example, NH2 groups from guanine systems and the like are used in both steps 1 and 2, but it is understood that completely different nucleophilic groups on the target can be used to attack the linkage and release the cannabinoid in the second step. [ka]

[0050] In some embodiments, the temozolomide analog moiety of the conjugate molecule has the structure [ka] In some embodiments, the temozolomide analog moiety of the conjugate molecule has the structure [ka] In some embodiments, the temozolomide analog moiety of the conjugate molecule has the following structure: [ka] Here, R x and R y is independently H or a C1-C3 straight chain or branched alkyl. In some embodiments, R x is H and R y is H. In some embodiments, R x is a C1-C3 linear or branched alkyl; R y is H. In some embodiments, R x and R y are both independently selected from C1-C3 straight or branched alkyl.

[0051] 5-Fluorouracil and 5-Fluorouracil Analogues In some embodiments, the therapeutic component is 5-fluorouracil (either alone or as part of a 5-fluorouracil-containing product, such as VERRUCA HERMAL (5-fluorouracil, salicylic acid)) or an analog of 5-fluorouracil: [ka]

[0052] The following is an example of how cannabinoid can be released from conjugated molecule when 5-fluorouracil analog moiety is bound to target.It is understood that the molecular structure of target contains nucleophilic groups such as NH, OH and SH that can react at 6-position of uracil system or its FdUMP metabolite.It is understood that the nucleophilic group that is bound to 6-position can be different from the nucleophilic group that reacts with cannabinoid in step 2 to release it. [ka] [ka]

[0053] In some embodiments, the therapeutic component is [ka] where: [ka] denotes a bond that covalently attaches the therapeutic moiety to the linker. In some embodiments, the therapeutic moiety is [ka] In some embodiments, the therapeutic moiety is [ka] In some embodiments, the therapeutic moiety is [ka] In these embodiments, the two cannabinoid components can be covalently linked to the therapeutic component via a linker. The two cannabinoid components can be the same or different; independently, the two linkers can be the same or different.

[0054] In some embodiments, the therapeutic component is [ka] wherein G1 is O, S, or NR. In some embodiments, the therapeutic moiety is [ka] In some embodiments, the therapeutic moiety is [ka] In some embodiments, the therapeutic moiety is [ka] wherein G1 and G2 are independently selected from O, S, and NR; in these embodiments, the two cannabinoid components can be covalently linked to the therapeutic component via a linker. The two cannabinoid components can be the same or different; independently, the two linkers can be the same or different.

[0055] In some embodiments, the therapeutic moiety is diclofenac or a diclofenac analog: [ka]

[0056] In some embodiments, the diclofenac component has the structure [ka] In some embodiments, the diclofenac component has the structure [ka] In some embodiments, the diclofenac component has the structure [ka] has.

[0057] Conjugates containing a diclofenac component can be administered alone or in combination with other diclofenac-containing products, such as, for example, MOBIZOX® (diclofenac, paracetamol, and chlozoxazone), SOLARAZE® (diclofenac sodium), Voltaren® (diclofenac sodium), VOLITRA® (benzyl alcohol, capsaicin, diclofenac diethylamine, linseed oil, menthol, methyl salicylate), VOLITRA® MR (diclofenac, thiocolchicoside), VOLITRA® PLUS (diclofenac diethylamine), VOLITRA® MR (diclofenac, thiocolchicoside ... dethylamine, linseed oil, methyl salicylate, menthol, eucalyptus oil), VOLITRA® S (diclofenac sodium ip, serratiopeptidase), FLEXURA® D (diclofenac potassium bp, metaxalone), MOBISWIFT® D (diclofenac, methoxolone), THIOACT® D (thiocochicoside, diclofenac sodium ip), etc.

[0058] In some embodiments, the therapeutic agent component is celecoxib (e.g., CELEBREX®) or an analog of celecoxib: [ka]

[0059] In some embodiments, the celecoxib component has the structure [ka] has.

[0060] In some embodiments, the therapeutic moiety is gemcitabine (e.g., Gemzar®) or an analog of gemcitabine: [ka]

[0061] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] has.

[0062] In some embodiments, the therapeutic moiety is emtricitabine (e.g., Descovy®, Biktarvy®, Emtriva®) or an analog of emtricitabine: [ka]

[0063] In some embodiments, the emtricitabine moiety has the structure [ka] In some embodiments, the emtricitabine moiety has the structure [ka] In some embodiments, the emtricitabine moiety has the structure [ka] has.

[0064] In some embodiments, the therapeutic moiety is entecavir (e.g., Baraclude®) or an analog of entecavir: [ka]

[0065] In some embodiments, the entecavir moiety has the following structure: [ka] has.

[0066] In some embodiments, the therapeutic moiety is axitinib (e.g., Inlyta®) or an analog of axitinib: [ka]

[0067] In some embodiments, the axitinib moiety has the structure [ka] has.

[0068] In some embodiments, the therapeutic component is batimastat or an analog of batimastat: [ka]

[0069] In some embodiments, the batimastat component has the structure [ka] has.

[0070] In some embodiments, the therapeutic moiety is bosutinib (e.g., Bosulif®) or an analog of bosutinib: [ka]

[0071] In some embodiments, the bosutinib moiety has the structure [ka] has.

[0072] In some embodiments, the therapeutic moiety is crizotinib (e.g., Xalkori®) or an analog of crizotinib: [ka]

[0073] In some embodiments, the crizotinib component has the structure [ka] In some embodiments, the crizotinib component has the structure [ka] In some embodiments, the crizotinib component has the structure [ka] has.

[0074] In some embodiments, the therapeutic moiety is erlotinib (e.g., Tarceva®) or an analog of erlotinib: [ka]

[0075] In some embodiments, the erlotinib component has the structure [ka] has.

[0076] In some embodiments, the therapeutic moiety is gefitinib (e.g., Iressa®) or an analog of gefitinib: [ka]

[0077] In some embodiments, the gefitinib moiety has the structure [ka] has.

[0078] In some embodiments, the therapeutic component is everolimus (e.g., ZORTRESS®, AFINITOR DISPERZ®, Afinitor®) or an analog of everolimus: [ka]

[0079] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] has.

[0080] In some embodiments, the therapeutic component is temsirolimus (e.g., Torisel®) or an analog of temsirolimus: [ka]

[0081] In some embodiments, the temsirolimus moiety has one of the following structures, where each arrow indicates a point at which a linker, as described below, can be attached. [ka] [ka] [ka] [ka] [ka]

[0082] In some embodiments, the therapeutic moiety is ganetespib or an analog of ganetespib: [ka]

[0083] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] has.

[0084] In some embodiments, the therapeutic component is glasdegib (e.g., Glasdegib®) or an analog of glasdegib: [ka]

[0085] In some embodiments, the glasdegib component has the structure [ka] has.

[0086] In some embodiments, the therapeutic moiety is imatinib (e.g., Gleevec®) or an analog of imatinib: [ka]

[0087] In some embodiments, the imatinib component has the structure [ka] In some embodiments, the imatinib component has the structure [ka] In some embodiments, the imatinib component has the structure [ka] has.

[0088] In some embodiments, the therapeutic moiety is lapatinib (e.g., Tykerb®) or an analog of lapatinib: [ka]

[0089] In some embodiments, the lapatinib moiety has the structure [ka] In some embodiments, the lapatinib moiety has the structure [ka] In some embodiments, the lapatinib moiety has the structure [ka] has.

[0090] In some embodiments, the therapeutic component is navitoclax or an analog of navitoclax: [ka] Navitoclax

[0091] In some embodiments, the navitoclax component has the structure [ka] In some embodiments, the navitoclax component has the structure [ka] In some embodiments, the navitoclax component has the structure [ka] has.

[0092] In some embodiments, the therapeutic moiety is nilotinib (e.g., Tasigna®) or an analog of nilotinib: [ka]

[0093] In some embodiments, the nilotinib component has the structure [ka] In some embodiments, the nilotinib component has the structure [ka] In some embodiments, the nilotinib component has the structure [ka] has.

[0094] In some embodiments, the therapeutic moiety is pazopanib (e.g., Opdivo®, Votrient®) or an analog of pazopanib: [ka]

[0095] In some embodiments, the pazopanib component has the structure [ka] In some embodiments, the pazopanib component has the structure [ka] In some embodiments, the pazopanib component has the structure [ka] has.

[0096] In some embodiments, the therapeutic moiety is luminespib or an analog of luminespib: [ka]

[0097] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] has.

[0098] In some embodiments, the therapeutic moiety is obatoclax or an analog of obatoclax: [ka]

[0099] In some embodiments, the obatoclax component has the structure [ka] In some embodiments, the obatoclax component has the structure [ka] In some embodiments, the obatoclax component has the structure [ka] has.

[0100] In some embodiments, the therapeutic moiety is ruxolitinib (e.g., JAKAFI®) or an analog of ruxolitinib: [ka]

[0101] In some embodiments, the ruxolitinib moiety has the structure [ka] has.

[0102] In some embodiments, the therapeutic moiety is salidegib (e.g., ODOMZO®) or an analog of salidegib: [ka]

[0103] In some embodiments, the salidegib component has the structure [ka] In some embodiments, the sari degib moiety has the structure [ka] In some embodiments, the sari degib moiety has the structure [ka] has.

[0104] In some embodiments, the therapeutic moiety is sunitinib (e.g., Sutent®) or an analog of sunitinib: [ka]

[0105] In some embodiments, the sunitinib component has the following structure: [ka] In some embodiments, the sunitinib moiety has the structure [ka] In some embodiments, the sunitinib moiety has the structure [ka] In some embodiments, the sunitinib moiety has the structure [ka] In some embodiments, the sunitinib moiety has the structure [ka] In some embodiments, the sunitinib moiety has the structure [ka] In some embodiments, the sunitinib moiety has the structure [ka] has.

[0106] In some embodiments, the therapeutic moiety is trametinib (e.g., Mekinist®) or an analog of trametinib: [ka]

[0107] In some embodiments, the trametinib moiety has the structure [ka] In some embodiments, the trametinib moiety has the structure [ka] In some embodiments, the trametinib moiety has the structure [ka] has.

[0108] In some embodiments, the therapeutic moiety is warfarin (e.g., COUMADIN®, JANTOVEN®) or a warfarin analogue: [ka]

[0109] In some embodiments, the warfarin component has the structure [ka] has.

[0110] In some embodiments, the therapeutic moiety is daclatasvir (e.g., DAKLINZA®) or an analog of daclatasvir: [ka]

[0111] Since daclatasvir is a symmetric drug, numerous polyconjugate structures are envisioned with up to at least four cannabinoid moieties linked to the parent drug. In some embodiments, the daclatasvir moiety is [ka] having cannabinoid moieties linked at one or more of sites (a), (b), (c), (d), (e), and (f) in any combination.

[0112] In some embodiments, the cannabinoid component is linked at site (a).

[0113] In some embodiments, the cannabinoid components are linked at site (a) and site (b). In some embodiments, the cannabinoid components are linked at site (a) and site (c). In some embodiments, the cannabinoid components are linked at site (a) and site (d). In some embodiments, the cannabinoid components are linked at site (a) and site (e). In some embodiments, the cannabinoid components are linked at site (a) and site (f).

[0114] In some embodiments, the cannabinoid components are linked at site (a), site (b), and site (c). In some embodiments, the cannabinoid components are linked at site (a), site (b), and site (d). In some embodiments, the cannabinoid components are linked at site (a), site (b), and site (e). In some embodiments, the cannabinoid components are linked at site (a), site (b), and site (f).

[0115] In some embodiments, the cannabinoid components are linked at site (a), site (c), and site (d). In some embodiments, the cannabinoid components are linked at site (a), site (c), and site (e). In some embodiments, the cannabinoid components are linked at site (a), site (c), and site (f).

[0116] In some embodiments, the cannabinoid components are linked at site (a), site (d), and site (e). In some embodiments, the cannabinoid components are linked at site (a), site (d), and site (f).

[0117] In some embodiments, the cannabinoid components are linked at positions (a), (e), and (f).

[0118] In some embodiments, the cannabinoid components are linked at site (a), site (b), site (c), and site (d). In some embodiments, the cannabinoid components are linked at site (a), site (b), site (c), and site (e). In some embodiments, the cannabinoid components are linked at site (a), site (b), site (c), and site (f).

[0119] In some embodiments, the cannabinoid components are linked at site (a), site (d), site (d), and site (e). In some embodiments, the cannabinoid components are linked at site (a), site (d), site (d), and site (f).

[0120] In some embodiments, the cannabinoid components are linked at position (a), position (d), position (e), and position (f).

[0121] In some embodiments, the cannabinoid components are linked at site (a), site (b), site (c), site (d), and site (e). In some embodiments, the cannabinoid components are linked at site (a), site (b), site (c), site (d), and site (f).

[0122] In some embodiments, the cannabinoid components are linked at site (a), site (b), site (c), site (d), site (e), and site (f).

[0123] In some embodiments, the cannabinoid component is linked at position (b).

[0124] In some embodiments, the cannabinoid components are linked at site (b) and site (c). In some embodiments, the cannabinoid components are linked at site (b) and site (d). In some embodiments, the cannabinoid components are linked at site (b) and site (e). In some embodiments, the cannabinoid components are linked at site (b) and site (f).

[0125] In some embodiments, the cannabinoid components are linked at site (b), site (c), and site (d). In some embodiments, the cannabinoid components are linked at site (b), site (c), and site (e). In some embodiments, the cannabinoid components are linked at site (b), site (c), and site (f).

[0126] In some embodiments, the cannabinoid components are linked at site (b), site (d), and site (e). In some embodiments, the cannabinoid components are linked at site (b), site (d), and site (f).

[0127] In some embodiments, the cannabinoid components are linked at positions (b), (e), and (f).

[0128] In some embodiments, the cannabinoid components are linked at site (b), site (c), site (d), and site (e). In some embodiments, the cannabinoid components are linked at site (b), site (c), site (d), and site (f).

[0129] In some embodiments, the cannabinoid components are linked at position (b), position (d), position (e), and position (f).

[0130] In some embodiments, the cannabinoid components are linked at position (b), position (c), position (d), position (e), and position (f).

[0131] In some embodiments, the cannabinoid component is linked at position (c).

[0132] In some embodiments, the cannabinoid components are linked at sites (c) and (d). In some embodiments, the cannabinoid components are linked at sites (c) and (e). In some embodiments, the cannabinoid components are linked at sites (c) and (f).

[0133] In some embodiments, the cannabinoid components are linked at site (c), site (d), and site (e). In some embodiments, the cannabinoid components are linked at site (c), site (d), and site (f).

[0134] In some embodiments, the cannabinoid components are linked at positions (c), (e), and (f).

[0135] In some embodiments, the cannabinoid components are linked at positions (c), (d), (e), and (f).

[0136] In some embodiments, the cannabinoid moiety is linked at position (d).

[0137] In some embodiments the cannabinoid components are linked at positions (d) and (e). In some embodiments the cannabinoid components are linked at positions (d) and (f).

[0138] In some embodiments, the cannabinoid components are linked at positions (d), (e), and (f).

[0139] In some embodiments, the cannabinoid component is linked at position (e).

[0140] In some embodiments, the cannabinoid components are linked at positions (e) and (f).

[0141] In some embodiments, the cannabinoid component is linked at position (f).

[0142] In some embodiments, the therapeutic moiety is etoposide (e.g., ETOPOPHOS®, TOPOSAR®) or an analog of etoposide: [ka]

[0143] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] has.

[0144] In some embodiments, the therapeutic moiety is atazanavir (e.g., Reyataz®) or an analog of atazanavir: [ka]

[0145] In addition to the OH group (or possibly the NH hydrazinyl group), either or both of the carbamates in the atazanavir may be linked to the cannabinoid moiety. In some embodiments, the atazanavir moiety has the structure [ka] In some embodiments, the atazanavir moiety has the structure [ka] has. [ka] In some embodiments, the atazanavir moiety has the structure [ka] In some embodiments, the atazanavir moiety has the structure [ka] In some embodiments, the atazanavir moiety has the structure [ka] has.

[0146] In some embodiments, the therapeutic moiety is pravastatin (e.g., PRAVACHOL®) or an analog of pravastatin: [ka]

[0147] Any or all of the three hydroxyl and carboxylic acid groups can be linked to the cannabinoid moiety. In some embodiments, the pravastatin moiety has the following structure: [ka] [ka] has one of the following:

[0148] In some embodiments, the therapeutic moiety is dasatinib (e.g., Sprycel®) or an analog of dasatinib: [ka]

[0149] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] has.

[0150] In some embodiments, the therapeutic moiety is didanosine (e.g., VIDEX®) or an analog of didanosine: [ka]

[0151] In some embodiments, the didanosine moiety has the structure [ka] In some embodiments, the didanosine moiety has the structure [ka] In some embodiments, the didanosine moiety has the structure [ka] has.

[0152] In some embodiments, the therapeutic moiety is stavudine (e.g., ZERIT®) or an analog of stavudine: [ka]

[0153] In some embodiments, the stavudine moiety has the structure [ka] In some embodiments, the stavudine moiety has the structure [ka] In some embodiments, the stavudine moiety has the structure [ka] has.

[0154] Additional therapeutic agents can be conjugated as described above, with examples shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0155] In any of the above embodiments in which two or more cannabinoid components may be linked, each cannabinoid component may be the same or different, and, if a linker is used, each linker may be the same or different.

[0156] Linker In some embodiments, the linker used to link the therapeutic and cannabinoid components is typically 2-10 atoms in length and is functionalized to facilitate release of the cannabinoid, which in some embodiments can occur approximately when the therapeutic is associated with its biological target.

[0157] A variety of linkers can be used within the conjugate molecule, examples are shown below. [ka] Where: [ka] denotes the bond where the linker is attached to the therapeutic moiety, and # indicates the site of covalent attachment to the cannabinoid moiety, where: Y, Y1, and Y2 are independently absent or Y, Y1, and Y2 are independently selected from the group consisting of: (a) C1-C12 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents selected from Group 1 substituents; (b) C2-C12 straight or branched alkenyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents selected from Group 1 substituents; (c) C1-C12 straight or branched heteroalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents selected from Group 1 substituents; (d) a 6- to 10-membered aromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (1) phenyl, (2) Halides, (3) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents, and (4) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (e) 6-10 membered heteroaromatic rings containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (1) phenyl, (2) Halides, (3) trifluoromethyl, (4) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents, and (5) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents; and (f) C1-C24 straight or branched heteroalkyl containing 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, 3, 4, 5, or 6 substituents selected from Group 1 substituents; Ar is one of the following: (a) a 6- to 10-membered aromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (1) phenyl, (2) Halides, (3) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; or (b) 6-10 membered heteroaromatic rings containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (1) phenyl, (2) Halides, (3) trifluoromethyl, (4) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents, and (5) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents; and R e , R f , and R g is independently R as defined above.

[0158] In other embodiments, several other types of linkers can be used, including self-cleaving linkers (such as acid-labile linkers and protease-labile linkers), linkers that contain negatively charged groups, and linkers that contain sugar moieties.

[0159] Examples of acid-labile linkers include acetals, hydrazones (including acylhydrazones, hydrazines), imines, esters, linkers containing disulfide bonds, and linkers containing pH-sensitive chelators. See, e.g., Vlahov & Leamon, Bioconjug. Chem. 23, 1357-69, 2012; Xiao et al., Nanoscale 4, 7185-93, 2012; Abu et al., Eur. J. Cancer 48, 2054-65, 2011; DiJoseph et al., Clin Cancer Res. 12, 242-49, 2006; Kale & Torchilin, Bioconjugate Chemistry 18, 363-70, 2007; Sawant et al., Bioconjugate Chemistry 17, 943-49, 2006; Reddy et al., Sci. Rep. 8, 8943, 2018.

[0160] Examples of protease labile linkers include linkers containing a valine-citrulline bond, β-glucuronic acid based linkers, and imides. For example, Weinstain et al.,Chem.Commun.(Camb.)46,553-55,2010;Shao et al.,Cancer 118,2986-96,2010;Liang et al.,J.Controlled Release 160,618-29,2012;Barthel et al. al.,J.Med.Chem.55,6595-607,2012;Nolting,Methods Mol.Biol.1045,71-100,2013;Erickson,Cancer Res.66,4426-33,2006;Jeffrey et al.,Bioconjugate Chem.17,831-40,2006;Dubowchik et al. al.,Bioconjugate Chem.13,855-69,2002;Mhidia et al. See, al., Org. Lett. 12, 3982-85, 2010.

[0161] Examples of linkers containing negatively charged groups are disclosed, for example, in Leamon et al., J. Pharm. Exp. Ther. 336, 336-43, 2011.

[0162] Examples of linkers containing sugar moieties are disclosed, for example, in Mikuni et al., Biol. Pharm. Bull. 31, 1155-58, 2008.

[0163] Other types of linkers include thioether-based linkers and N-succinimidyl-4-(N-maleimidylmethyl)cyclohexane-1-carboxylate (SMCC) linkers (see, e.g., Juarez-Hernandez et al., ACS Med. Chem. Lett. 3, 799-803, 2012), as well as linkers that contain an acetamide moiety and linkers that contain sulfur-containing amides or esters (Davaran et al., J. Pharm. Pharmacol. 55, 513-17, 2003).

[0164] Cannabinoid composition As used in this disclosure, a "cannabinoid moiety" is the portion of a cannabinoid that is present in a conjugate molecule and covalently attached to a linker, as shown in the example below. [ka]

[0165] The cannabinoid moiety can be obtained from any cannabinoid that contains a hydroxy group to which a linker can be attached or a therapeutic moiety can be covalently attached, or a carboxylic acid to which a linker can be linked by an ester bond, an amide bond, or a thioester bond.Cannabinoids can be isolated or synthesized naturally occurring molecules, or modified naturally occurring molecules.See, for example, Morales et al., Frontiers in Pharmacology June 2017 review, 1-18.

[0166] Examples of cannabinoids include, but are not limited to, cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol.

[0167] Examples of cannabigerol include cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerol (CBG), cannabigerol monomethyl ether (CBGM), cannabigerovaric acid (CBGVA), and cannabigerovarin (CBGV).

[0168] Examples of cannabichromenes include cannabichromenic acid (CBC), cannabichromene (CBC), cannabichromevaric acid (CBCVA), and cannabichromevarin (CBCV).

[0169] Examples of cannabidiols include cannabidiol acid (CBDA), cannabidiol (CBD), cannabidiol monomethyl ether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivaric acid (CBDVA), cannabidivarin (CBDV), and cannabidiolcol (CBD-C1).

[0170] Examples of tetrahydrocannabinols include Δ-9-tetrahydrocannabinolic acid A (THCA-A), Δ-9-tetrahydrocannabinolic acid B (THCA-B), Δ-9-tetrahydrocannabinol (THC), Δ-9-tetrahydrocannabinolic acid-C4 (THCA-C4), Δ-9-tetrahydrocannabinol-C4 (THC-C4), Δ-9-tetrahydrocannabivarinic acid (THCVA), Δ-9-tetrahydrocannabivarin (THCV), Δ-9-tetrahydrocannabinolic acid (THCA-C1), Δ-9-tetrahydrocannabiorcol (THC-C1), Δ-7-cis-tetrahydrocannabivarin, Δ-8-tetrahydrocannabinolic acid (Δ 8 -THCA), and Δ-8-tetrahydrocannabinol (Δ 8 -THC).

[0171] Examples of cannabicyclols include cannabicycloronic acid (CBLA), cannabicyclol (CBL), and cannabicyclovaline (CBLV).

[0172] Examples of cannabielsoins include cannabielsonic acid A (CBEA-A), cannabielsonic acid B (CBEA-B), and cannabielsoin (CBE).

[0173] Examples of cannabinols and cannabinodivalins include cannabinolic acid (CBNA), cannabinol (CBN), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabinol-C2 (CBN-C2), cannabiorcol (CBN-C1), cannabinodivalin (CBND), and cannabinodivalin (CBVD).

[0174] Examples of cannabidiols include cannabidiol (CBT), 10-ethoxy-9-hydroxy-Δ-6a-tetrahydrocannabinol, cannabidiol valine (CBTV), and ethoxy-cannabidiol valine (CBTVE).

[0175] Cannabifurans include dehydrocannabifuran (DCBF) and cannabifuran (CBF).

[0176] Examples of other cannabinoids include cannabichromanone (CBCN), 10-oxo-Δ-6a-tetrahydrocannabinol (OTHC), cannabilipsol (CBR), and trihydroxy-Δ-9-tetrahydrocannabinol (triOH-THC).

[0177] In some embodiments, the cannabinoid component is provided by cannabidiol.

[0178] Conjugate molecules containing two therapeutic moieties In some embodiments where the cannabinoid component has two hydroxyl groups, a second therapeutic component can be covalently attached to the second hydroxyl group by a second linker such that the conjugate molecule comprises a first therapeutic component and a second therapeutic component covalently attached to the cannabinoid component by a first linker and a second linker, respectively.

[0179] At least one of the linkers [ka] The conjugate molecule may include a second therapeutic agent covalently attached to the linker rather than to the cannabinoid moiety. In some embodiments, the first therapeutic agent moiety is covalently attached at Y2. In some embodiments, the first therapeutic agent moiety is covalently attached at Y1.

[0180] In conjugate molecules that contain two therapeutic moieties, the therapeutic moieties can be the same or different.

[0181] A conjugated molecule containing two cannabinoid components The therapeutic ingredient [ka] A conjugate molecule having the formula: may, for example, have a cannabinoid moiety covalently bound at both nitrogen atoms. In some embodiments, the two cannabinoid moieties are the same. In some embodiments, the two cannabinoid moieties are different.

[0182] Examples of conjugated molecules In the following examples, "CBN" is the cannabinoid component. The spatial arrangement of the cannabinoid is not shown in the examples, as it is generally understood that all stereoisomers are permitted. The examples showing the spatial arrangement do not exclude other isomers. The examples shown include linkers derived from ester, carbonate, and carbamate functional groups. Additional linkers as described above can also be used. Conjugated molecules containing a temozolomide analogue moiety [ka] Conjugated molecules containing a 5-fluorouracil analog moiety [ka] Conjugated molecules containing diclofenac moieties [ka] Conjugated molecules containing the celecoxib moiety [ka] Conjugated molecules containing gemcitabine moieties [ka] Conjugated molecules containing an axitinib moiety [ka] Conjugated molecules containing the batimastat moiety [ka] Conjugated molecules containing bosutinib moieties [ka] Conjugated molecules containing a crizotinib moiety [ka] Conjugated molecules containing an erlotinib moiety [ka] Conjugated molecules containing an everolimus moiety [ka] Conjugated molecules containing a ganetespib moiety [ka] Conjugated molecules containing glasdegib moieties [ka] Conjugated molecules containing an imatinib moiety [ka] Conjugated molecules containing lapatinib moieties [ka] Conjugated molecules containing navitoclax moieties [ka] Conjugated molecules containing a nilotinib moiety [ka] Conjugated molecules containing a luminespib (NVP-AUY922) component [ka] Conjugated molecules containing the obatoclax moiety [ka] Conjugated molecules containing a ruxolitinib moiety [ka] Conjugated molecules containing the salidegib moiety [ka] Conjugated molecules containing sunitinib moieties [ka] Conjugated molecules containing a trametinib moiety [ka] Conjugated molecules containing a warfarin moiety [ka] Conjugated molecules containing the daclatasvir moiety [ka] Conjugated molecules containing an etoposide moiety [ka] Conjugated molecules containing an atazanavir moiety [ka] Conjugated molecules containing a pravastatin moiety [ka] Conjugated molecules containing a dasatinib moiety [ka] [ka] Conjugated molecules containing a didanosine moiety [ka] Conjugated molecules containing a stavudine moiety [ka]

[0183] Examples of conjugated molecules containing epoxide, aziridine, sulfonate, or halide moieties Examples of conjugate molecules containing epoxide, aziridine, sulfonate, or halide moieties using various linker types are shown below. For simplicity, the cannabinoid moiety is a cannabidiol moiety linked to a single therapeutic moiety. "X" in some examples represents a halide (Cl, Br, or I). Carbamate Linker [ka] [ka] [ka] [ka] Carbonate Linker [ka] [ka] [ka] [ka] Xanthate Linker [ka] [ka] [ka] [ka] Ester Linker [ka] [ka] [ka] [ka] Thiocarbamate Linker [ka] [ka] [ka] [ka] Thiocarbonate Linker [ka] [ka] [ka]

[0184] Pharmaceutical Compositions, Routes of Administration, and Dosages One or more conjugate molecules (which may be the same or different) can be provided in a pharmaceutical composition with a pharma- ceutically acceptable vehicle. A "pharmaceutically acceptable vehicle" can include one or more substances that do not affect the biological activity of the conjugate molecule and do not cause side effects when administered to a patient. Excipients can be included, such as calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, and gelatin. Pharmaceutically acceptable vehicles for liquid compositions include, but are not limited to, water, saline, polyalkylene glycols (e.g., polyethylene glycol), vegetable oils, and hydrogenated naphthalenes. For example, biocompatible biodegradable polymers of lactide or copolymers of lactide / glycolide or polyoxyethylene / polyoxypropylene can be used to effect controlled release.

[0185] The method of preparing pharmaceutical compositions is well known. Pharmaceutical compositions can be prepared as solid, semi-solid or liquid (tablet, capsule, powder, granule, ointment, liquid, suspension, emulsion, suppository, injection, inhalant, gel, microsphere, aerosol and mist, etc.). Liquid pharmaceutical compositions can be lyophilized. Lyophilized compositions can be provided in kits with suitable liquid for reconstituting the composition, typically water for injection (WFI).

[0186] Typical routes of administration include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.

[0187] Dosages of the pharmaceutical compositions can be based on the dosages typically used for the particular therapeutic agent(s) that provide the therapeutic agent moiety(s) of the conjugate molecule. These dosages are well known in the art.

[0188] Treatment method The disclosed conjugate molecules have a variety of therapeutic uses depending on which therapeutic moiety(s) are contained within the conjugate molecule. As used in this disclosure, "treat" means to alleviate one or more symptoms or inhibit the progression of the disorder or disease (such as inflammation or pain) for which the conjugate molecule is administered.

[0189] In some come embodiments, the conjugate molecules are particularly useful for treating proliferative disorders, including cancer. For example, treating cancer can include inhibiting the progression of cancer, for example, by reducing the proliferation of neoplastic or preneoplastic cells; destroying neoplastic or preneoplastic cells; or inhibiting metastasis or reducing the size of tumors. Cancers that can be treated include multiple myeloma (including systemic light-chain amyloidosis and Waldenstrom's macroglobulinemia / lymphocytic plasmacytic lymphoma), myelodysplastic syndromes, myeloproliferative neoplasms, gastrointestinal malignancies (e.g., cancer of the esophagus, esophagogastric junction, gallbladder, stomach, colon, pancreas, hepatobiliary duct, anus, and rectum), leukemia (e.g., acute myeloid, acute myeloid, chronic myeloid, chronic myeloid, acute lymphocytic, acute lymphoblastic, chronic lymphocytic, and hairy cell leukemia), Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., B-cell lymphoma, hairy cell leukemia, primary cutaneous B-cell lymphoma, and T-cell lymphoma), lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), basal cell carcinoma, plasmacytoma, breast cancer, bladder cancer, kidney cancer. , neuroendocrine tumors, adrenal tumors, bone cancer, soft tissue sarcoma, head and neck cancer, thymoma, thymic carcinoma, cervical cancer, uterine cancer, ovarian cancer (e.g., fallopian tube carcinoma and primary peritoneal carcinoma), vaginal cancer, vulvar cancer, penile cancer, testicular cancer, prostate cancer, melanoma (e.g., cutaneous melanoma and uveal melanoma), non-melanoma skin cancer (e.g., basal cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, and squamous cell skin cancer), malignant pleural effusion melanoma, central nervous system (CNS) cancer (e.g., astrocytoma, oligodendroglioma, anaplastic glioma, glioblastoma, intracranial ependymoma, spinal ependymoma, medulloblastoma, CNS lymphoma, spinal cord tumor, meningioma, brain metastasis, leptomeningeal metastasis, metastatic spinal tumor), and cancer of unknown primary (i.e., cancer of unknown origin).

[0190] The conjugate molecules described herein can be administered in combination with one or more other cancer therapies, such as chemotherapy, immunotherapy, tumor-treating fields (TTF; e.g., the Optune® System), radiation therapy (XRT), and other therapies (e.g., hormones, autologous bone marrow transplant, stem cell reinfusion). "In combination with" includes administration simultaneously with, before, or after the administration of one or more other cancer therapies.

[0191] Chemotherapeutic agents include FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, irinotecan), FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan, oxaliplatin), irinotecan (e.g., CAMPTOSAR®), capecitabine (e.g., XELODA®), gemcitabine (e.g., Gemzar®), paclitaxel (e.g., AB RAXANE®), dexamethasone, lenalidomide (e.g., REVLIMID®), pomalidomide (e.g., POMALYST®), cyclophosphamide, regorafenib (e.g., STIVARGA®), erlotinib (e.g., TARCEVA®), ixazomib (e.g., NINLARO®), bevacizumab (e.g., AVASTIN®), bortezomib (e.g., VELCADE®, NEOMIB (registered trademark), (e.g., cefotaxime ... E®), 5-fluorouracil, RVD (lenalidomide, bortezomib, dexamethasone), pomalidomide (e.g., POMALYST®), temozolomide (e.g., TEMODAR®), PCV (procarbazine, lomustine, vincristine), methotrexate (e.g., TREXALL®, RASUVO®, XATMEP®), carmustine (e.g., BICNU®, GLIADEL®),WAFER®), etoposide (e.g., ETOPOPHOS®, TOPOSAR®), sunitinib (e.g., SUTENT®), everolimus (e.g., ZORTRESS®, AFINITOR®), rituximab (e.g., RITUXAN®, MABTHERA®), R-MPV (vincristine, procarbazine, rituximab), cytarabine (e.g., DEPOCYT®, CYTOSAR-U®), thiotepa (e.g., TEPADINA®), busulfan (e.g., BUSULFEX®, MYLERAN®), TBC (thiotepa, busulfan, cyclophosphamide), ibrutinib (e.g., IMBRUVICA®), topotecan (e.g., HYCAMTIN®), pemetrexed (e.g., ALI, MTA®), vemurafenib (e.g., ZELBORAF®), cobimetinib (e.g., COTELLIC®), dabrafenib (e.g., TAFINLAR®), trametinib (e.g., Mekinist®), alectinib (e.g., ALECENSA®), lapatinib (e.g., Tykerb®), neratinib (e.g., NERLYNX®), seriticinib (e.g., SERTINI®), These include, but are not limited to, nibs (e.g., ZYKADIA®), brigatinib (e.g., ALUNBRIG®), afatinib (e.g., GILOTRIF®, GIOTRIF®), gefitinib (e.g., IRESSA®), osimertinib (e.g., TAGRISSO®, TAGRIX®), and crizotinib (e.g., Xalkori®).

[0192] Immunotherapies include, but are not limited to, checkpoint inhibitors (including monoclonal antibodies such as ipilimumab (e.g., YERVOY®), nivolumab (e.g., OPDIVO®), pembrolizumab (e.g., KEYTRUDA®)); cytokines; cancer vaccines; and adoptive cell transfer.

[0193] In some embodiments, one or more of the above conjugated molecules are administered to a cancer patient, including any of the cancers listed above. In some embodiments, the patient has colon cancer, rectal cancer, pancreatic cancer, multiple myeloma, or glioblastoma multiforme, as described below, and the conjugated molecule(s) are administered in combination with an additional treatment appropriate for the particular cancer.

[0194] The disclosed conjugate molecules can be used to treat these and other disorders in the same manner that the therapeutic component of these molecules is used, and these methods are well known.For example, conjugate molecules that contain entecavir, emtricitabine, daclatasvir, atazanavir, didanosine, and / or stavudine can be used to treat viral infections; conjugate molecules that contain diclofenac or celecoxib components can be used as anti-inflammatory agents; conjugate molecules that contain warfarin components can be used as anticoagulants; conjugate molecules that contain pravastatin components can be used to treat cardiovascular disorders.However, the advantage of conjugate molecules is that cannabinoids can be delivered directly to the therapeutic action site, and the released cannabinoids at this site can provide additional therapeutic benefits.These therapeutic and potential benefits of cannabinoids are well known. See, e.g., Dzierzanowski, Cancers 11, 129-41, 2019 (oncology and palliative care); Urits et al., Pain Ther. 8, 41-51, 2019 (pain); Hillen et al., Ther. Adv. Drug Safety 10, 1-23 2019 (neuropsychiatric symptoms in dementia). EXAMPLES

[0195] Working Example The following synthetic procedures for various types and classes of compounds are general representative procedures for constructing the key functionalities of the compounds. Reagent systems, reaction conditions, and protecting group strategies may vary with any particular analog. The particular building blocks vary according to the particular product desired. Bromide compounds may be synthesized as the corresponding chloride or iodide compounds. The following procedures show cannabidiol (CBD) as a representative cannabinoid, but other cannabinoids containing a hydroxyl group may be substituted to produce other analogs.

[0196] Example 1. Epoxide-Containing Conjugated Molecules The epoxide carbamate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with phosgene (or a suitable phosgene substitute) and an aminoepoxide (in this example, [5689-75-8]) under standard basic conditions to form the desired carbamate linked product. [ka]

[0197] The epoxide carbonate-linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene substitute) and a hydroxy epoxide ([556-52-5] in this example) under standard basic conditions to form the desired carbonate-linked product. [ka]

[0198] Epoxide ester linked compounds are synthesized as follows: A cannabinoid (in this example, CBD) is esterified under standard conditions, in this example with an epoxy acid building block [86310-98-7], to give the desired product. [ka]

[0199] Epoxide imidate linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with an imide carbonyl chloride (in this case, [5652-90-4]) and a hydroxy epoxide ([556-52-5] in this example) under standard basic conditions to form the desired imidate linked product. [ka]

[0200] The epoxide isourea linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case [5652-90-4]) and an aminoepoxide ([5689-75-8] in this example) under standard basic conditions to form the desired isourea linked product. [ka]

[0201] The epoxide phosphorodiamide linked compound is synthesized as follows: Using conditions similar to those referenced in the scheme, N,N-dimethyl phosphoroamido dichloridate ([677-43-0]) is reacted with an aminoepoxide ([5689-75-8] in this example). The adduct is then reacted with a cannabinoid (CBD in this example) under standard basic conditions to form the desired product. [ka]

[0202] Epoxide S-alkylthiocarbonate linked compounds are synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and a thiol-epoxide ([45357-98-0] in this example) under standard basic conditions to form the desired S-alkylthiocarbonate linked product. [ka]

[0203] The epoxide thiocarbamate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and an aminoepoxide (in this example, [5689-75-8]) under standard basic conditions to form the desired thiocarbamate linked product. [ka]

[0204] The epoxide thiocarbonate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a hydroxy epoxide (in this example, [556-52-5]) under standard basic conditions to form the desired thiocarbonate linked product. [ka]

[0205] Epoxide thioimidate linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with an imide carbonyl chloride (in this case [5652-90-4]) and a thiol-epoxide ([45357-98-0] in this example) under standard basic conditions to form the desired thioimidate linked product. [ka]

[0206] The epoxidethiophosphinodiamide linked compound is synthesized as follows: Dimethyl phosphoramidothioic acid dichloride ([1498-65-3]) is reacted with an aminoepoxide ([5689-75-8] in this example) using conditions similar to those referenced in the scheme. The adduct is then reacted with a cannabinoid (CBD in this example) under standard basic conditions to form the desired product. [ka]

[0207] Epoxide xanthate-linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a thiol-epoxide (in this example, [45357-98-0]) under standard basic conditions to form the desired xanthate-linked product. [ka]

[0208] Example 2. Aziridine-containing conjugated molecules The aziridine carbamate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with phosgene (or a suitable phosgene substitute) and an aminoaziridine (in this example, [88714-40-3]) under standard basic conditions to form the desired carbamate linked product. [ka]

[0209] The aziridine carbonate linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene substitute) and a hydroxyaziridine ([25662-15-1] in this example) under standard basic conditions to form the desired carbonate linked product. [ka]

[0210] The aziridine ester linked compounds are synthesized as follows: the previously reported hydroxymethyl building block [126587-35-7] is treated with base (sodium hydride in this example) to generate an aziridinyl intermediate. The resulting amine, after removal of the BOC protecting group, is alkylated to give the alkylaziridine-ester intermediate. Standard hydrolysis of the ester gives the carboxylic acid precursor, which is esterified with a cannabinoid under standard esterification conditions to give the desired product. [ka]

[0211] Aziridine imidate linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with imidocarbonyl chloride (in this case [5652-90-4]) and hydroxyaziridine (in this example [25662-15-1]) under standard basic conditions to form the desired imidate linked product. [ka]

[0212] The aziridine isourea linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case [5652-90-4]) and an aminoaziridine (in this example [88714-40-3]) under standard basic conditions to form the desired isourea linked product. [ka]

[0213] The aziridine phosphorodiamide linked compound is synthesized as follows: Using conditions similar to those referenced in the scheme, N,N-dimethyl phosphoroamido dichloridate ([677-43-0]) is reacted with aminoaziridine (in this example [88714-40-3]). The adduct is then reacted with a cannabinoid (in this example CBD) under standard basic conditions to form the desired product. [ka]

[0214] The aziridine thiocarbamate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and an aminoaziridine (in this example, [88714-40-3]) under standard basic conditions to form the desired thiocarbamate linked product. [ka]

[0215] Aziridine thiocarbonate linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a hydroxyaziridine ([25662-15-1] in this example) under standard basic conditions to form the desired thiocarbonate linked product. [ka]

[0216] The aziridinethiophosphinodiamide linked compounds are synthesized as follows: Dimethyl phosphoramidothioic acid dichloride ([1498-65-3]) is reacted with aminoaziridine (in this example [88714-40-3]) using conditions similar to those referenced in the scheme. The adduct is then reacted with a cannabinoid (in this example CBD) under standard basic conditions to form the desired product. [ka]

[0217] The sulfonate carbamate linked compounds are synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene substitute) and an amino-alcohol ([156-87-6] in this example) under standard basic conditions to form a carbamate linked intermediate. Reaction with a sulfonyl chloride (mesyl chloride in this case) gives the desired product. [ka]

[0218] The sulfonate carbonate linked compounds are synthesized as follows: A diol compound (in this case 1,3-propanediol [13392-69-3]) is reacted with a sulfonyl chloride (in this case tosyl chloride) to give a monosulfonate intermediate. The remaining hydroxyl group in this intermediate is reacted with phosgene (or a suitable surrogate) and a cannabinoid (CBD in this example) under standard basic conditions to form the desired carbonate linked product. [ka]

[0219] The sulfonate ester linked compounds are synthesized as follows: the hydroxy acid starting material (in this case [13392-69-3]) is esterified under the conditions referenced for the selective esterification of aromatic OH in the presence of aliphatic OH. The ester linked intermediate is then subjected to sulfonylation (in this case with mesyl chloride) under the conditions referenced to give the desired product. [ka]

[0220] The sulfonate imidate linked compounds are synthesized as follows: A diol compound (in this case 1,3-propanediol [13392-69-3]) is reacted with a sulfonyl chloride (in this case tosyl chloride) to give a monosulfonate intermediate. The remaining hydroxyl group in this intermediate is reacted with an imidocarbonyl chloride (in this case [5652-90-4]) under standard basic conditions to form the desired imidate linked product. [ka]

[0221] The sulfonate isourea linked compound is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this example, [5652-90-4]) and an amino-alcohol (in this example, [156-87-6]) under standard basic conditions to form an isourea linked intermediate. Sulfonylation (in this case, using mesyl chloride) under reference conditions (see sulfonic acid esters above) gives the desired product. [ka]

[0222] The sulfonate phosphorodiamide linked compound is synthesized as follows. Using conditions similar to those referenced in the epoxide phosphorodiamide scheme, N,N-dimethyl phosphorodiamide dichloridate ([677-43-0]) is reacted with a cannabinoid (CBD in this example) and an amino-alcohol ([156-87-6] in this example). The adduct is then subjected to sulfonylation (using mesyl chloride in this case) under reference conditions (see sulfonate ester above) to obtain the desired product. [ka]

[0223] The sulfonate S-alkylthiocarbonate linked compounds are synthesized as follows: A cannabinoid (in this example, CBD) is reacted with phosgene (or a suitable phosgene surrogate) and a thiol-alcohol (in this example, [19721-22-3]) under standard basic conditions to form an S-alkylthiocarbonate linked intermediate. Sulfonylation (in this case with tosyl chloride) gives the desired product. [ka]

[0224] The sulfonate thiocarbamate linked compounds are synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene substitute) and an amino-alcohol ([156-87-6] in this example) under standard basic conditions to form a thiocarbamate linked intermediate. Sulfonylation (in this case with mesyl chloride) under reference conditions (see sulfonic acid esters above) gives the desired product. [ka]

[0225] The sulfonate thiocarbonate linked compounds are synthesized as follows: A diol compound (in this case 1,3-propanediol [13392-69-3]) is reacted with a sulfonyl chloride (in this case tosyl chloride) to give a monosulfonate intermediate. The remaining hydroxyl group in this intermediate is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a cannabinoid (CBD in this example) under standard basic conditions to form the desired thiocarbonate linked product. [ka]

[0226] The sulfonate thioimidate linked compound is synthesized as follows. Cannabinoid (CBD in this example) is reacted with imidocarbonyl chloride (in this example, [5652-90-4]) and thiol-alcohol (in this example, [19721-22-3]) under standard basic conditions to form a thioimidate linked intermediate. Sulfonylation (using tosyl chloride in this case) under reference conditions (see sulfonic acid esters above) gives the desired product. [ka]

[0227] The sulfonate thiophosphinodiamide linked compounds are synthesized as follows: Dimethyl phosphoramidothioic acid dichloride ([1498-65-3]) is reacted with a cannabinoid (CBD in this example) and an amino-alcohol ([156-87-6] in this example) using conditions similar to those referenced in the epoxide thiophosphinodiamide scheme. Sulfonylation of the adduct (in this case with mesyl chloride) under reference conditions (see sulfonate esters above) gives the desired product. [ka]

[0228] The sulfonate xanthate linked compounds are synthesized as follows: the cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene substitute) and a thiol-alcohol ([19721-22-3] in this example) under standard basic conditions to form a xanthate linked intermediate. Sulfonylation (in this case with mesyl chloride) under reference conditions (see sulfonic acid esters above) gives the desired product. [ka]

[0229] The halide carbamate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with phosgene (or a suitable phosgene substitute) and an amino halide (in this example, [18370-81-5]) under standard basic conditions to form the desired carbamate linked product. [ka]

[0230] The halide carbonate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with phosgene (or a suitable phosgene substitute) and a hydroxyalkyl halide (in this example, [627-18-9]) under standard basic conditions to form the desired carbonate linked product. [ka]

[0231] Halide ester linked compounds are synthesized as follows: A cannabinoid (in this example, CBD) is esterified under standard conditions, in this example with a haloalkyl acid building block [2067-33-6], to give the desired product. [ka]

[0232] Halide imidate linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case, [5652-90-4]) and a hydroxyalkyl halide ([627-18-9] in this example) under standard basic conditions to form the desired imidate linked product. [ka]

[0233] The halide isourea linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case, [5652-90-4]) and an aminoalkyl halide (in this example, [18370-81-5]) under standard basic conditions to form the desired isourea linked product. [ka]

[0234] Halide phosphorodiamide linked compounds are synthesized as follows: Using conditions similar to those referenced in the epoxide phosphorodiamide scheme, N,N-dimethyl phosphoroamido dichloridate ([677-43-0]) is reacted with a cannabinoid (CBD in this example) and an aminoalkyl halide ([18370-81-5] in this example) to form the desired product. [ka]

[0235] Halide S-alkylthiocarbonate linked compounds are synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene substitute) and a haloalkylthiol ([75694-39-2] in this example) under standard basic conditions to form the desired S-alkylthiocarbonate linked product. [ka]

[0236] The halide thiocarbamate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with thiophosgene (or a suitable thiophosgene substitute) and an aminoalkyl halide (in this example, [18370-81-5]) under standard basic conditions to form the desired thiocarbamate linked product. [ka]

[0237] The halide thiocarbonate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with thiophosgene (or a suitable thiophosgene substitute) and a hydroxyalkyl halide (in this example, [627-18-9]) under standard basic conditions to form the desired thiocarbonate linked product. [ka]

[0238] Halide thioimidate linked compounds are synthesized as follows: a cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case, [5652-90-4]) and a haloalkylthiol (in this example, [75694-39-2]) under standard basic conditions to form the desired thioimidate linked product. [ka]

[0239] The halide thiophosphinodiamide linked compounds are synthesized as follows: Using conditions similar to those referenced in the epoxide thiophosphinodiamide scheme, dimethyl phosphoramidothioic acid dichloride ([1498-65-3]) is reacted with a cannabinoid (CBD in this example) and an aminoalkyl halide ([18370-81-5] in this example) to form the desired product. [ka]

[0240] Halide xanthate linked compounds are synthesized as follows: a cannabinoid (in this example, CBD) is reacted with thiophosgene (or a suitable thiophosgene substitute) and a haloalkylthiol (in this example, [75694-39-2]) under standard basic conditions to form the desired xanthate linked product. [ka]

[0241] Compounds linked to a temozolomide moiety are synthesized as follows: an iodic acid [7425-27-6] is reacted with a cannabinoid (CBD) under standard esterification conditions to give an iodoester intermediate. The desired compound is generated by N-alkylation of [108030-65-5] following conditions similar to those published for the synthesis of temozolomide from iodomethane (see scheme). [ka]

[0242] The ester compound linked at the 1-position to a 5-fluorouracil moiety is synthesized as follows: A known building block [6214-60-4] is reacted with a cannabinoid (CBD) under standard esterification conditions to give the product. [ka]

[0243] The carbonate compound linked at the 1-position to a 5-fluorouracil moiety is synthesized as follows: The building block [106206-99-9] is reacted with phosgene (or a suitable surrogate) and CBD under standard basic conditions to give the product. [ka]

[0244] The carbamate compound linked at the 1-position to a 5-fluorouracil moiety is synthesized as follows: The building block [1339797-10-2] is reacted with phosgene (or a suitable surrogate) and CBD under standard basic conditions to give the product. [ka]

[0245] The ester compound linked at the 3-position to a 5-fluorouracil moiety is synthesized as follows: A known building block [905265-53-4] is reacted with a cannabinoid (CBD) under standard esterification conditions to give the product. [ka]

[0246] The carbonate compound linked at the 3-position to a 5-fluorouracil moiety is synthesized as follows: The building block [948036-30-4] is reacted with phosgene (or a suitable surrogate) and CBD under standard basic conditions to give the product. [ka] The present invention provides, for example, the following items. (Item 1) A conjugate molecule, or a pharma- ceutically acceptable salt thereof, comprising a first therapeutic moiety and a first cannabinoid moiety, said first therapeutic moiety being covalently attached to said first cannabinoid moiety, either directly or via a linker to a first linker, wherein: (A) the first therapeutic agent component is selected from the group consisting of: (1) [ka] Here, R a is absent or is a C1-C3 straight chain or branched alkyl, or a C1-C3 straight chain or branched heteroalkyl containing O, N, or S atoms; (2) [ka] Here, R a is as defined above, and R b is R or -PS(NR c1 R c2 ) and R c1 and R c2 is independently a C1-C6 straight chain or branched alkyl, or a C1-C6 cycloalkyl, and R is selected from the group consisting of: (a) H; (b) C1-C8 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 1 substituents; (c) C1-C8 straight chain or branched heteroalkyl containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 1 substituents; (d) Phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: (1) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and / or (ii) one or two substituents independently selected from Group 2 substituents; and (2) C1-C6 straight or branched heteroalkyl containing 1 or 2 heteroatoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and / or (ii) one or two substituents independently selected from Group 1 substituents; (e) a 6- to 10-membered aromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (1) Phenyl; (2) Halides; (3) Cyano; (4) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents, and (5) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (f) 5-10 membered heteroaromatic rings containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (1) Phenyl; (2) Halides; (3) Cyano; (4) trifluoromethyl; (5) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents; and (6) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (g) optionally substituted with one, two, or three substituents independently selected from the group consisting of: [ka] (1) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (h) 3-9 membered cycloheteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: (1) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (2) C1-C6 straight or branched heteroalkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (3) phenyl optionally substituted with 1, 2, or 3 substituents independently selected from Group 2 substituents, and (4) a 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, or 3 substituents independently selected from Group 2 substituents; and (i) C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from: (1) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (2) C1-C6 straight or branched heteroalkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (3) phenyl optionally substituted with 1, 2, or 3 substituents independently selected from Group 2 substituents; and (4) a 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, or 3 substituents independently selected from Group 2 substituents; Group 1 substituents are the group of substituents consisting of: (a) -OH; (b)-NH2; (c)=O; (d)=S; (e) = NR7, where R7 is H or C1-C3 straight or branched alkyl, or C1-C3 straight or branched heteroalkyl containing O, N, or S atoms; (f) -C(O)OR4, where R4 is H or a C1-C3 straight chain or branched alkyl; (g) -C(O)NR5R6, where R5 and R6 are independently H, or C1-C6 straight chain or branched alkyl; (h) halide; (i) C1-C6 linear or branched alkoxyl; (j) C1-C6 linear or branched alkylamino; (k) C1-C6 linear or branched dialkylamino; (l) a 6- to 10-membered aromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (i) phenyl; (ii) Halides; (iii) cyano; (iv) C1-C6 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (v) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; (m) a 5-10 membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (i) phenyl; (ii) Halides; (iii) cyano; (iv) C1-C6 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (v) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; (n) 3-9 membered cycloheteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, 3, or 4 substituents independently selected from: (i) phenyl; (ii) Halides; (iii) cyano; (iv) C1-C6 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (v) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (o) C3-C6 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (i) phenyl; (ii) Halides; (iii) cyano; (iv) C1-C6 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; and (v) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents independently selected from Group 2 substituents; Group 2 substituents are the group of substituents consisting of: (a) -OH; (b)-NH2; (c)=O; (d)=S; (e) = NR7, where R7 is H or C1-C3 straight or branched alkyl, or C1-C3 straight or branched heteroalkyl containing O, N, or S atoms; (f) -C(O)OR4, where R4 is H or a C1-C3 straight chain or branched alkyl; (g) -C(O)NR5R6, where R5 and R6 are independently H or C1-C6 straight chain or branched alkyl; (h) halide; (i) Cyano; (j) trifluoromethyl; (k) C1-C6 linear or branched alkoxyl; (l) C1-C6 linear or branched alkylamino; (m) C1-C6 linear or branched dialkylamino; (n) 6- to 10-membered aromatic; and (o) 5-10 membered heteroaromatic rings containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; (3) [ka] Here, R d is: (a) C1-C8 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 1 substituents; or (b) phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and / or (ii) one or two substituents independently selected from Group 2 substituents; (4) [ka] where X is Cl, Br, or I; (5) [ka] Here, R x and R y are independently H or C1-C3 straight chain or branched alkyl; (6) [ka] wherein G1 and G2 are independently selected from the group consisting of O, S, and NR; and (7) Diclofenac components, celecoxib components, gemcitabine components, entecavir components, emtricitabine components, axitinib components, batimastat components, bosutinib components, crizotinib components, erlotinib components, gefitinib components, erlotinib components, everolimus components, temsirolimus components, ganetespib components, glasdegib components, imatinib components, lapatinib components a therapeutic agent component selected from the group consisting of a navitoclax component, a nilotinib component, a pazopanib component, a component, a luminespib component, an obatoclax component, a ruxolitinib component, a salidegib component, a sunitinib component, a trametinib component, a warfarin component, a daclatasvir component, an etoposide component, an atazanavir component, a pravastatin component, a dasatinib component, a didanosine component, and a stavudine component; (B) the first linker is selected from the group consisting of: [ka] Where: [ka] denotes the bond through which a type (Ib) linker is attached to the therapeutic moiety, and # indicates the site of covalent attachment to the cannabinoid moiety, where: Y, Y1, and Y2 are independently absent or Y, Y1, and Y2 are independently selected from the group consisting of: (a) C1-C12 straight or branched alkyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents selected from Group 1 substituents; (b) C2-C12 straight or branched alkenyl optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents selected from Group 1 substituents; (c) C1-C12 straight or branched heteroalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, and optionally substituted with: (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (2) one, two, or three substituents selected from Group 1 substituents; (d) a 6- to 10-membered aromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (1) phenyl, (2) Halides, (3) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents, and (4) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) one, two, or three substituents independently selected from Group 2 substituents; (e) 6-10 membered heteroaromatic rings containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: (1) phenyl, (2) Halides, (3) trifluoromethyl, (4) C1-C6 straight or branched alkyl optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents, and (5) C1-C6 straight or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, or 3 substituents independently selected from Group 2 substituents; and (f) C1-C24 straight or branched heteroalkyl containing 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms independently selected from O, N, and S, and optionally substituted with: (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and / or (ii) 1, 2, 3, 4, 5, or 6 substituents selected from Group 1 substituents; (2) R1, R2, and R3 are independently R as defined above, or a pharma- ceutically acceptable salt thereof. (Item 2) 2. The conjugated molecule of claim 1, wherein the first therapeutic agent moiety is covalently attached to the first cannabinoid moiety via a first linker. (Item 3) 2. The conjugated molecule of claim 1, wherein the first linker is covalently attached to a first carboxylic acid group of the first cannabinoid component. (Item 4) 3. The conjugated molecule of claim 2, wherein the first therapeutic agent moiety is covalently bonded to a first hydroxy group of the first cannabinoid moiety. (Item 5) 2. The conjugated molecule of claim 1, wherein the first therapeutic agent moiety is covalently attached to a first carboxylic acid group of the first cannabinoid moiety. (Item 6) 2. The conjugated molecule of claim 1, wherein the first therapeutic agent moiety is covalently bonded to a first hydroxy group of the first cannabinoid moiety. (Item 7) 7. The conjugated molecule of any one of items 1 to 6, further comprising a second therapeutic moiety covalently attached to the first cannabinoid moiety. (Item 8) The second therapeutic component is (a) is covalently attached to a first hydroxy group of the first cannabinoid component; (b) is covalently attached to a second hydroxy group of the first cannabinoid component; (c) is covalently attached to a first carboxylic acid group of the first cannabinoid component; (d) covalently attached to a second carboxylic acid group of the first cannabinoid component; (e) is covalently attached to the first cannabinoid component via a second linker to a first hydroxy group of the first cannabinoid component; (f) covalently attached to the first cannabinoid component via a second linker to a second hydroxy group of the first cannabinoid component; (g) covalently attached to the first cannabinoid component via a second linker to a first carboxylic acid group of the first cannabinoid component; or (h) the conjugate molecule of claim 7, covalently attached to the first cannabinoid component via a second linker to a second carboxylic acid group of the first cannabinoid component. (Item 9) The second therapeutic component [ka] 9. The conjugate molecule according to any one of items 5 to 8, (Item 10) The second therapeutic component [ka] 9. The conjugate molecule according to any one of items 5 to 8, (Item 11) The second therapeutic component [ka] 9. The conjugate molecule according to any one of items 5 to 8, (Item 12) The second therapeutic component [ka] 9. The conjugate molecule according to any one of items 5 to 8, (Item 13) The second therapeutic component [ka] 9. The conjugate molecule according to any one of items 5 to 8, (Item 14) The second therapeutic component is [ka] 9. The conjugate molecule according to any one of items 5 to 8, (Item 15) The second therapeutic agent component is a diclofenac component, a celecoxib component, a gemcitabine component, an entecavir component, an emtricitabine component, an axitinib component, a batimastat component, a bosutinib component, a crizotinib component, an erlotinib component, a gefitinib component, an erlotinib component, an everolimus component, a temsirolimus component, a ganetespib component, a glasdegib component, an imatinib component, a lapatinib component, a navitoclax component, 9. The conjugate molecule according to any one of items 5 to 8, wherein the therapeutic agent moiety is selected from the group consisting of a nilotinib moiety, a pazopanib moiety, a moiety, a luminespib moiety, an obatoclax moiety, a ruxolitinib moiety, a salidegib moiety, a sunitinib moiety, a trametinib moiety, a warfarin moiety, a daclatasvir moiety, an etoposide moiety, an atazanavir moiety, a pravastatin moiety, a dasatinib moiety, a didanosine moiety, and a stavudine moiety. (Item 16) The first and second linkers are [ka] 16. The conjugate molecule according to any one of items 1 to 15, independently selected from the group consisting of: (Item 17) The first linker is [ka] 17. The conjugate molecule according to item 16, selected from the group consisting of: (Item 18) The conjugated molecule of claim 16 or 17, wherein the first therapeutic moiety is covalently attached at Y1. (Item 19) The conjugated molecule of claim 16 or 17, wherein the first therapeutic agent moiety is covalently attached at Y2. (Item 20) The conjugated molecule of claim 16 or 17, wherein the first therapeutic moiety is covalently attached at Y1 and a further therapeutic moiety is covalently attached at Y2. (Item 21) The additional therapeutic component is [ka] [ka] As well as diclofenac components, celecoxib components, gemcitabine components, entecavir components, emtricitabine components, axitinib components, batimastat components, bosutinib components, crizotinib components, erlotinib components, gefitinib components, erlotinib components, everolimus components, temsirolimus components, ganetespib components, glasdegib components, imatinib components, lapatinib components, navitoclax components, 21. The conjugate molecule according to item 20, wherein the therapeutic moiety is selected from the group consisting of a nilotinib moiety, a pazopanib moiety, a moiety, a luminespib moiety, an obatoclax moiety, a ruxolitinib moiety, a slidegib moiety, a sunitinib moiety, a trametinib moiety, a warfarin moiety, a daclatasvir moiety, an etoposide moiety, an atazanavir moiety, a pravastatin moiety, a dasatinib moiety, a didanosine moiety, and a stavudine moiety. (Item 22) The first therapeutic component [ka] 22. The conjugated molecule according to any one of items 1 to 21, wherein the conjugated molecule further comprises a second cannabinoid component. (Item 23) 23. The conjugated molecule according to any one of items 1 to 22, wherein the first cannabinoid component is provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol, or an active metabolite thereof. (Item 24) 24. The conjugated molecule according to item 23, wherein the first cannabinoid moiety is a cannabidiol moiety. (Item 25) 23. The conjugated molecule according to item 22, wherein the second cannabinoid component is provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone and cannabilipsol, or an active metabolite thereof. (Item 26) 26. The conjugated molecule according to item 25, wherein the second cannabinoid moiety is a cannabidiol moiety. (Item 27) 27. A pharma- ceutically acceptable salt of the conjugate molecule according to any one of items 1 to 26. (Item 28) 27. A pharmaceutical composition comprising the conjugate molecule according to any one of items 1 to 26, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable vehicle. (Item 29) 29. The pharmaceutical composition according to item 28, comprising a racemic mixture of the conjugate molecule. (Item 30) 29. The pharmaceutical composition according to item 28, comprising a single enantiomer of the conjugated molecule. (Item 31) 29. The pharmaceutical composition according to item 28, comprising a mixture of diastereomers of said conjugate molecule. (Item 32) 29. The pharmaceutical composition according to item 28, comprising a mixture of double bond isomers of the conjugated molecule. (Item 33) 29. The pharmaceutical composition according to item 28, comprising a Z-double bond isomer of the conjugated molecule. (Item 34) 29. The pharmaceutical composition according to item 28, comprising the E-double bond isomer of the conjugated molecule. (Item 35) 29. The pharmaceutical composition according to item 28, comprising an isotopic variant of the conjugate molecule. (Item 36) 27. A method for treating a hyperproliferative disorder, comprising administering to a patient in need of treating the hyperproliferative disorder a conjugate molecule or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 26. (Item 37) 37. The method of claim 36, wherein the hyperproliferative disorder is cancer. (Item 38) 39. The method of claim 38, wherein the conjugated molecule is administered in combination with a second cancer treatment.

Claims

[Claim 1] The invention described in this specification.

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