Phosphate prodrugs of cannabinoids

Abstract

Disclosed herein are phosphate prodrugs of cannabinoids and pharmaceutical compositions comprising one or more of the prodrugs.Such compounds and compositions are useful for treating diseases, disorders, and / or conditions, including neuropathy and neuropathic pain.In some embodiments, disclosed is a method for treating and / or preventing at least one disease, disorder, and / or condition for which treatment with cannabinoids is useful, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising at least one compound of formula (I).

Description

[Technical field]

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 227,296, filed July 29, 2021, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to prodrugs of cannabinoids (CB), pharmaceutical compositions containing same, and uses relating thereto. [Background technology]

[0003] Cannabinoids refer to a heterogeneous family of molecules extracted from Cannabis sativa that have been shown to exhibit pharmacological properties through interaction with specific receptors, such as G protein-coupled membrane receptors. The pharmacology of these compounds is expanding rapidly, and the pharmacological effects and therapeutic properties of CB receptor agonists are becoming more numerous. These include analgesia, muscle relaxation, immunosuppression, anti-inflammatory and anti-allergic effects, anxiolytic effects, mood improvement, appetite stimulation, antiemetic, intraocular pressure reduction, bronchodilator, neuroprotective, anticonvulsant effects, and antineoplastic effects.

[0004] Cannabidiol (CBD), the main non-psychotropic component of this family, constitutes up to 40% of Cannabis extracts. CBD is a pharmacologically heterogeneous compound, and the complete mechanism of action for all of its biological actions has not yet been determined. CBD acts as an allosteric antagonist of the cannabinoid type 1 receptor (CB1R) and the cannabinoid type 2 receptor (CB2R). CBD inhibits serotonin 1A (5-HT 1A Evidence suggests that it exerts many of its effects in vivo through stimulatory interactions with opioid receptors, including μ and δ opioid receptors, and transient receptor potential vanilloid type 1 (TRPV1) cation channels.

[0005] Over the past two decades, comprehensive clinical and preclinical studies have revealed several positive physiological and behavioral effects of CBD. CBD possesses anxiolytic, analgesic, antiemetic, and antipsychotic properties, allowing for the potential treatment of various conditions ranging from psychiatric disorders, e.g., dementia and schizophrenia, to addiction and nausea. In addition, CBD exhibits physiological effects that promote and maintain health, including anti-inflammatory, antioxidant, and neuroprotective effects. Due to these attractive properties, CBD has been utilized as an emerging therapeutic strategy for pain relief, as well as the treatment of diabetes, epilepsy, and cancer.

[0006] However, CBD therapy is not very accessible due to its complex pharmacokinetic properties that prevent the achievement of therapeutically effective systemic concentrations. Oral bioavailability of CBD has been shown to be very low (approximately 13-19%). CBD undergoes extensive first-pass metabolism, and its metabolites are mostly excreted by the kidney. Plasma and brain concentrations are dose-dependent. Systemic bioavailability of inhaled CBD ranged from 11-45%, and chronic administration of a daily oral dose of 10 mg / kg resulted in mean plasma concentrations of 5.9-11.2 ng / ml. CBD is highly lipid soluble and rapidly redistributes to adipose tissue throughout the body, where it can be stored for as long as 4 weeks and slowly released into the blood at subtherapeutic concentrations. Most CBD is excreted either intact or as its glucuronide metabolites.

[0007] The majority of clinical trials have been conducted with two commercially available preparations: EPIDIOLEX® and SATIVEX®. 9 -Tetrahydrocannabinol (Δ 9 SATIVEX®, which contains CBD and ΔTHC, is administered via an oromucosal spray and is approved for the treatment of symptoms of multiple sclerosis. 9It has been shown that co-administration with -THC can alter the latter's pharmacological effects, enhancing some of its putative benefits while attenuating some of its negative effects. GW Pharmaceuticals has developed a sesame seed oil-based oral formulation of pure CBD (EPIDIOLEX®) for the treatment of severe rare early-onset treatment-resistant epilepsy syndromes, and has shown a significant reduction in seizure frequency compared to placebo in several clinical trials. The recommended daily dose requires at least 400 mg (see U.S. Patent Nos. 9,066,920 and 9,522,123), which suggests that large amounts need to be administered for effective results. Therefore, there is a need for CB drugs with enhanced physicochemical, pharmacological, and / or pharmacokinetic properties, such as solubility and oral bioavailability. For example, there is a need for improved prodrug strategies that can overcome one or more of the physicochemical, pharmacological, and / or pharmacokinetic disadvantages of CB. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent No. 9,066,920 [Patent Document 2] U.S. Pat. No. 9,522,123 Summary of the Invention [Means for solving the problem]

[0009] Formula (I) [ka] and pharma- ceutically acceptable salts thereof, 1 and R 2 is defined herein] is disclosed.

[0010] As used herein, "compounds of formula (I)" include cannabinoid prodrugs of formula (I) and pharma- ceutically acceptable salts thereof.

[0011] In some embodiments, a pharmaceutical composition is provided that includes at least one compound of formula (I) and at least one additional pharma- ceutically acceptable ingredient.

[0012] In some embodiments, a method is disclosed for the treatment and / or prevention of at least one disease, disorder, and / or condition for which treatment with a cannabinoid is useful, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising at least one compound of formula (I). [Brief description of the drawings]

[0013] [Figure 1-1] FIG. 1 is a diagram showing the synthesis of compounds 7a to 7f. [Figure 1-2] Same as above.

[0014] [Diagram 2] FIG. 2 shows the synthesis of compounds 8 and 14a-14k.

[0015] [Diagram 3] FIG. 3 shows the synthesis of compound 24.

[0016] [Figure 4] FIG. 4 is a diagram showing the synthesis of compounds 29a-29c.

[0017] [Diagram 5] FIG. 5 shows the synthesis of compound 32.

[0018] [Figure 6] FIG. 6 shows a general synthesis of compounds 38a-38c.

[0019] [Figure 7] FIG. 7 shows a prophetic synthesis of compound 43.

[0020] [Figure 8] FIG. 8 is a graph showing hepatocyte cellular uptake of compound 7b, illustrating the metabolism of compound 7b and the formation of CBD.

[0021] [Figure 9] FIG. 9 is a graph showing hepatocyte cellular uptake of compound 8, illustrating the metabolism of compound 8 and the formation of both compound 7b and CBD.

[0022] [Figure 10] FIG. 10 is a graph depicting hepatocyte cellular uptake of compound 14a, showing the metabolism of compound 14a and the formation of both compound 7b and CBD.

[0023] [Figure 11] FIG. 11 is a graph depicting the brain homogenate stability of compound 7b, showing the metabolism of compound 7b and the formation of CBD.

[0024] [Figure 12] FIG. 12 is a graph showing the CYP inhibition of compound 7b and CBD at 10 μM concentration.

[0025] [Figure 13-1] FIG. 13 is a graph showing CBD released into plasma and brain from compounds 7c, 29a, 32 and 38c when administered at a PO dose of 50 mg / kg equivalent. [Figure 13-2] Same as above.

[0026] [Figure 14] FIG. 14 is a graph showing a study of compounds 7a, 7b, and CBD 2 hours after IP administration using 22 mA electroshock at 6 Hz. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Disclosed herein is a cannabinoid prodrug and pharmaceutical composition comprising the same.The disclosed compounds and compositions can be useful for treating and / or preventing at least one disease, disorder, and / or condition that can be treated or prevented by administering cannabinoids.

[0028] The compounds of the present disclosure can have at least one improved physicochemical, pharmacological, and / or pharmacokinetic property.

[0029] In some embodiments, formula (I) [ka] and pharma- ceutically acceptable salts thereof, R 1 teeth, [ka] is selected from the group Z is a divalent C 1~18 Alkyl and divalent C 1~18 haloalkyl groups, divalent C 1~18 Alkyl and divalent C 1~18 Haloalkyl groups are C 6~18 Aryl, C 1~13 Heteroaryl, C 2~12 Heterocyclyl, -OC 1~18 Alkyl, -SC 1~18 Alkyl, -N(T 2 ) C 1~18 Alkyl, and -N(T 2 ) AA groups, and 2 H and C 1~8 alkyl groups, AA being selected from amino acid residues attached to the nitrogen through their C-terminal carbonyl groups (i.e., forming an amide bond); X and Y may be the same or different, and may be H, Q, C 1~18 Alkyl, C1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] are independently selected from the group Each T 3 , T 4 , and T 5 may be the same or different, H and C 1~8 independently selected from alkyl groups, Each Q is independently selected from a pharma- ceutically acceptable cation; each n is independently selected from an integer ranging from 1 to 12; each m is independently selected from an integer ranging from 1 to 8; T 1 , H, C 1~18 Alkyl, and C 1~18 haloalkyl groups, R 2 is C 1~8 alkyl groups] is presented.

[0030] In some embodiments, R 1 teeth, [ka] In some embodiments, the carbon of Z adjacent to the carbonyl group (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon of Z adjacent to the carbonyl group (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon of Z adjacent to the carbonyl group (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0031] In some embodiments, R 1 teeth, [ka] is selected from the group.

[0032] In some embodiments, R 1 teeth, [ka] In some embodiments, T 1 is H. In some embodiments, T 1 is methyl.

[0033] In some embodiments, R 1 teeth, [ka] is selected from the group.

[0034] In some embodiments, Z is a divalent C 1~18 In some embodiments, Z is selected from the divalent C 1~12 In some embodiments, Z is selected from the divalent C 1~8 In some embodiments, Z is selected from the divalent C 1~6 In some embodiments, Z is selected from the divalent C 1~4 In some embodiments, Z is selected from the divalent C 1~3 In some embodiments, Z is selected from the divalent C 1~2 In some embodiments, Z is a divalent C alkyl group, i.e., a divalent methylene.

[0035] In some embodiments, Z is -CH-, -(CH)-, -(CH)-, -(CH)-, -(CH)-, -(CH)-, -(CH)-, -(CH)-, -(CH)-, -(CH)-, -(CH)-, -(CH)- 10 -, [ka] is selected from.

[0036] In some embodiments, Z is -CH2-.

[0037] In some embodiments, Z is -(CH2)2-.

[0038] In some embodiments, Z is -(CH2)3-.

[0039] In some embodiments, Z is [ka] It is.

[0040] In some embodiments, Z is [ka] It is.

[0041] In some embodiments, Z is [ka] It is.

[0042] In some embodiments, Z is [ka] It is.

[0043] In some embodiments, Z is [ka] It is.

[0044] In some embodiments, Z is [ka] It is.

[0045] In some embodiments, Z is [ka] It is.

[0046] In some embodiments, Z is a divalent C 1~18 In some embodiments, Z is selected from the group consisting of a divalent C 1~12 In some embodiments, Z is selected from the group consisting of a divalent C 1~8 In some embodiments, Z is selected from the group consisting of a divalent C 1~6 In some embodiments, Z is selected from the group consisting of a divalent C 1~4 In some embodiments, Z is selected from the group consisting of a divalent C 1~3 In some embodiments, Z is selected from the group consisting of a divalent C 1~2 haloalkyl groups.

[0047] In some embodiments, Z is [ka] It is.

[0048] In some embodiments, Z is [ka] It is.

[0049] In some embodiments, Z is C 6~18 A divalent C substituted with at least one group selected from an aryl group 1~18 In some embodiments, Z is selected from the group consisting of C 6~18 A divalent C substituted with at least one group selected from an aryl group 1~16 In some embodiments, Z is selected from the group consisting of C 6~18 A divalent C substituted with at least one group selected from an aryl group1~14 In some embodiments, Z is selected from the group consisting of C 6~18 A divalent C substituted with at least one group selected from an aryl group 1~12 In some embodiments, Z is selected from the group consisting of C 6~18 A divalent C substituted with at least one group selected from an aryl group 1~10 In some embodiments, Z is selected from the group consisting of C 6~18 A divalent C substituted with at least one group selected from an aryl group 1~8 In some embodiments, Z is selected from the group consisting of C 6~18 A divalent C substituted with at least one group selected from an aryl group 1~6 In some embodiments, Z is selected from the group consisting of C 6~18 A divalent C substituted with at least one group selected from an aryl group 1~4 In some embodiments, Z is selected from the group consisting of C 6~18 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from an aryl group. 6~18 It is a divalent C1 alkyl group substituted with at least one group selected from an aryl group.

[0050] In some embodiments, Z is C 6~10 A divalent C substituted with at least one group selected from an aryl group 1~18 In some embodiments, Z is selected from the group consisting of C 6~10 A divalent C substituted with at least one group selected from an aryl group 1~16 In some embodiments, Z is selected from the group consisting of C 6~10 A divalent C substituted with at least one group selected from an aryl group 1~14 In some embodiments, Z is selected from the group consisting of C 6~10 A divalent C substituted with at least one group selected from an aryl group 1~12 In some embodiments, Z is selected from the group consisting of C6~10 A divalent C substituted with at least one group selected from an aryl group 1~10 In some embodiments, Z is selected from the group consisting of C 6~10 A divalent C substituted with at least one group selected from an aryl group 1~8 In some embodiments, Z is selected from the group consisting of C 6~10 A divalent C substituted with at least one group selected from an aryl group 1~6 In some embodiments, Z is selected from the group consisting of C 6~10 A divalent C substituted with at least one group selected from an aryl group 1~4 In some embodiments, Z is selected from the group consisting of C 6~10 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from an aryl group. 6~10 In some embodiments, C is a divalent C alkyl group substituted with at least one group selected from an aryl group. 6~10 At least one group selected from the aryl groups is phenyl.

[0051] In some embodiments, Z is [ka] It is.

[0052] In some embodiments, Z is [ka] It is.

[0053] In some embodiments, Z is C 1~13 A divalent C substituted with at least one group selected from a heteroaryl group 1~18 In some embodiments, Z is selected from the group consisting of C 1~13 A divalent C substituted with at least one group selected from a heteroaryl group 1~16In some embodiments, Z is selected from the group consisting of C 1~13 A divalent C substituted with at least one group selected from a heteroaryl group 1~14 In some embodiments, Z is selected from the group consisting of C 1~13 A divalent C substituted with at least one group selected from a heteroaryl group 1~12 In some embodiments, Z is selected from the group consisting of C 1~13 A divalent C substituted with at least one group selected from a heteroaryl group 1~10 In some embodiments, Z is selected from the group consisting of C 1~13 A divalent C substituted with at least one group selected from a heteroaryl group 1~8 In some embodiments, Z is selected from the group consisting of C 1~13 A divalent C substituted with at least one group selected from a heteroaryl group 1~6 In some embodiments, Z is selected from the group consisting of C 1~13 A divalent C substituted with at least one group selected from a heteroaryl group 1~4 In some embodiments, Z is selected from the group consisting of C 1~13 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from a heteroaryl group. 1~13 It is a divalent C1 alkyl group substituted with at least one group selected from a heteroaryl group.

[0054] In some embodiments, Z is C 1~8 A divalent C substituted with at least one group selected from a heteroaryl group 1~18 In some embodiments, Z is selected from the group consisting of C 1~8 A divalent C substituted with at least one group selected from a heteroaryl group 1~16 In some embodiments, Z is selected from the group consisting of C 1~8 A divalent C substituted with at least one group selected from a heteroaryl group 1~14In some embodiments, Z is selected from the group consisting of C 1~8 A divalent C substituted with at least one group selected from a heteroaryl group 1~12 In some embodiments, Z is selected from the group consisting of C 1~8 A divalent C substituted with at least one group selected from a heteroaryl group 1~10 In some embodiments, Z is selected from the group consisting of C 1~8 A divalent C substituted with at least one group selected from a heteroaryl group 1~8 In some embodiments, Z is selected from the group consisting of C 1~8 A divalent C substituted with at least one group selected from a heteroaryl group 1~6 In some embodiments, Z is selected from the group consisting of C 1~8 A divalent C substituted with at least one group selected from a heteroaryl group 1~4 In some embodiments, Z is selected from the group consisting of C 1~8 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from a heteroaryl group. 1~8 It is a divalent C1 alkyl group substituted with at least one group selected from a heteroaryl group.

[0055] In some embodiments, Z is C 1~5 A divalent C substituted with at least one group selected from a heteroaryl group 1~18 In some embodiments, Z is selected from the group consisting of C 1~5 A divalent C substituted with at least one group selected from a heteroaryl group 1~16 In some embodiments, Z is selected from the group consisting of C 1~5 A divalent C substituted with at least one group selected from a heteroaryl group 1~14 In some embodiments, Z is selected from the group consisting of C 1~5 A divalent C substituted with at least one group selected from a heteroaryl group 1~12In some embodiments, Z is selected from the group consisting of C 1~5 A divalent C substituted with at least one group selected from a heteroaryl group 1~10 In some embodiments, Z is selected from the group consisting of C 1~5 A divalent C substituted with at least one group selected from a heteroaryl group 1~8 In some embodiments, Z is selected from the group consisting of C 1~5 A divalent C substituted with at least one group selected from a heteroaryl group 1~6 In some embodiments, Z is selected from the group consisting of C 1~5 A divalent C substituted with at least one group selected from a heteroaryl group 1~4 In some embodiments, Z is selected from the group consisting of C 1~5 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from a heteroaryl group. 1~5 A divalent C alkyl group substituted with at least one group selected from a heteroaryl group. 1~5 At least one group selected from the heteroaryl group is [ka] is selected from.

[0056] In some embodiments, Z is [ka] is selected from.

[0057] In some embodiments, Z is C 2~12 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~18 In some embodiments, Z is selected from the group consisting of C 2~12 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~16In some embodiments, Z is selected from the group consisting of C 2~12 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~14 In some embodiments, Z is selected from the group consisting of C 2~12 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~12 In some embodiments, Z is selected from the group consisting of C 2~12 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~10 In some embodiments, Z is selected from the group consisting of C 2~12 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~8 In some embodiments, Z is selected from the group consisting of C 2~12 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~6 In some embodiments, Z is selected from the group consisting of C 2~12 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~4 In some embodiments, Z is selected from the group consisting of C 2~12 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from a heterocyclyl group. 2~12 It is a divalent C1 alkyl group substituted with at least one group selected from a heterocyclyl group.

[0058] In some embodiments, Z is C 2~5 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~18 In some embodiments, Z is selected from the group consisting of C 2~5 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~16 In some embodiments, Z is selected from the group consisting of C 2~5 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~14In some embodiments, Z is selected from the group consisting of C 2~5 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~12 In some embodiments, Z is selected from the group consisting of C 2~5 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~10 In some embodiments, Z is selected from the group consisting of C 2~5 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~8 In some embodiments, Z is selected from the group consisting of C 2~5 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~6 In some embodiments, Z is selected from the group consisting of C 2~5 A divalent C substituted with at least one group selected from the group consisting of heterocyclyl groups 1~4 In some embodiments, Z is selected from the group consisting of C 2~5 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from a heterocyclyl group. 2~5 In some embodiments, C is a divalent C alkyl group substituted with at least one group selected from the group consisting of a heterocyclyl group and a cycloalkyl group. 2~5 At least one group selected from the heterocyclyl group is [ka] is selected from.

[0059] In some embodiments, Z is [ka] is selected from.

[0060] In some embodiments, Z is -OC 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~18In some embodiments, Z is selected from the group consisting of -OC 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~16 In some embodiments, Z is selected from the group consisting of -OC 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~14 In some embodiments, Z is selected from the group consisting of -OC 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~12 In some embodiments, Z is selected from the group consisting of -OC 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~10 In some embodiments, Z is selected from the group consisting of -OC 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~8 In some embodiments, Z is selected from the group consisting of -OC 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~6 In some embodiments, Z is selected from the group consisting of -OC 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~4 In some embodiments, Z is selected from the group consisting of -OC 1~18 In some embodiments, Z is selected from the group consisting of a divalent C alkyl group substituted with at least one group selected from the group consisting of an alkyl group, an -OC 1~18 It is a divalent C1 alkyl group substituted with at least one group selected from the alkyl groups.

[0061] In some embodiments, Z is -OC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~18 In some embodiments, Z is selected from the group consisting of -OC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~16In some embodiments, Z is selected from the group consisting of -OC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~14 In some embodiments, Z is selected from the group consisting of -OC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~12 In some embodiments, Z is selected from the group consisting of -OC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~10 In some embodiments, Z is selected from the group consisting of -OC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~8 In some embodiments, Z is selected from the group consisting of -OC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~6 In some embodiments, Z is selected from the group consisting of -OC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~4 In some embodiments, Z is selected from the group consisting of -OC 1~10 In some embodiments, Z is selected from the group consisting of a divalent C alkyl group substituted with at least one group selected from the group consisting of an alkyl group, an -OC 1~10 In some embodiments, the alkyl group is a divalent C alkyl group substituted with at least one group selected from the group consisting of -OC 1~10 At least one group selected from the alkyl group is [ka] is selected from.

[0062] In some embodiments, Z is [ka] is selected from.

[0063] In some embodiments, Z is -SC1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~18 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~16 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~14 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~12 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~10 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~8 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~6 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~4 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~18 In some embodiments, Z is selected from the group consisting of a divalent C2 alkyl group substituted with at least one group selected from the group consisting of an alkyl group, -SC 1~18 It is a divalent C1 alkyl group substituted with at least one group selected from the alkyl groups.

[0064] In some embodiments, Z is -SC 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~18 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~10A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~16 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~14 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~12 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~10 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~8 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~6 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~4 In some embodiments, Z is selected from the group consisting of -SC alkyl groups. 1~10 In some embodiments, Z is selected from the group consisting of a divalent C2 alkyl group substituted with at least one group selected from the group consisting of an alkyl group, -SC 1~10 In some embodiments, the alkyl group is a divalent C alkyl group substituted with at least one group selected from the group consisting of -SC alkyl groups. 1~10 At least one group selected from the alkyl group is [ka] is selected from.

[0065] In some embodiments, Z is [ka] is selected from.

[0066] In some embodiments, Z is -N(T 2 ) C 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~18 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~16 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~14 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~12 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~10 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~8 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~6 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~18 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~4 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~18 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from an alkyl group. 2 ) C 1~18In some embodiments, the -N(T 2 ) C 1~18 At least one group selected from the alkyl group is -NHC 1~18 alkyl groups, i.e. T 2 is H. In some embodiments, -N(T 2 ) C 1~18 At least one group selected from the alkyl group is -N(C 1~8 Alkyl group)C 1~18 alkyl groups, i.e. T 2 is C 1~8 It is an alkyl group.

[0067] In some embodiments, Z is -N(T 2 ) C 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~18 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~16 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~14 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~12 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~10 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~8 In some embodiments, Z is selected from the group consisting of -N(T2 ) C 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~6 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~10 A divalent C substituted with at least one group selected from the group consisting of alkyl groups. 1~4 In some embodiments, Z is selected from the group consisting of -N(T 2 ) C 1~10 In some embodiments, Z is selected from a divalent C alkyl group substituted with at least one group selected from an alkyl group. 2 ) C 1~10 In some embodiments, the -N(T 2 ) C 1~10 At least one group selected from the alkyl group is -NHC 1~10 In some embodiments, the -N(T 2 ) C 1~10 At least one group selected from the alkyl group is -N(C 1~8 Alkyl group)C 1~10 In some embodiments, the -N(T 2 ) C 1~10 At least one group selected from the alkyl group is [ka] is selected from.

[0068] In some embodiments, Z is [ka] is selected from.

[0069] In some embodiments, Z is -N(T 2 ) a divalent C substituted with at least one group selected from the AA group; 1~18 In some embodiments, Z is selected from the group consisting of -N(T2 ) a divalent C substituted with at least one group selected from the AA group; 1~16 In some embodiments, Z is selected from the group consisting of -N(T 2 ) a divalent C substituted with at least one group selected from the AA group; 1~14 In some embodiments, Z is selected from the group consisting of -N(T 2 ) a divalent C substituted with at least one group selected from the AA group; 1~12 In some embodiments, Z is selected from the group consisting of -N(T 2 ) a divalent C substituted with at least one group selected from the AA group; 1~10 In some embodiments, Z is selected from the group consisting of -N(T 2 ) a divalent C substituted with at least one group selected from the AA group; 1~8 In some embodiments, Z is selected from the group consisting of -N(T 2 ) a divalent C substituted with at least one group selected from the AA group; 1~6 In some embodiments, Z is selected from the group consisting of -N(T 2 ) a divalent C substituted with at least one group selected from the AA group; 1~4 In some embodiments, Z is selected from the group consisting of -N(T 2 In some embodiments, Z is selected from a divalent C2 alkyl group substituted with at least one group selected from -N(T 2 In some embodiments, the -N(T) is a divalent C alkyl group substituted with at least one group selected from the group consisting of -N(T)AA. 2 At least one group selected from the -N(T)AA groups is selected from the -NHAA group. 2 At least one group selected from the -N(C)AA groups is 1~8 The alkyl group is selected from the AA group.

[0070] In some embodiments, Z is [ka] is selected from the group.

[0071] In some embodiments, AA is selected from natural amino acid residues. In some embodiments, AA is selected from unnatural amino acid residues. Exemplary unnatural amino acids can be found in (1) Unnatural Amino Acid: Tools for Drug Discovery, ChemFiles (Sigma-Aldrich), Vol. 4, No. 5, and (2) Schultz et al., J. Bio., Chem, 2010, 285(15), 11039-11044. In some embodiments, AA is selected from L-amino acid residues. In some embodiments, AA is selected from natural L-amino acid residues.

[0072] In some embodiments, X is C 1~18 In some embodiments, X is selected from the group consisting of C 1~14 In some embodiments, X is selected from the group consisting of C 1~12 In some embodiments, X is selected from the group consisting of C 1~10 In some embodiments, X is selected from the group consisting of C 1~8 In some embodiments, X is selected from the group consisting of C 1~4 In some embodiments, X is selected from the group consisting of C 3~10 In some embodiments, X is selected from -CH3, -(CH2)CH3, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, and -(CH2)9CH3.

[0073] In some embodiments, X is [ka] is selected from.

[0074] In some embodiments, X is C 1~18In some embodiments, X is selected from the group consisting of haloalkyl groups. 1~14 In some embodiments, X is selected from the group consisting of haloalkyl groups. 1~12 In some embodiments, X is selected from the group consisting of haloalkyl groups. 1~10 In some embodiments, X is selected from the group consisting of haloalkyl groups. 1~8 In some embodiments, X is selected from the group consisting of haloalkyl groups. 1~4 haloalkyl groups.

[0075] In some embodiments, X is C 6~18 Aryl and C 7~19 In some embodiments, X is selected from the group consisting of C 6~12 Aryl and C 7~13 In some embodiments, X is selected from the group consisting of C 6~18 In some embodiments, X is selected from the group consisting of C 6~12 In some embodiments, X is selected from the group consisting of C 7~19 In some embodiments, X is selected from the group consisting of C 7~13 The radicals are selected from arylalkyl radicals.

[0076] In some embodiments, X is [ka] It is.

[0077] In some embodiments, X is [ka] It is.

[0078] In some embodiments, X is C 1~13 Heteroaryl and C 2~14 In some embodiments, X is selected from the group consisting of C 1~13 In some embodiments, X is selected from the group consisting of C 1~10In some embodiments, X is selected from the group consisting of C 1~8 In some embodiments, X is selected from the group consisting of C 1~6 In some embodiments, X is selected from the group consisting of C 2~14 In some embodiments, X is selected from the group consisting of C 2~11 In some embodiments, X is selected from the group consisting of C 2~9 In some embodiments, X is selected from the group consisting of C 2~7 heteroarylalkyl groups.

[0079] In some embodiments, X is -(CHCHO). n In some embodiments, n is selected from an integer ranging from 1 to 10. In some embodiments, n is selected from an integer ranging from 1 to 8. In some embodiments, n is selected from an integer ranging from 1 to 6. In some embodiments, n is selected from an integer ranging from 1 to 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0080] In some embodiments, X is [ka] It is.

[0081] In some embodiments, X is [ka] It is.

[0082] In some embodiments, X is [ka] is selected from the group.

[0083] In some embodiments, X is [ka] is selected from the group.

[0084] In some embodiments, X is [ka] groups, where m is selected from an integer ranging from 1 to 6. In some embodiments, m is selected from an integer ranging from 1 to 5. In some embodiments, m is selected from an integer ranging from 1 to 4. In some embodiments, m is selected from an integer ranging from 1 to 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0085] In some embodiments, X is [ka] groups, where m is selected from an integer ranging from 1 to 6. In some embodiments, m is selected from an integer ranging from 1 to 5. In some embodiments, m is selected from an integer ranging from 1 to 4. In some embodiments, m is selected from an integer ranging from 1 to 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0086] In some embodiments, X is [ka] wherein T 3 and T 4 may be the same or different, H and C 1~5 In some embodiments, T 3 and T 4 are each H. In some embodiments, T 3 and T 4may be the same or different, C 1~5 In some embodiments, T 3 is H and T 4 is C 1~5 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0087] In some embodiments, X is [ka] wherein T 3 , T 4 , and T 5 may be the same or different, H and C 1~5 In some embodiments, T 3 , T 4 , and T 5 are each H. In some embodiments, T 3 , T 4 , and T 5 may be the same or different, C 1~5 In some embodiments, T 3 is H and T 4 and T 5 may be the same or different, C 1~5 In some embodiments, T 3 and T 4 are H and T, respectively. 5 is C 1~5 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0088] In some embodiments, X is [ka] is selected from.

[0089] In some embodiments, X is [ka] is selected from.

[0090] In some embodiments, X is [ka] It is.

[0091] In some embodiments, Y is C 1~18 In some embodiments, Y is selected from the group consisting of C 1~14 In some embodiments, Y is selected from the group consisting of C 1~12 In some embodiments, Y is selected from the group consisting of C 1~10 In some embodiments, Y is selected from the group consisting of C 1~8 In some embodiments, Y is selected from the group consisting of C 1~4 In some embodiments, Y is selected from the group consisting of C 3~10 In some embodiments, Y is selected from -CH3, -(CH2)CH3, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, and -(CH2)9CH3.

[0092] In some embodiments, Y is [ka] is selected from.

[0093] In some embodiments, Y is C 1~18 In some embodiments, Y is selected from the group consisting of haloalkyl groups. 1~14 In some embodiments, Y is selected from the group consisting of haloalkyl groups. 1~12 In some embodiments, Y is selected from the group consisting of haloalkyl groups. 1~10 In some embodiments, Y is selected from the group consisting of haloalkyl groups. 1~8 In some embodiments, Y is selected from the group consisting of haloalkyl groups. 1~4 haloalkyl groups.

[0094] In some embodiments, Y is C 6~18 Aryl and C 7~19 In some embodiments, Y is selected from the group consisting of C 6~12 Aryl and C 7~13 In some embodiments, Y is selected from the group consisting of C 6~18 In some embodiments, Y is selected from the group consisting of C 6~12 In some embodiments, Y is selected from the group consisting of C 7~19 In some embodiments, Y is selected from the group consisting of C 7~13 The radicals are selected from arylalkyl radicals.

[0095] In some embodiments, Y is [ka] It is.

[0096] In some embodiments, Y is [ka] It is.

[0097] In some embodiments, Y is C 1~13 Heteroaryl and C 2~14 In some embodiments, Y is selected from the group consisting of C 1~13 In some embodiments, Y is selected from the group consisting of C 1~10 In some embodiments, Y is selected from the group consisting of C 1~8 In some embodiments, Y is selected from the group consisting of C 1~6 In some embodiments, Y is selected from the group consisting of C 2~14 In some embodiments, Y is selected from the group consisting of C 2~11 In some embodiments, Y is selected from the group consisting of C 2~9 In some embodiments, Y is selected from the group consisting of C 2~7heteroarylalkyl groups.

[0098] In some embodiments, Y is -(CHCHO). n In some embodiments, n is selected from an integer ranging from 1 to 10. In some embodiments, n is selected from an integer ranging from 1 to 8. In some embodiments, n is selected from an integer ranging from 1 to 6. In some embodiments, n is selected from an integer ranging from 1 to 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0099] In some embodiments, Y is [ka] It is.

[0100] In some embodiments, Y is [ka] It is.

[0101] In some embodiments, Y is [ka] is selected from the group.

[0102] In some embodiments, Y is [ka] is selected from the group.

[0103] In some embodiments, Y is [ka] groups, where m is selected from an integer ranging from 1 to 6. In some embodiments, m is selected from an integer ranging from 1 to 5. In some embodiments, m is selected from an integer ranging from 1 to 4. In some embodiments, m is selected from an integer ranging from 1 to 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0104] In some embodiments, Y is [ka] groups, where m is selected from an integer ranging from 1 to 6. In some embodiments, m is selected from an integer ranging from 1 to 5. In some embodiments, m is selected from an integer ranging from 1 to 4. In some embodiments, m is selected from an integer ranging from 1 to 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0105] In some embodiments, Y is [ka] wherein T 3 and T 4 may be the same or different, H and C 1~5 In some embodiments, T 3 and T 4 are each H. In some embodiments, T 3 and T 4 may be the same or different, C 1~5 In some embodiments, T 3 is H and T 4 is C 1~5 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0106] In some embodiments, Y is [ka] wherein T 3 , T 4 , and T 5 may be the same or different, H and C 1~5 In some embodiments, T 3 , T 4 , and T 5 are each H. In some embodiments, T 3 , T 4 , and T 5 may be the same or different, C 1~5 In some embodiments, T 3 is H and T 4 and T 5 may be the same or different, C 1~5 In some embodiments, T 3 and T 4 are H and T, respectively. 5 is C 1~5 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0107] In some embodiments, Y is [ka] is selected from.

[0108] In some embodiments, Y is [ka] is selected from.

[0109] In some embodiments, Y is [ka] is selected from.

[0110] In some embodiments, Y is [ka] It is.

[0111] In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q.

[0112] In some embodiments, X is selected from H and Q, and Y is C 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] is selected from the group.

[0113] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0114] Non-limiting examples of Q include aluminum, arginine, benzathine, calcium, choline, copper, amines (substituted amines, e.g., diethylamine, and unsubstituted amines), diolamine, glycine, iron, lithium, lysine, magnesium, manganese, meglumine, olamine, potassium, sodium, tromethamine, and zinc cations. In some embodiments, at least one Q is selected from (substituted and unsubstituted) ammonium cations. In some embodiments, at least one Q is an unsubstituted ammonium cation. In some embodiments, each Q is selected from (substituted and unsubstituted) ammonium cations. In some embodiments, each Q is an unsubstituted ammonium cation.

[0115] In some embodiments, T 1 is H. In some embodiments, T 1 is C 1~18 In some embodiments, T 1 is C 1~12 In some embodiments, T 1 is C 1~10 In some embodiments, T 1 is C 1~8 In some embodiments, T 1 is C 1~4 In some embodiments, T 1 is selected from Me, Et, n-Pr, iPr, n-Bu, s-Bu, i-Bu, t-Bu, cyclopropyl, and cyclobutyl. 1 is Me.

[0116] In some embodiments, T 1 is C 1~18 In some embodiments, T is selected from haloalkyl groups. 1 is C 1~12 In some embodiments, T is selected from haloalkyl groups. 1 is C 1~10 In some embodiments, T is selected from haloalkyl groups. 1 is C1~8 In some embodiments, T is selected from haloalkyl groups. 1 In some embodiments, T 1 is CF3.

[0117] In some embodiments, R 2 is C 2~6 In some embodiments, R 2 is selected from a C alkyl group. 2 is selected from a C4 alkyl group. 2 is selected from a C alkyl group. 2 is n-propyl. In some embodiments, R 2 is n-pentyl.

[0118] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, the carbon of Z next to the carbonyl group (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon of Z next to the carbonyl group (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon of Z next to the carbonyl group (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, wherein at least one of the aforementioned substituents is on the alpha carbon. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0119] In some embodiments, the compound of formula (I) has the formula: [ka] In some embodiments, the carbon of Z adjacent to the carbonyl group (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon of Z adjacent to the carbonyl group (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon of Z adjacent to the carbonyl group (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0120] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0121] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0122] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0123] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0124] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0125] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0126] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0127] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0128] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0129] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0130] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. 1 is H. In some embodiments, T 1 is methyl. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0131] In some embodiments, the compound of formula (I) has the formula: [ka] In some embodiments, the compound is selected from compounds having the formula: 1 is H. In some embodiments, T 1 is methyl.

[0132] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0133] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0134] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0135] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0136] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof.

[0137] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0138] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0139] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0140] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0141] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0142] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0143] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0144] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0145] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0146] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0147] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0148] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0149] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0150] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0151] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0152] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0153] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0154] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0155] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0156] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0157] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof.

[0158] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0159] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0160] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0161] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0162] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0163] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0164] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0165] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0166] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0167] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0168] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0169] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0170] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0171] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0172] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0173] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0174] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0175] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0176] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0177] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0178] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0179] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0180] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0181] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0182] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0183] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0184] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0185] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0186] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0187] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0188] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0189] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0190] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0191] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0192] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0193] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0194] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0195] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0196] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0197] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0198] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0199] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0200] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0201] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0202] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0203] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0204] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0205] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0206] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0207] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0208] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, the carbon of Z next to the carbonyl group (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon of Z next to the carbonyl group (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon of Z next to the carbonyl group (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, wherein at least one of the aforementioned substituents is on the alpha carbon. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0209] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0210] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0211] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0212] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0213] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has no hydrogen atoms. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has one hydrogen atom. In some embodiments, the carbon adjacent to the carbonyl group of Z (i.e., the alpha carbon) has two hydrogen atoms. In some embodiments, Z is substituted with one or more groups as described above, with at least one of the aforementioned substituents being present on the alpha carbon.

[0214] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0215] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0216] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0217] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0218] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0219] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0220] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. 1 is H. In some embodiments, T 1 is methyl. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0221] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0222] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0223] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0224] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0225] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0226] In some embodiments, the compound of formula (I) has the formula: [ka] and a pharma- ceutically acceptable salt of any of the foregoing.

[0227] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0228] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0229] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0230] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0231] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0232] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] [ka] The compound is selected from compounds having the formula:

[0233] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0234] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] [ka] The compound is selected from compounds having the formula:

[0235] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0236] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0237] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0238] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0239] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0240] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0241] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0242] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0243] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0244] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0245] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0246] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0247] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof.

[0248] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0249] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0250] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0251] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0252] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0253] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0254] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0255] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0256] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0257] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0258] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0259] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0260] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0261] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0262] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0263] In some embodiments, the compound of formula (I) has the formula: [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, X is H. In some embodiments, X is Q. In some embodiments, Y is H. In some embodiments, Y is Q. In some embodiments, X and Y are each H. In some embodiments, X and Y are each Q. In some embodiments, only one of X or Y is H. In some embodiments, only one of X or Y is Q. In some embodiments, X is H and Y is Q. In some embodiments, X is selected from H and Q and Y is C. 1~18 Alkyl, C 1~18 Haloalkyl, C 6~18 Aryl, C 1~13 Heteroaryl, C 7~19 Aryl alkyl, C 2~14 Heteroarylalkyl, -(CH2CH2O) n CH3, [ka] In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, and C. 1~5 In some embodiments, X is selected from H and Q, and Y is selected from phenyl, benzyl, ethyl, and isopropyl.

[0264] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0265] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0266] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0267] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0268] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0269] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0270] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0271] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0272] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0273] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0274] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0275] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0276] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0277] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0278] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0279] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0280] In some embodiments, the compound of formula (I) has the formula: [ka] as well as pharma- ceutically acceptable salts of any of the foregoing.

[0281] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0282] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0283] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0284] In some embodiments, the compound of formula (I) has the formula: [ka] [ka] The compound is selected from compounds having the formula:

[0285] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0286] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0287] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0288] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0289] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0290] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0291] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0292] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0293] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0294] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0295] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0296] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0297] In some embodiments, the compound of formula (I) has the formula: [ka] The compound is selected from compounds having the formula:

[0298] In some embodiments, the compound of formula (I) has a human plasma stable T 1 / 2 For example, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 In some embodiments, the compound of formula (I) has a human plasma stability T 1 / 2 is about 15 hours or more.

[0299] As used herein, the "human plasma stability T 1 / 2 " is determined according to the procedure described in Example 11.

[0300] In some embodiments, the compound of formula (I) has a human liver microsomal stable T 1 / 2 For example, the compound of formula (I) has a human liver microsome stability T 1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stable T 1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stability T1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 is about more than two hours.

[0301] In some embodiments, the compound of formula (I) has a human liver microsomal stable T 1 / 2 is greater than the stability of CBD measured under the same experimental conditions. In some embodiments, the compounds of formula (I) have a human liver microsomal stability T 1 / 2 In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 is at least twice as stable as CBD. In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 is at least 2.5 times as stable as CBD. In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 is at least three times as stable as CBD. In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 is at least 3.5 times more stable than CBD. In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 is at least four times as stable as CBD. In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 is at least 4.5 times more stable than CBD. In some embodiments, the compound of formula (I) has a human liver microsomal stability T 1 / 2 is at least five times more stable than CBD.

[0302] As used herein, the “human liver microsomal stability T 1 / 2 " is determined according to the procedure described in Example 10.

[0303] In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of about 50 μM or more at 25° C. For example, the compound of formula (I) may have a solubility in 1% DMSO of about 50 to about 500 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of about 50 to about 75 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of about 75 to about 100 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of about 100 to about 125 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of about 125 to 150 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of more than about 150 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of greater than about 200 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of greater than about 300 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of greater than about 400 μM at 25° C. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO of greater than about 500 μM at 25° C.

[0304] In some embodiments, the compound of formula (I) has a greater solubility in 1% DMSO than CBD measured under the same experimental conditions. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO that is at least twice as high as that of CBD. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO that is at least three times as high as that of CBD. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO that is at least five times as high as that of CBD. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO that is at least 10 times as high as that of CBD. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO that is at least 20 times as high as that of CBD. In some embodiments, the compound of formula (I) has a solubility in 1% DMSO that is at least 30 times as high as that of CBD.

[0305] As used herein, the "solubility in 1% DMSO" of the compound of formula (I) is determined by conducting nephelometric experiments according to the procedure described in Example 8.

[0306] Terms in this specification may be used to describe a range of 1~4 Whenever a range is specified as "a range of alkyl," the range independently discloses and includes each element of the range. 1~4 Alkyl groups independently include C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, and C4 alkyl groups. As another non-limiting example, "n is an integer ranging from 0 to 2" independently includes 0, 1, and 2.

[0307] The term "at least one" refers to one or more, e.g., 1, 2, etc. For example, the term "at least one group" refers to one or more groups, e.g., 1 group, 2 groups, etc.

[0308] The term "alkyl" includes saturated straight-chain, branched, and cyclic (also specified as cycloalkyl) hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, secbutyl, isobutyl, tertbutyl, cyclobutyl, 1-methylbutyl, 1,1-dimethylpropyl, pentyl, cyclopentyl, isopentyl, neopentyl, cyclopentyl, hexyl, isohexyl, and cyclohexyl. Unless otherwise specifically stated in the specification, alkyl groups can be optionally substituted.

[0309] The term "aryl" includes hydrocarbon ring system groups that contain at least 6 carbon atoms and at least one aromatic ring. Aryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, and may include fused or bridged ring systems. Non-limiting examples of aryl groups include aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, aryl groups may be optionally substituted.

[0310] The term "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

[0311] The term "haloalkyl" includes an alkyl group as defined herein that is substituted with at least one halogen as defined herein. Non-limiting examples of haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. A "fluoroalkyl" is a haloalkyl group in which at least one halogen is fluoro. Unless otherwise specifically stated herein, a haloalkyl group can be optionally substituted.

[0312] The terms "heterocyclyl" or "heterocyclic ring" include 3- to 24-membered saturated or partially unsaturated non-aromatic ring groups containing 2 to 23 ring carbon atoms and 1 to 8 ring heteroatoms, each independently selected from N, O, and S. Unless stated otherwise specifically in the specification, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, can include fused, spiro or bridged ring systems, and combinations thereof, can be partially or fully saturated, and any nitrogen, carbon or sulfur atom of a heterocyclyl group can be optionally oxidized, and any nitrogen atom of a heterocyclyl group can be optionally quaternized. Non-limiting examples of heterocyclic rings include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, heterocyclyl groups may be optionally substituted.

[0313] The term "heteroaryl" includes 5- to 14-membered ring groups containing 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms each independently selected from N, O and S, and at least one aromatic ring. Unless stated otherwise specifically in the specification, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and can include fused or bridged ring systems, and the nitrogen, carbon or sulfur atoms of the heteroaryl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized. Non-limiting examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoi These include indolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.

[0314] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Non-limiting examples of pharmaceutically acceptable acid addition salts include acetate, adipate, ascorbate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and the like. The base addition salts include, but are not limited to, ammonium salts, isethionate, lactate, malate, maleate, malonate, mesylate, sulfate, sulfonate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, salicylate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Non-limiting examples of pharmaceutically acceptable base addition salts include aluminum, arginine, benzathine, calcium, choline, copper, diethylamine, diolamine, glycine, iron, lithium, lysine, magnesium, manganese, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Suitable base salts also include both unsubstituted and substituted ammonium salts. Hemi-salts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts.Pharmaceutically acceptable salts can be obtained, for example, by using standard procedures well known in the pharmaceutical field.For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002), which is incorporated herein by reference.

[0315] When the compounds of the present disclosure contain acidic and basic groups, they can also form internal salts, and such compounds are within the scope of the present disclosure. When the compounds contain hydrogen donating heteroatoms (e.g., NH), the salts are intended to cover the isomers formed by the transfer of said hydrogen atom to a basic group or atom within the molecule.

[0316] The term "substituted" includes situations in which at least one hydrogen atom in any of the above-mentioned groups is replaced by a non-hydrogen atom, such as a halogen atom, e.g., F, Cl, Br, and I; a carbon atom in groups such as alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, heterocyclylalkyl, and heteroarylalkyl; an oxygen atom in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also includes situations in which at least one hydrogen atom in any of the above groups is replaced by a heteroatom, such as the oxygen of oxo, carbonyl, carboxyl, and ester groups; and a higher order bond (e.g., a double or triple bond) to the nitrogen of groups such as imines, oximes, hydrazones, and nitriles.

[0317] The present disclosure includes within its scope all possible optical isomers of the compounds, such as diastereomers and enantiomers.Furthermore, the present disclosure includes within its scope both individual isomers and any mixtures thereof, such as racemic mixtures.Individual isomers can be obtained using the corresponding isomeric forms of starting materials, or can be separated according to conventional separation methods after preparation of the final compound.Conventional resolution methods, such as fractional crystallization and chiral chromatography, can be used to separate optical isomers, such as enantiomers, from their mixtures.

[0318] The present disclosure includes within its scope all possible tautomers. Furthermore, the present disclosure includes within its scope both the individual tautomers and any mixtures thereof.

[0319] The biological activity of the compounds described herein can be determined, for example, by performing at least one in vitro and / or in vivo study as conventionally performed in the art and described herein or in the art. In vitro assays include, but are not limited to, binding assays, immunoassays, competitive binding assays, and cell-based activity assays.

[0320] Conditions for a particular assay include temperature, buffers (including salts, cations, and media), and other components that maintain the integrity of any cells used in the assay and compounds, which are well known and / or can be readily determined by those of skill in the art. Those of skill in the art will also readily appreciate that appropriate controls can be designed and included when performing the in vitro and in vivo methods described herein.

[0321] Also provided is a pharmaceutical composition comprising at least one compound of formula (I).Such pharmaceutical compositions are described in more detail herein.These compounds and compositions can be used in the methods described herein.

[0322] In some embodiments, a method is disclosed for treating and / or preventing at least one disease, disorder, and / or condition for which treatment with a cannabinoid may be useful, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0323] In some embodiments, a method is disclosed for treating and / or preventing at least one disease, disorder, and / or condition for which treatment with an antagonist of the cannabinoid type 1 receptor (CB1R) and / or the cannabinoid type 2 receptor (CB2R) may be useful, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0324] In some embodiments, a method is disclosed for treating and / or preventing at least one disease, disorder, and / or condition for which treatment with an anti-anxiety, analgesic, anti-emetic, mood stabilizer, and / or anti-psychotic agent may be useful, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0325] In some embodiments, a method for treating and / or preventing at least one psychiatric disease, disorder, and / or condition is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0326] In some embodiments, the at least one psychiatric disease, disorder, and / or condition is selected from depression, anxiety, dementia, bipolar disorder, schizophrenia, addiction, and nausea. In some embodiments, the at least one psychiatric disease, disorder, and / or condition is selected from depression and anxiety.

[0327] In some embodiments, the at least one psychiatric disease, disorder, and / or condition is selected from depression, anxiety, dementia, schizophrenia, addiction, and nausea. In some embodiments, the at least one psychiatric disease, disorder, and / or condition is selected from depression and anxiety.

[0328] In some embodiments, a method is disclosed for treating and / or preventing at least one disease, disorder, and / or condition for which treatment with an anti-inflammatory, antioxidant, and / or neuroprotective agent may be useful, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0329] In some embodiments, disclosed is a method for treating and / or preventing pain, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising it.In some embodiments, the pain is neuropathic pain.In some embodiments, the pain is chronic pain.

[0330] In some embodiments, a method for treating and / or preventing diabetes is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0331] In some embodiments, a method for treating and / or preventing epilepsy or similar seizure disorder is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising it. The patient may include a patient with epilepsy that is not adequately controlled by existing drug therapy, an individual with developmental epileptic encephalopathy, or an individual with a rare disease or genetic condition that causes epilepsy, seizures, spasms, abnormal hypersynchronous brain activity, or other conditions associated with enhanced neuronal synchrony. In some embodiments, the patient may be a pediatric patient with epilepsy.

[0332] In some embodiments, a method for treating and / or preventing at least one neurological disease, disorder, and / or condition is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0333] In some embodiments, the at least one neurological disease, disorder, and / or condition is selected from major depressive mental disorder, conditions involving the basal ganglia or dopamine alterations, movement disorders, substance abuse / dependence or predisposition to substance abuse / dependence, pain disorders, learning disabilities, intellectual disabilities, developmental delays or conditions involving memory and / or cognition, multiple sclerosis, and circuit disorders.

[0334] In some embodiments, the at least one neurological disease, disorder, and / or condition is selected from depression, autism, postpartum depression, attention deficit disorder, schizophrenia, anxiety, various psychoses, and epilepsy.

[0335] In some embodiments, the at least one neurological disease, disorder, and / or condition is selected from depression, postpartum depression, attention deficit disorder, schizophrenia, anxiety, various psychoses, and epilepsy.

[0336] In some embodiments, the at least one neurological disease, disorder, and / or condition is selected from dystonia and related movement disorders, Parkinson's disease, and L-dopa-induced dyskinesia or dyskinesia resulting from drug therapy.

[0337] In some embodiments, the at least one neurological disease, disorder, and / or condition is selected from a neurodegenerative disease.

[0338] In some embodiments, the at least one neurological disease, disorder, and / or condition is selected from Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and frontal lobe dementia, as well as motor retraining following acute injury, spasticity, and spasticity resulting from brain or spinal cord injury.

[0339] In some embodiments, the at least one neurological disease, disorder, and / or condition is selected from Alzheimer's disease, Parkinson's disease, and frontal lobe dementia, as well as motor retraining following acute injury, spasticity, and spasticity resulting from brain or spinal cord injury.

[0340] In some embodiments, the at least one neurological disease, disorder, and / or condition is multiple sclerosis.

[0341] In some embodiments, the at least one neurological disease, disorder, and / or condition is selected from a circuit disorder.

[0342] In some embodiments, a method is disclosed for treating and / or preventing at least one disease, disorder, and / or condition associated with schizophrenia, Parkinson's disease, depression, anxiety, neuropsychiatric or mood disorders, motor dysfunction, spasticity, movement disorders, neuropathic pain, amyotrophic lateral sclerosis (ALS), epilepsy or other neurological events, neurocognitive disorders, tardive dyskinesia, movement disorders, and / or mood disorders, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising the same. An exemplary movement disorder is Huntington's disease (Peres et al., Front Pharmacol, 2018, 9:482).

[0343] In some embodiments, a method for treating at least one symptom associated with epilepsy and / or similar seizure disorders is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0344] In some embodiments, a method for treating at least one symptom associated with Lennox-Gastaut syndrome, Dravet syndrome, developmental epileptic encephalopathy, and / or tuberous sclerosis is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of Formula (I) and / or a pharmaceutical composition comprising same.

[0345] In some embodiments, a method for treating at least one symptom associated with Lennox-Gastaut syndrome, Dravet syndrome, and / or tuberous sclerosis is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of Formula (I) and / or a pharmaceutical composition comprising same.

[0346] In some embodiments, a method for reducing the severity and / or intensity of seizures associated with epilepsy and / or rare genetic disorders / diseases (e.g., those that may cause spontaneous seizures or abnormal electroencephalography) is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0347] In some embodiments, a method for reducing the frequency of seizures associated with epilepsy and / or rare genetic disorders / diseases (e.g., those that may cause spontaneous seizures or abnormal electroencephalography) is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0348] In some embodiments, a method for treating Parkinson's disease is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0349] In some embodiments, a method for treating at least one symptom of Parkinson's disease is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0350] In some embodiments, the at least one symptom of Parkinson's disease is selected from spasticity, rigidity, dystonia, and movement disorders.

[0351] In some embodiments, a method for treating and / or preventing ischemic injury, stroke, or stroke-related damage is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same. In some embodiments, the ischemic injury is caused by coronary artery bypass graft (CABG) or subarachnoid hemorrhage (SAH).

[0352] In some embodiments, a method for treating and / or preventing stroke or stroke-related damage is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0353] In some embodiments, a method for treating and / or preventing ischemic injury, stroke, or stroke-related damage is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising the same, wherein the at least one compound of formula (I) and / or a pharmaceutical composition comprising the same is administered under emergency care for ischemic injury or stroke. In some embodiments, the ischemic injury is caused by CABG or SAH.

[0354] In some embodiments, a method for treating and / or preventing stroke or stroke-related damage is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same, wherein the at least one compound of formula (I) and / or a pharmaceutical composition comprising same is administered under emergency care for stroke.

[0355] In some embodiments, a method for treating and / or preventing ischemic injury, stroke, or stroke-related damage is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising the same, wherein the at least one compound of formula (I) and / or a pharmaceutical composition comprising the same is administered under the maintenance treatment of ischemic injury or stroke. In some embodiments, the ischemic injury is caused by CABG or SAH.

[0356] In some embodiments, a method for treating and / or preventing stroke or stroke-related damage is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same, wherein the at least one compound of formula (I) and / or a pharmaceutical composition comprising same is administered under maintenance treatment of stroke.

[0357] In some embodiments, disclosed is a method for treating and / or preventing ischemic injury, stroke or stroke-related damage, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same, wherein at least one compound of formula (I) and / or a pharmaceutical composition comprising same is administered for rehabilitation of ischemic injury or stroke. In some embodiments, the ischemic injury is caused by CABG or SAH.

[0358] In some embodiments, a method for treating and / or preventing stroke or stroke-related damage is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same, wherein at least one compound of formula (I) and / or a pharmaceutical composition comprising same is administered for stroke rehabilitation.

[0359] In some embodiments, a method for treating traumatic brain injury (TBI) is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising the same. The effectiveness of cannabidiol in treating TBI has been documented in the art (e.g., Belardo et al., Front Pharmacol, 2019, 10:352; Friedman et al., Exp Neurol, 2021 346:113844).

[0360] In some embodiments, a method for treating TBI is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same, wherein the at least one compound of formula (I) and / or a pharmaceutical composition comprising same is administered under emergency care for TBI.

[0361] In some embodiments, a method for treating TBI is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same, wherein the at least one compound of formula (I) and / or a pharmaceutical composition comprising same is administered under maintenance treatment of TBI.

[0362] In some embodiments, a method for treating TBI is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same, wherein the at least one compound of formula (I) and / or a pharmaceutical composition comprising same is administered for rehabilitation of TBI.

[0363] In some embodiments, a method for treating sleep disorders is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising the same. The use of cannabidiol in treating sleep disorders has been documented in the art (e.g., Shannon et al., Perm J, 2019, 23:18-041; Babson et al., Curr Psychiatry Rep, 2017, 19(4):23; Suraev et al., Sleep Med Rev, 2020, 53:101339; de Almeida et al., Mov Disord, 2021, 36(7):1711-1715).

[0364] In some embodiments, disclosed is a method for treating hypertension or hypertension, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.The use of cannabidiol in reducing blood pressure has been documented in the art (e.g., Jadoon et al., JCI Insight, 2017, 2(12):e93760).

[0365] In some embodiments, methods for treating and / or preventing neuropathic pain are disclosed.In some embodiments, the neuropathic pain is selected from diabetic peripheral neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, rheumatoid arthritis, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic lower back pain, HIV neuropathic pain, trigeminal neuralgia and / or central post-stroke pain.

[0366] In some embodiments, neuropathic pain results from pathological events in the peripheral or central nervous system.

[0367] In some embodiments, the neuropathic pain results from trauma, ischemia; cancer (e.g., neuropathic pain caused by sensory fibers at the site of a tumor); infectious or ongoing metabolic or toxic disease, infectious or endocrinological disorder, including, but not limited to, diabetes mellitus, diabetic neuropathy, amyloidosis, amyloid polyneuropathy (primary and familial), neuropathy associated with monoclonal proteins, vasculitic neuropathy, HIV infection; neuropathy associated with Guillain-Barre syndrome; neuropathy associated with Fabry disease; trigeminal neuralgia and other CNS neuralgias; inflammatory conditions or autoimmune disorders, including, but not limited to, demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus; and idiopathic distal small fiber neuropathy. Other causes of neuropathic pain that can be treated according to the methods and compositions described herein include, but are not limited to, exposure to toxins or drugs (e.g., arsenic, thallium, alcohol, vincristine, cisplatin and dideoxynucleosides), dietary or absorption abnormalities, gammopathy.Neuropathic pain can also result from compression of nerve fibers, such as radiculopathy and carpal tunnel syndrome.

[0368] In some embodiments, a method is disclosed for treating and / or preventing at least one disease, disorder, and / or condition selected from chronic nerve injury, chronic pain syndrome, seizures, spreading depression, restless legs syndrome, hypoxic-ischemic encephalopathy, spinal cord injury, status epilepticus, concussion, migraine, hyperventilation, and / or retinopathy, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0369] In some embodiments, a method for treating and / or preventing ischemia following transient or permanent vascular occlusion is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0370] In some embodiments, a method is disclosed for reducing at least one symptom of neuropathic pain, stroke, epilepsy, and / or other neurological event or neurodegeneration, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0371] In some embodiments, a method for treating a subject being treated for cancer is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0372] In some embodiments, a method for reducing pain and / or nausea in a subject being treated for cancer is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0373] In some embodiments, a method for increasing appetite in a subject being treated for cancer is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0374] In some embodiments, a method for reducing cell viability in a subject being treated for cancer is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0375] In some embodiments, a method for increasing cancer cell death in a subject being treated for cancer is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0376] In some embodiments, a method for reducing tumor growth in a subject being treated for cancer is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0377] In some embodiments, a method for inhibiting metastasis of at least one cancer is disclosed, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) and / or a pharmaceutical composition comprising same.

[0378] In some embodiments, the administration of at least one compound of the present disclosure or the pharmaceutical composition comprising at least one such compound can be combined with one or more other treatments.For example, at least one symptom-relieving agent can be administered to counter (at least partially) the side effects of treatment (e.g., antidepressant treatment, antiepileptic treatment).The agents (chemical or biological) that promote recovery or counter the side effects of administering antibiotics or corticosteroids are examples of such symptom-relieving agents.

[0379] At least one compound described herein can be administered before, after, or simultaneously with the administration of at least one additional therapeutic agent or at least one symptom-relieving agent. When administration is simultaneous, the combination can be administered from a single container or from two (or more) separate containers.

[0380] The terms "treat" and "treatment" include medical management of a disease, disorder, and / or condition of a subject, as should be understood by those skilled in the art (see, for example, Stedman's Medical Dictionary). In general, an appropriate dose and treatment regimen provides at least one of the compounds of the present disclosure in an amount sufficient to provide a therapeutic benefit. Therapeutic benefit includes, for example, improved clinical outcomes, the purpose of which is to slow or reduce undesirable physiological changes or disorders, or to slow or reduce the spread or severity of such disorders. As discussed herein, improved clinical outcomes from treating a subject include, but are not limited to, attenuation, reduction, or alleviation of symptoms resulting from or associated with the disease, condition, and / or disorder being treated; reduced occurrence of symptoms; improved quality of life; reduced extent of disease; stabilization of disease state (i.e., not worsening); delayed or slow disease progression; remission or symptomatic relief of disease condition; and detectable or undetectable remission (whether partial or total); and / or overall survival. "Treatment" can include prolonging survival as compared to expected survival if the subject is not receiving treatment.

[0381] The terms "prevent" and "preventing" include reducing or lowering the likelihood of occurrence, recurrence, spread, or onset in a statistically or clinically significant manner. The present disclosure is not intended to be limited to complete prevention. In some embodiments, the onset of the disease is delayed or the severity is reduced.

[0382] In some embodiments of the methods described herein, the subject is a human. In some embodiments of the methods described herein, the subject is a human under the age of 18. In some embodiments of the methods described herein, the subject is a non-human animal. Non-human animals that can be treated include mammals, such as non-human primates (e.g., monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, rabbits), rabbits, pigs (e.g., pigs, mini pigs), horses, dogs, cats, cows, and other pets, livestock and zoo animals.

[0383] In some embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, gel, granule, aerosol, solution (e.g., aqueous solution, such as saline or phosphate buffer), suspension, nanoparticle formulation (including liposome), emulsion, etc. The pharmaceutical composition can also include one or more additional active agents, or can be administered in combination with one or more such active agents. In some embodiments, the pharmaceutical composition is an oral formulation. For example, the oral formulation can be in solid form, such as tablet, capsule, pill, and granule. Alternatively, the oral formulation can be in liquid form, such as solution, suspension, and emulsion.

[0384] The pharmaceutical composition for use in the present disclosure comprises an effective amount of at least one compound of formula (I) and a suitable pharmaceutically acceptable carrier if necessary.The preparation can be prepared in a manner known per se, which usually comprises mixing at least one compound according to the present disclosure with one or more pharmaceutically acceptable carriers, optionally with other pharmaceutically active compounds, under aseptic conditions if necessary.Again, please refer to standard texts, such as the latest edition of Remington's Pharmaceutical Sciences.

[0385] In some embodiments, the compounds of the present disclosure can be formulated as pharmaceutical compositions comprising at least one compound of formula (I), and at least one pharma- ceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally one or more additional pharma- ceutically active compounds.

[0386] In some embodiments, the pharmaceutical compositions of the present disclosure are in unit dosage form, suitably packaged, for example, in boxes, blisters, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose holders or containers (which may be precisely labeled), together with one or more leaflets containing product information and / or instructions for use, as appropriate. In some embodiments, such unit dosages contain between 1 and 1000 mg, or between 5 and 500 mg, of at least one compound of the present disclosure, for example, about 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg per unit dosage. For human patients (including both adult and pediatric patients), the dose of the compound of formula (I) may be less than 20 mg / kg per day, less than 15 mg / kg per day, less than 12.5 mg / kg per day, less than 10 mg / kg per day, less than 5 mg / kg per day, or less than 2.5 mg / kg per day. In some embodiments, the dose of the compound of formula (I) is less than 2.5 mg / kg per day.

[0387] The compounds and compositions of the present disclosure can be administered by various routes, including oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. In some embodiments, at least one compound of formula (I) or a composition comprising it is administered by inhalation through the lungs. In some embodiments, at least one compound of formula (I) or a composition comprising it is administered orally. In some embodiments, at least one compound of formula (I) or a composition comprising it is administered topically. In some embodiments, at least one compound of formula (I) or a composition comprising it is administered intravenously.

[0388] The effectiveness of the compounds of the present disclosure in treating and / or preventing disease, disorder, and / or condition can be easily determined by those skilled in the relevant field.The determination and adjustment of suitable administration regimen (e.g., the amount of compound per dose and / or the number of doses and the frequency of administration) can also be easily performed by those skilled in the relevant field.One or any combination of diagnostic methods, including physical examination, evaluation and monitoring of clinical symptoms, and carrying out the test and method for analysis described herein, can be used to monitor the health status of the subject.

[0389] The compounds described herein can be formulated in various ways depending on the mode of introduction. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, solutions (e.g., aqueous solutions, such as saline and buffered saline), suspensions, emulsions, creams, gels, ointments, salves, lotions, or aerosols. In some embodiments, these formulations are used in solid dosage forms suitable for easy oral administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms, such as solutions, syrups, suspensions, shakes, and the like, can also be utilized. In another embodiment, the formulation is administered topically. Suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels. In some embodiments, the topical formulation is a gel. In another embodiment, the formulation is administered intranasally.

[0390] In some embodiments, the pharmaceutical composition comprises at least one compound of formula (I) and a propellant.In some embodiments, the propellant is an aerosolized propellant.In some embodiments, the aerosolized propellant is selected from compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFAs), 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and combinations thereof.

[0391] In some embodiments, the present disclosure contemplates a pressurized or non-pressurized container comprising at least one compound of formula (I). In some embodiments, the container is a manual pump spray, an inhaler, a metered dose inhaler, a dry powder inhaler, a nebulizer, a vibrating mesh nebulizer, a jet nebulizer, or an ultrasonic nebulizer.

[0392] The formulation containing at least one compound of formula (I) can be prepared using a pharma- ceutically acceptable carrier, which is composed of a material that can be administered to an individual without causing undesirable biological side effects or undesirable interactions and is deemed safe and effective.Carrier is any component other than one or more active ingredients present in a pharmaceutical formulation.The term "carrier" generally used herein includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, pH modifiers, preservatives, antioxidants, solubility enhancers, and coating compositions.

[0393] Carriers also include all components of coating compositions, which may include additives, plasticizers, pigments, colorants, stabilizers, and glidants. Delayed-release, extended-release, and / or pulsatile-release dosage forms can be prepared as described in standard references, such as "Pharmaceutical dosage form tablets", eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), "Remington-The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6th Edition, Ansel et al., (Media, PA: Williams and Wilkins, 1995). These references provide information on carriers, materials, equipment, and methods for preparing tablets and capsules, as well as delayed-release dosage forms of tablets, capsules, and granules.

[0394] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers and methacrylic resins commercially available under the trademark Eudragit® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

[0395] In addition, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, flow promoters, stabilizers, pore formers, and surfactants.

[0396] Optional pharma- ceutically acceptable additives present in drug-containing tablets, beads, granules, or microgranules include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also called "fillers," may be desirable to bulk solid dosage forms so that a practical size is provided for tablet compression or bead and granule formation. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate, and powdered sugar.

[0397] Binders can be used to impart cohesive properties to solid dosage formulations and thus ensure that tablets or beads or granules remain intact after formation of the dosage form.Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, celluloses and veegum including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and synthetic polymers such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone.

[0398] Lubricants can be used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

[0399] Disintegrants can be used to facilitate the disintegration or "breakup" of the dosage form after administration. Exemplary disintegrants include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropylcellulose, pregelatinized starch, clay, cellulose, alginine, gums, and cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).

[0400] Stabilizers can be used to inhibit or retard drug decomposition reactions that include, for example, oxidative reactions.

[0401] The surfactant may be anionic, cationic, amphoteric or nonionic surface active agent.Suitable anionic surfactants include, but are not limited to, those containing carbonate, sulfonate and sulfate ions.Examples of anionic surfactants include sodium, potassium, ammonium long chain alkyl sulfonates and alkylaryl sulfonates, such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinate, such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinate, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates, such as sodium lauryl sulfate.Cationic surfactants include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4 oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0402] If desired, the tablets, beads, granules, or microgranules may also contain non-toxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.

[0403] The concentration of at least one compound of formula (I) relative to the carrier and / or other substances may vary from about 0.5 to about 100 wt% (weight percent). Pharmaceutical formulations for oral use may contain from about 5 to about 100 wt% of the active material. Pharmaceutical formulations for other uses may contain from about 0.5 to about 50 wt% of the active material.

[0404] The pharmaceutical compositions described herein can be formulated for modified or controlled release. Examples of controlled release dosage forms include extended release dosage forms, delayed release dosage forms, pulsatile release dosage forms, and combinations thereof.

[0405] Extended release formulations can be prepared as diffusion or osmotic systems, for example, as described in "Remington-The science and practice of pharmacy" (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000). Diffusion systems can consist of two types of devices, reservoirs and matrices, which are well known and described in the art. Matrix devices can be prepared by compressing the drug into tablet form with a slowly dissolving polymeric carrier. The three main types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, cellulose polymers, such as methyl and ethyl cellulose, and hydroxyalkyl celluloses, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and carbopol, i.e., CARBOPOL® 934, polyethylene oxide, and mixtures thereof. Fatty compounds include, but are not limited to, various waxes, such as carnauba wax and glyceryl tristearate, and waxy substances including hydrogenated castor oil or hydrogenated vegetable oil, and mixtures thereof.

[0406] In some embodiments, the plastic material is a pharma- ceutically acceptable acrylic polymer, including, but not limited to, acrylic and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer.

[0407] In some embodiments, the acrylic polymer is composed of one or more ammonio methacrylate copolymers, which are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters containing a low content of quaternary ammonium groups.

[0408] In some embodiments, the acrylic polymer is an acrylic resin lacquer, for example, commercially available from Rohm Pharma under the trademark EUDRAGIT®. In further embodiments, the acrylic polymer comprises a mixture of two acrylic resin lacquers, commercially available from Rohm Pharma under the trademarks EUDRAGIT® RL30D and EUDRAGIT® RS30D, respectively. EUDRAGIT® RL30D and EUDRAGIT® RS30D are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, with the molar ratio of ammonium groups to the remaining neutral (meth)acrylic acid esters being 1:20 for EUDRAGIT® RL30D and 1:40 for EUDRAGIT® RS30D. The average molecular weight is about 150,000. EUDRAGIT® S-100 and EUDRAGIT® L-100 are also contemplated. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. EUDRAGIT® RL / RS mixtures are insoluble in water and digestive fluids. However, multiparticulate systems formed to contain the mixtures can swell with and be permeable to aqueous solutions and digestive fluids.

[0409] The above-mentioned polymers, such as EUDRAGIT® RL / RS, can be mixed together in any desired ratio to ultimately obtain a sustained release formulation with a desired dissolution profile. A desirable sustained release multiparticulate system can be obtained, for example, from 100% EUDRAGIT® RL, 50% EUDRAGIT® RL and 50% EUDRAGIT® RS and 10% EUDRAGIT® RL and 90%:EUDRAGIT® 90% RS. Those skilled in the art will recognize that other acrylic polymers, such as, for example, EUDRAGIT® L, can also be used.

[0410] Alternatively, extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low and high permeability coating materials in suitable ratios.

[0411] The devices with the various drug release mechanisms described above can be combined into final dosage forms containing single or multiple units, including but not limited to multi-layer tablets, capsules containing tablets, beads or granules, etc.

[0412] The immediate release portion can be added to the extended release system by applying an immediate release layer on top of the extended release core using a coating or compression process, or in a multiple unit system, such as a capsule containing extended release and immediate release beads.

[0413] Extended release tablets containing hydrophilic polymers are prepared by techniques generally known in the art, such as direct compression, wet granulation, or dry granulation processes. Their formulations can incorporate polymers, diluents, binders, and lubricants, as well as pharmacoactive ingredients. Common diluents include inert powdered substances, such as starch, powdered cellulose, crystalline and microcrystalline cellulose, sugars, such as fructose, mannitol, and sucrose, granules, and similar edible powders. Diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts, such as sodium chloride, and powdered sugar. Powdered cellulose derivatives can also be useful. Tablet binders can include substances such as starch, gelatin, and sugars, such as lactose, fructose, and glucose. Natural and synthetic gums can also be used, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone. Polyethylene glycol, hydrophilic polymers, ethylcellulose, and waxes can also act as binders. Lubricants can be used in tablet formulations to prevent the tablet and punches from sticking in the die. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.

[0414] Extended release tablets containing wax materials can be prepared using methods known in the art, such as direct blending, congealing, and aqueous dispersion methods, in which the drug is mixed with the wax material, spray congealed or congealed, sieved, and processed.

[0415] Delayed release formulations can be fabricated by coating a solid dosage form with a polymer film that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

[0416] A delayed release dosage unit can be prepared, for example, by coating a drug or drug-containing composition with a selected coating material. The drug-containing composition can be, for example, a tablet for incorporation into a capsule, a tablet for use as an inner core of a "coated core" dosage form, or a plurality of drug-containing beads, granules, or granules for incorporation into a tablet or capsule. In some embodiments, the coating material includes a biodegradable polymer, a gradually hydrolyzable polymer, a gradually water-soluble polymer, and / or an enzymatically degradable polymer, and may be a conventional "enteric" polymer. Enteric polymers, as understood by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon.Suitable coating materials for delayed release include cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and sodium carboxymethyl cellulose; acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and Acrylic acid polymers and copolymers formed from and / or ethyl methacrylate, and EUDRAGIT® (Rohm) trademarks including EUDRAGIT® L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT® L-100 (soluble at pH 6.0 and above), EUDRAGIT® S (soluble at pH 7.0 and above as a result of a higher degree of esterification) and EUDRAGIT® NE, RL and RS (water-insoluble polymers with different degrees of permeability and extensibility). Other methacrylic resins commercially available from Pharma; Westerstadt, Germany; vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azopolymers, pectin, chitosan, amylose and guar gum; and zein and shellac. Combinations of different coating materials can also be used. Multiple coatings using different polymers can also be applied.

[0417] The coating weight of a particular coating material can be easily determined by those skilled in the art by evaluating the individual release profiles of tablets, beads, and granules prepared with different amounts of various coating materials. It is the combination of materials, methods, and application forms that results in the desired release characteristics, which combination can only be determined from clinical studies.

[0418] The coating composition may include conventional additives such as plasticizers, pigments, colorants, stabilizers, glidants, etc. The plasticizer may be present to reduce the brittleness of the coating. The plasticizer may be about 10 wt% to 50 wt% based on the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil, and acetylated monoglycerides. Stabilizers may be used to stabilize the particles in the dispersion. The stabilizers may be non-ionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. The glidants may reduce sticking effects during film formation and drying. The glidants may be approximately 25 wt% to 100 wt% of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearate can also be used. Pigments such as titanium dioxide can also be used. Small amounts of antifoaming agents such as silicones (e.g., simethicone) can also be added to the coating composition.

[0419] The formulation can provide a pulsatile delivery of one or more compounds of the present disclosure. By "pulsatile" it is meant that multiple drug doses are released at intervals. In some embodiments, when the dosage form is ingested, the release of the initial dose is substantially immediate, i.e., the first drug release "pulse" occurs within about 1 hour of ingestion. This initial pulse is followed by a first time interval (lag time) during which little or no drug is released from the dosage form, and then a second dose is released. Similarly, a second interval of little drug release may be designed between the second and third drug release pulses. The duration of the time interval of little drug release varies depending on the design of the dosage form, e.g., twice-daily dosing profile, three times-daily dosing profile, etc. For dosage forms that provide a twice-daily dosing profile, the interval of little drug release has a duration of approximately 3 hours to 14 hours between the first and second doses. For dosage forms that provide a three times a day profile, the interval during which little drug is released has a duration of approximately 2 to 8 hours between each of the three doses.

[0420] In some embodiments, a pulsatile release profile is achieved using a dosage form that is a closed, sealed capsule containing at least two drug-containing "dosage units," where each dosage unit within the capsule provides a different drug release profile. Control of the delayed-release dosage unit(s) can be achieved by controlled-release polymer coating of the dosage unit or by incorporating the active agent into a controlled-release polymer matrix. Each dosage unit can include a compressed or molded tablet, where each tablet within the capsule provides a different drug release profile. For a dosage form that mimics a twice-daily dosing profile, the first tablet releases drug substantially immediately after ingestion of the dosage form, while the second tablet releases drug approximately 3 hours to less than 14 hours after ingestion of the dosage form. For a dosage form that mimics a three times a day dosing profile, the first tablet releases drug substantially immediately after ingestion of the dosage form, the second tablet releases drug approximately 3 hours to less than 10 hours after ingestion of the dosage form, and the third tablet releases drug at least 5 hours to approximately 18 hours after ingestion of the dosage form. The dosage form may contain more than three tablets. The dosage form generally does not contain more than a third tablet, although dosage forms containing more than three tablets are available.

[0421] Alternatively, each dosage unit in the capsule may contain multiple drug-containing beads, granules, or fines. As known in the art, drug-containing "beads" refer to beads made with a drug and one or more additives or polymers. Drug-containing beads can be produced by applying the drug to an inert support, for example, coating an inert sugar bead with the drug, or by fabricating a "core" that contains both the drug and one or more additives. As also known, drug-containing "granules" and "fines" contain drug particles that may or may not contain one or more additional additives or polymers. In contrast to drug-containing beads, granules and fines do not contain an inert support. Granules contain drug particles and may require further processing. In some embodiments, fines are smaller than granules and are not further processed. Beads, granules, and fines can be formulated to provide immediate release, but beads and granules can also be used to provide delayed release.

[0422] In some embodiments, at least one compound of formula (I) is formulated for topical administration. Suitable topical dosage forms include lotions, creams, ointments and gels. A "gel" is a semi-solid system that contains a dispersion of an active agent, i.e., a compound, in a liquid vehicle, which is made semi-solid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. A liquid may contain a lipophilic component, an aqueous component, or both. Some emulsions may be gels or may otherwise contain gel components. However, some gels are not emulsions, for example because they do not contain a homogenized blend of immiscible components. Methods for preparing lotions, creams, ointments, and gels are well known in the art.

[0423] At least one compound of formula (I) can be administered adjunctively with other active compounds (i.e., in the same dosage form as one or more other active agents or in separate dosage forms).These other active compounds include, but are not limited to, analgesics, antinociceptive agents, anti-inflammatory agents, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatics, cardiovascular drugs (e.g., antihypertensives and antiarrhythmics), corticosteroids, dopaminergic substances, electrolytes, gastrointestinal drugs, mood stabilizers (e.g., for treating bipolar disorder), muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, appetite suppressants, and antinarcoleptics.

[0424] Specific examples of other active compounds that may be administered adjunctively with at least one compound of formula (I) include acetazolamide, aceclofenac, acetaminophen, atomoxetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amlodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, Budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clobazam, clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptyline, desipramine, desomorphine, dexamethasone , dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimethacrine, divalproex, zizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, felbamate, femoxetine, fenamate, pheno profen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, gabitril, galantamine, gepirone, ginkgo, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketaserin, ketoprofen, ketorolac,Lacosamide, Lamotrigine (Anticonvulsant and Mood Stabilizer), Lesopitron, Levodopa, Levetiracetam, Lipase, Lithium (Mood Stabilizer), Lofepramine, Lorazepam, Loxapine, Maprotiline, Mazindol, Mefenamic Acid, Melatonin, Melitracen, Memantine, Meperidine, Meprobamate, Mesalamine, Methsuximide, Metapramine, Metaxalone, Methadone, Methamphetamine, Methocarbamol, Methyldopa, Methylphenidate, Methylsalicylate, Methysergide, Metoclopramide, Mianserin, Mifepramine Liston, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (anti-narcolepsy drug), molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neurontin, nitrazepam, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozan, oxaprozin, oxazepam, oxytriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemorylamide pentazocine, pepsin, perphenazine, phenobarbital, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirlindole, piroxicam, pizotifen, pizotyline, pramipexole, prednisolone, prednisone, pregabalin, primidone, propranolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxetine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, Xib, ropinirole, rotigotine, rufinamide, salsalate, sertraline, sibutramine, sildenafil, stiripentol, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenazine, thiazide, thioridazine, thiothixene, tiapride, taziprinone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine,These include, but are not limited to, vigabatrin, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zonisamide, zopiclone, and isomers, salts and combinations of any of the foregoing.

[0425] The additional active agent(s) may be formulated together or separately from the compounds of the present disclosure for immediate release, controlled release, or a combination thereof.

[0426] Kits are provided that contain unit doses of at least one compound of the present disclosure, for example, oral or injectable doses.Such kits can include a container that contains the unit dose, an information package insert that describes the use and associated benefits of the therapeutic agent in treating the pathological condition of interest, and / or an appliance or device for delivery of at least one compound of formula (I) and / or pharmaceutical compositions that contain it, if necessary. EXAMPLES

[0427] Compounds of formula (I) can be prepared, for example, as shown in Figures 1-7. It is understood that those skilled in the art can make these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art can make other compounds of formula (I) that are not specifically shown herein by using appropriate starting components and modifying the parameters of the synthesis, if necessary. In general, the starting components can be obtained from sources such as, for example, Sigma-Aldrich, Alfa Aesar, Maybridge, Matrix Scientific, TCI, and Fluorochem USA, and / or can be synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), and / or can be prepared as described herein.

[0428] It will also be appreciated by those skilled in the art that the methods described herein may require the protection of functional groups of intermediate compounds by suitable protecting groups even if not specifically described. Such functional groups include hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include, but are not limited to, trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include, but are not limited to, t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include, but are not limited to, -C(O)R" (wherein R" is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include, but are not limited to, alkyl, aryl, or arylalkyl esters. Protecting groups can be added or removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As would be understood by one of skill in the art, the protecting group may be a polymer resin, such as a Wang resin, a Rink resin, or a 2-chlorotrityl chloride resin.

[0429] Reactants similar to those described herein can be identified by the index of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, available in most public and university libraries, as well as in online databases (for further details, the American Chemical Society, Washington, DC, can be contacted). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis companies, and many of the standard chemical supply companies (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0430] Methods known to those skilled in the art can be identified in various reference books, articles, and databases.Suitable reference books and specialized books that detail the synthesis of reactants useful in preparing the compounds of the present disclosure or refer to articles that describe the preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions," 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992. Further suitable reference and technical books detailing the synthesis of reactants useful in the preparation of the compounds of the present disclosure or referencing articles describing the preparation include, for example, Fuhrhop, J. and Penzlin, G., "Organic Synthesis: Concepts, Methods, Starting Materials," Second, Revised and Enlarged Edition, John Wiley & Sons ISBN: 3-527-29074-5, 1994; Hoffman, RV, "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC, "Organic Synthesis: Concepts, Methods, Starting Materials," Second, Revised and Enlarged Edition, John Wiley & Sons ISBN: 3-527-29074-5, 1994;"Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4、March, J., "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2、Otera, J. (editor), "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1、Patai, S., "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9、Quin, L.D., et al., "A Guide to Organophosphorus Chemistry" (2000) Wiley-Interscience, ISBN: 0-471-31824-8、Solomons, T.W.G., "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0、Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopaedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes, "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes, and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0431] The present disclosure will now be described in more detail with reference to the following non-limiting Examples. It should be noted that the particular assays used in the Examples section are designed to demonstrate activity.

[0432] All publications and patent documents cited in this specification are incorporated herein by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated herein by reference to disclose and describe the methods and / or materials in which the publications are cited.

[0433] The following examples describe work to create phosphate-based prodrugs of CBD that have increased water solubility, enhanced cellular absorption, improved metabolic stability, and / or more favorable tissue distribution. General chemical synthesis and characterization

[0434] Automated flash column chromatography was performed using a Teledyne ISCO CombiFlash® Companion system equipped with a silica gel packed column (SiliCycle Inc. or RediSep® Rf). Analytical thin layer chromatography (TLC, commercially available from Sigma-Aldrich) was performed using a fluorescent indicator (F-254) on silica gel plates with aluminum support (200 μm thick) or glass support (240 μm thick). Visualization of compounds on the TLC plates was achieved using UV light (254 nm) and / or with phosphomolybdic acid (PMA), potassium permanganate (KMnO4) or ammonium cerium molybdate (CAM) dyes. NMR spectra ( 1 H, 31 P) were obtained using either a Varian INOVA 600 MHz spectrometer, a Varian INOVA 500 MHz spectrometer, a Varian INOVA 400 MHz spectrometer, a Varian VNMR 400 MHz spectrometer, a Bruker AVIIIHD 600 MHz spectrometer or a Mercury 300 MHz spectrometer. NMR samples were analyzed in deuterated dimethylsulfoxide (DMSO-d6) or deuterated methanol (CD3OD) using the residual solvent peak (DMSO-d6: 1 H=2.54ppm, CD3OD: 1 H=3.31 ppm. Alternatively, 1 Residual dimethyl sulfoxide or methanol peaks in H NMR were 31 P NMR was used as the absolute reference. In some cases, phosphoric acid ( 31 P=40.48ppm) 31P was used as an external reference for NMR. All NMR spectra were processed using MestReNova software. NMR data are reported including chemical shift (δ) (reported in ppm), multiplicity indicated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad line), or app (apparent), coupling constant (J) (reported in Hz), and integrals normalized to one atom (H, P). The purity of the final compounds was determined by the following formula: 1 It was characterized using 1 H NMR and LC-MS. General bioanalysis experiments, measurement methods and materials

[0435] All solvents for LC-MS / MS analysis were UHPLC grade. Methanol and water were purchased from Thermo Fischer, and acetonitrile was obtained from Sigma-Aldrich. HPLC grade formic acid was obtained from Thermo Fischer. LC-MS vials with integrated inserts and screw caps were obtained from VWR.

[0436] An Agilent 1260 Infinity II HPLC system was utilized, including a micro vacuum degasser, a quaternary pump, a high-performance autosampler with a thermostat, and a thermostated column compartment connected to an Agilent 6460C triple quadrupole mass spectrometer. The mass spectrometer was operated in ESI mode using Agilent Jet Stream Technology. Agilent MassHunter Workstation (version B.02.00) was used for data acquisition, and MassHunter quantitative analysis software (version B.01.04) was used for data analysis. We optimized two important MS parameters, namely fragmentor voltage and collision energy, using Agilent MassHunter Optimizer software (B.02.00). The optimization tool also yielded the most abundant MRM transitions used in this study. Individual methods were developed for each compound in the positive mode in the presence of the internal standard (ISTD) d5-7-ethoxycoumarin. All compounds were analyzed using multiple reaction monitoring (MRM) with quantification and qualification of ions for increased confidence. For each compound, reversed-phase HPLC separation was achieved on an Agilent Infinity Poroshell 120 EC C18 or C8 column, or an Eclipse XDB C18 column (2.1 x 50 mm, 2.7 micron). The mobile phase consisted of water (0.1% formic acid) and ACN (0.1% formic acid) at a flow rate of 0.5 mL / min. The column temperature was maintained at 40°C for most of the samples unless otherwise noted. Other MS conditions were as follows: residence time 100 ms, gas flow 10 L / min, nebulizer pressure 45 psi, Delta EMV200V. Example 1 (Compounds 7a~f) Synthesis of alpha-substituted ester linked monoester phosphate prodrug derivatives. Synthesis Procedure:

[0437] Compounds with a monoester phosphate prodrug moiety attached to the CBD by an alpha-substituted ester linker were designed and synthesized using the procedure described below. The synthesis of monoester phosphate prodrugs 7a-f is shown in FIG. 1.

[0438] The glycolic acid derivatives 3a–e were obtained by two synthetic routes. First, the glycolic acid ethyl ester derivatives 1a–c were reacted with tetrabenzyl pyrophosphate by slow addition of DBU acting as a base to give the dibenzyl phosphate analogs 2a–c. In contrast, the methyl-substituted glycolic acid ester analogs 1d–e were first reacted with dibenzyl N,N-diisopropyl phosphoramidite in the presence of 5-methyl-1H-tetrazole and subsequently oxidized to the phosphate by hydrogen peroxide to give the dibenzyl phosphate analogs 2d–e. The glycolic acid ester derivatives 2a–e were then hydrolyzed using lithium hydroxide monohydrate to give the glycolic acid derivatives 3a–e. To avoid the formation of diester intermediates, silyl protecting groups were incorporated on CBD and cannabidivarin (CBDV). Commercially available cannabidiol or cannabidivarin isolates (4a or 4b, respectively) and imidazole were treated with TBDMSOTf and stirred overnight at room temperature to generate TBDMS-protected CBD or CBDV intermediates 5a–b. Stöcklich esterification between 5a–b and presynthesized carboxylic acids 3a–e proceeded smoothly to give silyl-protected intermediates, which were isolated by aqueous workup and column chromatography and deprotected using a 1 M solution of TBAF in THF. This afforded the penultimate dibenzyl phosphate compounds 6a–f, which were catalyzed by palladium acetate and triethylsilane promoted debenzylation of the phosphate moiety.

[0439] Exposure of the compounds to NH4OH followed by purification afforded the desired prodrugs 7a-f as bisammonium salts. Chemical Characterization: [ka]

[0440] Compound 7a: 2-(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)-2-oxoethyl phosphate diammonium salt.

[0441] 1 H NMR (600 MHz, DMSO-d6) δ 7.36 (s, 1H), 6.49 (s, 1H), 6.24 (s, 1H), 4.98 (s, 1H), 4.46 - 4.37 (m, 3H), 4.30 (s, 1H), 3.81 (br s, 1H), 2.62 (br s, 1H), 2.43 - 2.36 (m, 2H), 2.16 (s, 1H), 1.96 - 1.88 (m, 1H), 1.70 - 1.62 (m, 2H), 1.60 (s, 3H), 1.58 (s, 3H), 1.53 - 1.45 (m, 2H), 1.33 - 1.20 (m, 4H), 0.85 (t, J = 7.1 Hz, 3H); 31 P NMR (243 MHz, DMSO-d6) δ -1.14. [ka]

[0442] Compound 7b: 1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl phosphate diammonium salt.

[0443] 1H NMR (400 MHz, DMSO-d6) δ 7.32 (s, 1H), 6.45 (s, 1H), 6.24 (s, 1H), 5.02 (s, 1H), 4.51 (s, 1H), 4.41 (s, 1H), 3.80 (br s, 1H), 2.74 (br s, 1H), 2.41 - 2.33 (m, 2H), 2.14 (s, 1H), 1.97 - 1.87 (m, 1H), 1.74 - 1.60 (m, 2H), 1.59 (s, 3H), 1.56 (s, 3H), 1.53 - 1.44 (m, 2H), 1.38 - 1.08 (m, 8H), 0.86 (t, J = 6.9 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -1.73. [ka]

[0444] Compound 7c: 3-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclobutyl phosphate diammonium salt.

[0445] 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 6.47 (s, 1H), 6.19 (s, 1H), 5.00 (s, 1H), 4.51 - 4.39 (m, 3H), 3.82 (br s, 1H), 2.94 (q, J = 7.2 Hz, 1H), 2.75 (br s, 1H), 2.63 - 2.54 (m, 2H), 2.39 (t, J = 7.7 Hz, 2H), 2.26 - 2.15 (m, 2H), 2.11 (s, 1H), 1.98 - 1.88 (m, 1H), 1.72 - 1.60 (m, 2H), 1.57 (s, 6H), 1.53 - 1.44 (m, 2H), 1.33 - 1.20 (m, 4H), 0.85 (t, J = 7.0 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -2.49. [ka]

[0446] Compound 7d: 1-(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)-1-oxopropan-2-yl phosphate diammonium salt.

[0447] 1H NMR (400 MHz, DMSO-d6) δ 7.32 (s, 1H), 6.48 (s, 1H), 6.25 (s, 1H), 5.04 (s, 1H), 4.77 - 4.65 (m, 1H), 4.48 (s, 1H), 4.41 (s, 1H), 3.82 (br s, 1H), 2.70 (br s, 1H), 2.43 - 2.34 (m, 2H), 2.13 (s, 1H), 1.96 - 1.87 (m, 1H), 1.66 (dq, J = 12.5, 7.4, 5.2 Hz, 2H), 1.57 (s, 6H), 1.53 - 1.45 (m, 2H), 1.40 (d, J = 6.7 Hz, 2H), 1.33 - 1.20 (m, 4H), 0.86 (t, J = 6.9 Hz, 4H); 31 P NMR (162 MHz, DMSO-d6) δ -1.23. [ka]

[0448] Compound 7e: 1-(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)-2-methyl-1-oxopropan-2-yl phosphate diammonium salt.

[0449] 1H NMR (600 MHz, CD3OD) δ 6.47 (d, J = 1.7 Hz, 1H), 6.41 (d, J = 1.7 Hz, 1H), 5.21 (s, 1H), 4.55 - 4.52 (m, 1H), 4.45 (s, 1H), 3.35 (s, 1H), 2.46 (t, J = 7.68 Hz, 2H), 2.22 - 2.11 (m, 1H), 2.04 - 1.97 (m, 1H), 1.79 - 1.71 (m, 8H), 1.65 - 1.53 (m, 8H), 1.39 - 1.26 (m, 5H), 0.90 (t, J = 7.1 Hz, 3H). 31 P NMR (243 MHz, CD3OD) δ -4.93. [ka]

[0450] Compound 7f: 1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl phosphate diammonium salt.

[0451] 1H NMR (400 MHz, DMSO-d6) δ 6.46 (d, J = 1.7 Hz, 1H), 6.23 (d, J = 1.7 Hz, 1H), 5.04 - 4.99 (m, 1H), 4.53 - 4.48 (m, 1H), 4.43 - 4.37 (m, 1H), 3.69 (br s, 1H), 2.85 - 2.67 (m, 1H), 2.36 (t, J = 7.7 Hz, 2H), 2.20 - 2.08 (m, 1H), 1.97 - 1.87 (m, 1H), 1.72 - 1.60 (m, 1H), 1.58 (s, 3H), 1.56 (s, 3H), 1.54 - 1.44 (m, 2H), 1.25 - 1.17 (m, 2H), 1.14 (t, J = 7.3 Hz, 4H), 0.86 (t, J = 7.3 Hz, 3H). 31 P NMR (162 MHz, DMSO-d6) δ -1.41. Example 2 (Compounds 8 and 14a-k) Synthesis of Ester-Linked Diester Phosphate Prodrug Derivatives. Synthesis Procedure:

[0452] Compounds with a diester phosphate prodrug moiety attached to the CBD by a cyclopropyl glycolate linker were designed and synthesized using the procedure described below. The synthesis of diester phosphate prodrugs 8 and 14a-k is shown in FIG. 2.

[0453] First, the stoichiometry of triethylsilane added in the palladium acetate catalyzed deprotection of the benzyl phosphate of 6b was reduced to 1.2 equivalents, which promoted the monodebenzylation of 6b and the monobenzyl diester phosphate prodrug 8 (obtained as the ammonium salt by treatment with NH4OH).

[0454] To access the remaining diester phosphate prodrugs 14a-k, the corresponding substituted phosphorochloridates were first synthesized. The cooled phosphoryl chloride solution was treated sequentially by dropwise addition of 1 equivalent of triethylamine and the respective alcohol (9a-k), followed by 1 equivalent of triethylamine and benzyl alcohol. After aqueous workup with 1M citric acid, the pure phosphorochloridates 10a-k were isolated by column chromatography. Acylation of 2b with 10a-k was carried out utilizing DBU as base, followed by subsequent ester hydrolysis using lithium hydroxide monohydrate in a THF / H2O mixture to give the carboxylic acid derivatives 12a-k. As previously described, Stecklich esterification between 5a and 12a-k gave the silyl-protected intermediates, which were isolated by aqueous workup and column chromatography and deprotected using a 1M solution of TBAF in THF to give the respective substituted phosphate compounds 13a-k. Debenzylation using 1.2 equivalents of triethylsilane and palladium acetate afforded the desired diester phosphate prodrugs 14a-k as ammonium salts after treatment with NH4OH. Chemical Characterization: [ka]

[0455] Compound 8: benzyl (1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl)phosphate ammonium salt.

[0456] 1H NMR (400 MHz DMSO-d6) δ 9.39 (br s, 1H), 7.35 - 7.19 (m, 5H), 6.44 (s, 1H), 6.19 (s, 1H), 5.01 (s, 1H), 4.80 (s, 2H), 4.46 (s, 1H), 4.37 (s, 1H), 3.73 (br s, 1H), 2.74 (br s, 1H), 2.34 (t, J = 7.8 Hz, 2H), 2.21 - 2.08 (m, 1H), 1.97 - 1.87 (m, 1H), 1.70 - 1.59 (m, 2H), 1.57 (s, 3H), 1.54 (s, 3H), 1.48 - 1.40 (m, 2H), 1.31- 1.18 (m, 4H), 1.15 (t, J = 7.3 Hz, 4H), 0.84 (t, J = 6.9 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -2.48. [ka]

[0457] Compound 14a: 1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl isopropyl phosphate ammonium salt.

[0458] 1H NMR (400 MHz, DMSO-d6) δ 9.44 (br s, 1H), 6.45 (s, 1H), 6.25 (s, 1H), 5.01 (s, 1H), 4.47 (s, 1H), 4.40 (s, 1H), 4.39 - 4.31 (m, 1H), 3.72 (br s, 1H), 2.74 (br s, 1H), 2.38 (t, J = 7.8 Hz, 2H), 2.21 - 2.08 (m, 1H), 1.97 - 1.87 (m, 1H), 1.71 - 1.60 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.52 - 1.40 (m, 2H), 1.32- 1.20 (m, 4H), 1.17 (t, J = 7.3 Hz, 4H), 1.11 (dd, J = 6.2, 2.5 Hz, 6H), 0.85 (t, J = 6.9 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -2.86. [ka]

[0459] Compound 14b: 1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl pentyl phosphate ammonium salt.

[0460] 1H NMR (400 MHz, DMSO-d6) δ 9.49 (br s, 1H), 6.46 (s, 1H), 6.23 (s, 1H), 5.01 (s, 1H), 4.46 (s, 1H), 4.40 (s, 1H), 3.73 (br s, 3H), 2.70 (br s, 1H), 2.38 (t, J = 7.7 Hz, 2H), 2.20 - 2.08 (m, 1H), 1.97 - 1.87 (m, 1H), 1.72 - 1.61 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.54 - 1.41 (m, 5H), 1.32 - 1.19 (m, 9H), 1.17 (t, J = 7.3 Hz, 2H), 0.88 - 0.79 (m, 6H); 31 P NMR (162 MHz, DMSO-d6) δ -2.65. [ka]

[0461] Compound 14c: 1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl isopentyl phosphate ammonium salt.

[0462] 1H NMR (400 MHz, DMSO-d6) δ 9.44 (br s, 1H), 6.45 (s, 1H), 6.24 (s, 1H), 4.47 (s, 1H), 4.40 (s, 1H), 3.80 - 3.72 (m, 3H), 2.74 (br s, 1H), 2.38 (t, J = 7.7 Hz, 2H), 2.21 - 2.10 (m, 1H), 1.97 - 1.87 (m, 1H), 1.71 - 1.60 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.53 - 1.43 (m, 4H), 1.40 - 1.33 (m, 2H), 1.31 - 1.20 (m, 5H), 1.19 - 1.13 (m, 3H), 0.88 - 0.78 (m, 9H); 31 P NMR (162 MHz, DMSO-d6) δ -2.38. [ka]

[0463] Compound 14d: hexyl(1-((((1′R,2′R)-6-hydroxy-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl)phosphate ammonium salt.

[0464] 1H NMR (400 MHz, DMSO-d6) δ 9.55 (br s, 1H), 6.47 (s, 1H), 6.22 (s, 1H), 5.01 (s, 1H), 4.49 - 4.44 (m, 1H), 4.42 - 4.36 (m, 1H), 3.78 - 3.68 (m, 2H), 2.70 (br s, 1H), 2.37 (t, J = 7.7 Hz, 2H), 2.21 - 2.09 (m, 1H), 1.97 - 1.87 (m, 1H), 1.71 - 1.60 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.52 - 1.41 (m, 5H), 1.34 - 1.12 (m, 16H), 0.87 - 0.81 (m, 6H); 31 P NMR (162 MHz, DMSO-d6) δ -2.53. [ka]

[0465] Compound 14e: heptyl(1-((((1′R,2′R)-6-hydroxy-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl)phosphate ammonium salt.

[0466] 1H NMR (400 MHz, DMSO-d6) δ 9.55 (br s, 1H), 6.47 (s, 1H), 6.22 (s, 1H), 5.01 (s, 1H), 4.49 - 4.44 (m, 1H), 4.42 - 4.36 (m, 1H), 3.78 - 3.68 (m, 2H), 2.70 (br s, 1H), 2.37 (t, J = 7.7 Hz, 2H), 2.21 - 2.09 (m, 1H), 1.97 - 1.87 (m, 1H), 1.71 - 1.60 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.52 - 1.41 (m, 5H), 1.34 - 1.12 (m, 16H), 0.87 - 0.81 (m, 6H); 31 P NMR (162 MHz, DMSO-d6) δ -2.53. [ka]

[0467] Compound 14f: 1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl nonyl phosphate ammonium salt.

[0468] 1H NMR (400 MHz, DMSO-d6) δ 9.47 (br s, 1H), 6.45 (s, 1H), 6.23 (s, 1H), 5.01 (s, 1H), 4.47 (s, 1H), 4.39 (s, 1H), 3.75 - 3.66 (m, 3H), 2.74 (br s, 1H), 2.38 (t, J = 7.7 Hz, 2H), 2.22 - 2.08 (m, 1H), 1.97 - 1.86 (m, 1H), 1.72 - 1.61 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.52 - 1.40 (m, 5H), 1.32 - 1.12 (m, 20H), 0.90 - 0.80 (m, 6H); 31 P NMR (162 MHz, DMSO-d6) δ -2.18. [ka]

[0469] Compound 14g: decyl(1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl)phosphate ammonium salt.

[0470] 1H NMR (400 MHz, DMSO-d6) δ 9.46 (br s, 1H), 6.45 (s, 1H), 6.23 (s, 1H), 5.01 (s, 1H), 4.49 - 4.44 (m, 1H), 4.42 - 4.36 (m, 1H), 3.79 - 3.69 (m, 2H), 2.73 (br s, 1H), 2.38 (t, J = 7.7 Hz, 2H), 2.21 - 2.09 (m, 1H), 1.97 - 1.86 (m, 1H), 1.74 - 1.60 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.53 - 1.40 (m, 6H), 1.32 - 1.13 (m, 21H), 0.88 - 0.80 (m, 6H); 31 P NMR (162 MHz, DMSO-d6) δ -2.47. [ka]

[0471] Compound 14h: 1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl(2-propylpentyl)phosphate ammonium salt.

[0472] 1H NMR (400 MHz, DMSO-d6) δ 9.44 (br s, 1H), 6.45 (s, 1H), 6.24 (s, 1H), 5.01 (s, 1H), 4.49 - 4.44 (m, 1H), 4.42 - 4.36 (m, 1H), 3.69 (br s, 1H), 3.66 - 3.56 (m, 2H), 2.79 (br s, 1H), 2.37 (t, J = 7.7 Hz, 2H), 2.22 - 2.09 (m, 1H), 1.97 - 1.85 (m, 1H), 1.71 - 1.60 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.53 - 1.38 (m, 4H), 1.32 - 1.07 (m, 15H), 0.90 - 0.76 (m, 9H); 31 P NMR (162 MHz, DMSO-d6) δ -2.03. [ka]

[0473] Compound 14i: 1-((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl(2-methoxyethyl)phosphate ammonium salt.

[0474] 1H NMR (400 MHz, DMSO-d6) δ 9.44 (br s, 1H), 6.49 - 6.44 (m, 1H), 6.28 - 6.23 (m, 1H), 5.02 (s, 1H), 4.49 - 4.39 (m, 2H), 3.87 - 3.76 (m, 2H), 3.22 (s, 3H), 3.06 - 2.98 (m, 2H), 2.73 (br s, 1H), 2.42 - 2.35 (m, 2H), 2.15 (s, 1H), 1.93 (s, 1H), 1.71 - 1.62 (m, 2H), 1.59 (s, 3H), 1.56 (s, 3H), 1.53 - 1.44 (m, 2H), 1.34 - 1.22 (m, 4H), 1.21 - 1.12 (m, 4H), 0.86 (t, J = 6.9 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -2.30. [ka]

[0475] Compound 14j: 1-((((1′R,2′R)-6-hydroxy-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)carbonyl)cyclopropyl(2-(2-methoxyethoxy)ethyl)phosphate ammonium salt.

[0476] 1H NMR (400 MHz, DMSO-d6) δ 9.48 (br s, 1H), 6.51 - 6.41 (m, 1H), 6.30 - 6.23 (m, 1H), 5.07 - 4.99 (m, 1H), 4.53 - 4.37 (m, 2H), 3.82 (s, 2H), 3.52 - 3.43 (m, 6H), 3.23 (s, 3H), 2.74 (br s, 1H), 2.42 - 2.36 (m, 2H), 2.14 (s, 1H), 1.99 - 1.88 (m, 1H), 1.74 - 1.61 (m, 2H), 1.59 (s, 3H), 1.56 (s, 3H), 1.54 - 1.44 (m, 2H), 1.34 - 1.21 (m, 4H), 1.22 - 1.13 (m, 4H), 0.86 (t, J = 6.9 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -2.58. [ka]

[0477] Compound 14k: (1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl 1-(((2-aminoethoxy(hydroxy)phosphoryl)oxy)-cyclopropane-1-carboxylate.

[0478] 1H NMR (400 MHz, DMSO) δ 9.40 (br s, 1H), 8.36 (br s, 2H), 6.45 (d, J = 1.7 Hz, 1H), 6.21 (d, J = 1.6 Hz, 1H), 5.03 (s, 1H), 4.50 - 4.45 (m, 1H), 4.43 - 4.38 (m, 1H), 3.97 - 3.87 (m, 2H), 3.75 (br s, 1H), 3.00 - 2.88 (m, 2H), 2.69 (br s, 1H), 2.39 (t, J = 7.7 Hz, 2H), 2.21 - 2.08 (m, 1H), 1.98 - 1.88 (m, 2H), 1.72 - 1.64 (m, 2H), 1.59 (s, 3H), 1.56 (s, 3H), 1.53 - 1.42 (m, 4H), 1.34 - 1.18 (m, 6H), 0.85 (t, J = 6.9 Hz, 3H). 31 P NMR (162 MHz, DMSO) δ -1.29. Example 3 (Compound 24) Synthesis of carbonate linked monoester phosphate prodrug derivatives. Synthesis Procedure:

[0479] Compounds with a monoester phosphate prodrug moiety attached to the CBD by a carbonate linker were designed and synthesized using the following procedure: The synthesis of methylene carbonate linked monoester phosphate prodrug 24 is shown in FIG.

[0480] To obtain intermediate 21, the two component fragments 17 and 20 had to be synthesized first. Dibenzyl phosphate 15 was stepwise converted to its silver salt using silver nitrate, followed by treatment with tetrabutylammonium bromide to give tetrabutylammonium salt 17. For fragment 20, acylation between 2-butanethiol and chloromethyl chloroformate gave intermediate 19, which underwent Finkelstein reaction to give 20. Fragments 17 and 20 were then reacted in THF for 24 h to give intermediate 21. Conversion to acid chloride 22 was promoted by sulfuryl chloride, followed immediately by acylation with TBDMS-protected CBD (5a) and TBAF-mediated deprotection to give dibenzyl phosphate compound 23. Finally, palladium acetate and triethylsilane-mediated debenzylation, and treatment with NH4OH gave the target methylene carbonate-linked phosphate prodrug 24 as a diammonium salt. Chemical characterization [ka]

[0481] Compound 24: (1'R,2'R)-6-Hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl((phosphonooxy)methyl)carbonate diammonium salt.

[0482] 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 6.56 - 6.49 (m, 1H), 6.33 (d, J = 1.6 Hz, 1H), 5.49 - 5.41 (m, 1H), 5.37 - 5.31 (m, 1H), 5.10 - 4.97 (m, 1H), 4.50 - 4.38 (m, 2H), 3.19 - 3.14 (m, 1H), 2.72 (s, 1H), 2.45 - 2.37 (m, 2H), 2.13 (s, 1H), 1.98 - 1.86 (m, 1H), 1.71 - 1.62 (m, 2H), 1.62 - 1.55 (m, 6H), 1.53 - 1.44 (m, 2H), 1.36 - 1.21 (m, 4H), 0.86 (t, J = 6.9 Hz, 3H); 31 P NMR (162 MHz, DMSO) δ -2.27. Example 4 (Compounds 29a-c) Synthesis Procedure:

[0483] The synthesis of longer chain carbonate linked monoester phosphate prodrugs 29a-c is shown in FIG.

[0484] To synthesize the longer chain carbonate-linked phosphate prodrugs, commercially available TBDMS-protected alcohols 25a-c were reacted with dibenzyl N,N-diisopropyl phosphoramidite and then oxidized with hydrogen peroxide to give the dibenzyl phosphate intermediates 26a-c. Acylation of the aliphatic hydroxyl with p-nitrophenyl chloroformate afforded the p-nitrophenyl carbonate compounds 27a-c, which were reacted with 5a and 4-dimethylaminopyridine to give the penultimate intermediates 28a-c. Finally, debenzylation using triethylsilane and palladium acetate, and treatment with NH4OH afforded the desired longer chain carbonate-linked phosphate CBD prodrugs 29a-c as diammonium salts. Chemical Characterization: [ka]

[0485] Compound 29a: (1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl(2-(phosphonooxy)ethyl)carbonate diammonium salt.

[0486] 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (br s, 1H), 6.49 (s, 1H), 6.33 (s, 1H), 5.01 (s, 1H), 4.49 - 4.38 (m, 2H), 4.36 - 4.10 (m, 2H), 3.99 (s, 2H), 3.01 (br s, 1H), 2.72 (br s, 1H), 2.44 - 2.36 (m, 2H), 2.13 (s, 1H), 1.97 - 1.85 (m, 1H), 1.71 - 1.62 (m, 2H), 1.58 (s, 6H), 1.53 - 1.44 (m, 2H), 1.32 - 1.18 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -2.14. [ka]

[0487] Compound 29b: (1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl(3-(phosphonooxy)propyl)carbonate diammonium salt.

[0488] 1H NMR (400 MHz, DMSO-d6) δ 6.52 (s, 1H), 6.32 (s, 1H), 5.02 (s, 1H), 4.43 (s, 2H), 4.26 - 4.16 (m, 2H), 4.16 - 4.07 (m, 2H), 3.80 - 3.72 (m, 1H), 2.70 (br s, 1H), 2.45 - 2.36 (m, 2H), 2.10 (s, 1H), 1.97 - 1.90 (m, 1H), 1.93 - 1.83 (m, 2H), 1.72 - 1.60 (m, 2H), 1.62 - 1.55 (m, 6H), 1.56 - 1.44 (m, 2H), 1.35 - 1.18 (m, 4H), 0.85 (t, J = 6.9 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -0.08. [ka]

[0489] Compound 29c: (1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl(4-(phosphonooxy)butyl)carbonate diammonium salt.

[0490] 1H NMR (400 MHz, DMSO-d6) δ 6.52 (s, 1H), 6.31 (s, 1H), 5.02 (s, 1H), 4.42 (s, 2H), 4.21 - 4.11 (m, 2H), 4.08 - 4.01 (m, 2H), 3.75 - 3.66 (m, 1H), 2.71 (br s, 1H), 2.45 - 2.36 (m, 2H), 2.10 (s, 1H), 1.98 - 1.88 (m, 1H), 1.75 - 1.62 (m, 2H), 1.64 - 1.52 (m, 10H), 1.54 - 1.44 (m, 2H), 1.35 - 1.20 (m, 4H), 0.85 (t, J = 6.9 Hz, 3H); 31 P NMR (162 MHz, DMSO-d6) δ -0.16. Example 5 (Compound 32) Synthesis of long chain ester linked monoester phosphate prodrug derivatives. Synthesis Procedure:

[0491] Compounds with a monoester phosphate prodrug moiety attached to the CBD by a long-chain ester linker were designed and synthesized using the following procedure: The synthesis of long-chain ester linked monoester phosphate prodrug 32 is shown in FIG.

[0492] For longer chain ester linked phosphate CBD prodrugs, the presynthesized analog 26c underwent Jones oxidation to give the carboxylic acid 30. Subsequent Stecklich esterification followed by TBAF mediated silyl deprotection afforded the dibenzyl phosphate intermediate 31. Finally, debenzylation with triethylsilane and palladium acetate afforded the desired prodrug 32 as the diammonium salt after treatment with NH4OH. Chemical characterization [ka]

[0493] Compound 32: (1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl 4-(phosphonooxy)butanoate diammonium salt.

[0494] 1 H NMR (400 MHz, DMSO) δ 6.47 (s, 1H), 6.21 (s, 1H), 4.99 (s, 1H), 4.42 (dd, J = 6.6, 2.3 Hz, 1H), 3.80 - 1.73 (m, 1H), 3.72 (br s, 1H), 2.71 - 2.53 (br s, 1H), 2.38 (t, J = 7.7 Hz, 2H), 2.19 - 2.06 (m, 1H), 1.98 - 1.88 (m, 1H), 1.88 - 1.75 (m, 2H), 1.71 - 1.61 (m, 2H), 1.58 (s, 6H), 1.48 (p, J = 7.4 Hz, 2H), 1.35 - 1.12 (m, 5H), 0.84 (t, J = 6.9 Hz, 3H). 31 P NMR (162 MHz, DMSO) δ -0.53. Example 6 (Compounds 38a-c) Synthesis of carbamate linked monoester phosphate prodrug derivatives. Synthesis Procedure:

[0495] Compounds with a monoester phosphate prodrug moiety attached to the CBD by a carbamate linker were designed and synthesized using the procedure described below. The synthesis of carbamate-linked monoester phosphate prodrugs 38a-c is shown in FIG.

[0496] The dibenzyl phosphate moiety was introduced into commercially available N-boc-ethanolamine by reaction with dibenzyl N,N-diisopropyl phosphoramidite and subsequent oxidation with hydrogen peroxide to give intermediates 34a-c in good yields. Deprotection by stirring in a solution of trifluoroacetic acid in DCM formed amines 35a-c, which were dried under vacuum and used without further purification. Acylation of TBDMS-protected CBD (5a) with p-nitrophenyl chloroformate afforded the activated carbonate 36. This compound was directly loaded onto silica after removal of the solvent in vacuum and purified by column chromatography. Reaction of 35a-c with 36 was carried out in DCM with DMAP acting as a base, followed immediately by deprotection mediated by TBAF to give the dibenzyl phosphate intermediates 37a-c. Finally, this compound was subjected to debenzylation conditions using triethylsilane and palladium acetate to give the desired carbamate-linked phosphate prodrugs 38a-c as diammonium salts after treatment with NH4OH. Chemical characterization [ka]

[0497] Compound 38a: (1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl(2-(phosphonooxy)ethyl)carbamate diammonium salt.

[0498] 1H NMR (400 MHz, DMSO) δ 7.64 (br s, 1H), 6.40 (s, 1H), 6.20 (s, 1H), 5.00 (s, 1H), 4.44 (s, 1H), 4.39 (s, 1H), 3.32 - 3.03 (m, 3H), 2.84 (br s, 1H), 2.38 (t, J = 7.7 Hz, 2H), 2.30 - 2.17 (m, 1H), 1.90 - 1.83 (m, 1H), 1.68 - 1.40 (m, 11H), 1.35 - 1.18 (m, 5H), 0.85 (t, J = 6.9 Hz, 3H). 31 P NMR (162 MHz, DMSO) δ -0.42. [ka]

[0499] Compound 38b: (1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl methyl(2-(phosphonooxy)ethyl)carbamate diammonium salt.

[0500] 1 H NMR (500 MHz, DMSO) δ 6.42 (s, 1H), 6.20 (s, 1H), 5.09 (s, 1H), 4.41 (d, J = 9.4 Hz, 2H), 3.88 - 3.75 (m, 3H), 3.03 - 2.89 (m, 7H), 2.42 - 2.35 (m, 2H), 2.08 (s, 1H), 1.94 (d, J = 16.7 Hz, 1H), 1.72 - 1.54 (m, 8H), 1.53 - 1.44 (m, 2H), 1.34 - 1.20 (m, 4H), 0.88 - 0.82 (m, 3H). 31 P NMR (162 MHz, DMSO) δ -0.19. [ka]

[0501] Compound 38c: (1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl(3-(phosphonooxy)propyl)carbamate diammonium salt.

[0502] 1 H NMR (500 MHz, DMSO) δ 7.48 (s, 1H), 6.40 (s, 1H), 6.18 (s, 1H), 5.01 (s, 1H), 4.47 - 4.42 (m, 1H), 4.42 - 4.38 (m, 1H), 3.77 - 3.68 (m, 3H), 3.11 - 2.83 (m, 4H), 2.38 (t, J = 7.8 Hz, 2H), 1.92 - 1.84 (m, 1H), 1.73 - 1.54 (m, 11H), 1.53 - 1.44 (m, 2H), 1.35 - 1.20 (m, 4H), 0.88 - 0.79 (m, 3H). 31 P NMR (162 MHz, DMSO) δ -0.03. Example 7 (Prophetic compound 43) Synthesis of Ester-Linked Cyclic Diester Phosphate Prodrug Derivatives. Synthesis Procedure:

[0503] Compounds with a cyclic diester phosphate prodrug moiety attached to the CBD by an ester linker can be designed and synthesized using the procedure described below. A prophetic synthesis of the ester-linked cyclic diester phosphate prodrug 43 is shown in FIG.

[0504] For the prospective synthesis of cyclic diester phosphate prodrugs, the steps will be similar to those performed for the previously synthesized prodrugs. Reaction of commercially available 39 with benzyl N,N,N',N'-tetraisopropyl phosphorodiamidite using 5-methyl-1H-tetrazole, followed by oxidation to the desired phosphate, can give intermediate 40. This is followed by lithium hydroxide mediated hydrolysis and Stöcklich esterification with silyl protected CBD analog 5a. Subsequent silyl deprotection then gives monobenzyl protected cyclic phosphate intermediate 42. Finally, debenzylation with triethylsilane and palladium acetate, and treatment with ammonium hydroxide gives the desired prodrug 43 as the ammonium salt. Example 8 Nephelometric analysis

[0505] General Experiment: Nephelometric experiments were performed using untreated Corning® Costar® 96-well black polystyrene plates with clear flat bottom. Sample stock solutions and serial dilutions were prepared using DriSolv® DMSO purchased from MilliporeSigma. All 100-fold dilutions and replicates were prepared using Gibco® Dulbecco's Phosphate Buffered Saline (DPBS, no calcium, no magnesium) with a pH range of 7.0-7.3 as the aqueous medium. Incubation of the 96-well plates was accomplished using a Benchmark Incu-Shaker™ Mini shaking incubator. Nephelometric data were acquired using a NEPHELOstar® microplate reader and processed using MARS data analysis software from BMG LabTech.

[0506] Turbidimetric Experimental Procedure: Compounds to be tested were dissolved in 100% DMSO to make stock solutions of specific concentrations ranging from a minimum of 10 mM to a maximum of 50 mM. Samples were then serially diluted in a 96-well plate (Corning® Costar®). Well A1 of the plate contained 100% DMSO. Wells A2-A12 contained the test compound in DMSO at the following concentration factors: The following wells were prepared: XmM for A2, (0.8)XmM for A3, (0.6)XmM for A4, (0.4)XmM for A5, (0.2)XmM for A6, (0.1)XmM for A7, (0.05)XmM for A8, (0.025)XmM for A9, (0.0125)XmM for A10, (0.00625)XmM for A11, and (0.003125)XmM for A12. Using a 12-channel multichannel pipette, 2.5 μL of sample was transferred from row A to each well of rows B-H of the plate. Then, 30 μL of PBS (pH=7.0-7.3) was added to rows B-H, providing 32.5 μL to each well. The plate was then incubated for 30 seconds with shaking. Finally, 217.5 μL of PBS buffer was added to rows B-H and the entire plate was incubated at 25° C. for 90 min with shaking. Note: The final volume of DMSO in the actual experiment with PBS buffer was 1% across the plate. After 90 min, the 96-well plate was analyzed on a NEPHELOstar® instrument and the data was processed with MARS data analysis software. The solubility data determined by nephelometric experiments are summarized in Tables 1-3. Example 9 Simulated gastric fluid stability assay

[0507] General Experiment: Simulated gastric fluid (SGF) is a pH 1.2 HCl solution containing purified pepsin (activity between 800 and 2500 units) (Test Solutions, The United States Pharmacopoeia (USP), 2008). SGF was prepared according to the procedure described in Test Solution - USP and other published papers (Bioorganic Chemistry, 49 (2013), 40-48). 0.20 g sodium chloride and 0.32 g purified pepsin derived from porcine gastric mucosa with activity between 800 and 2500 units per mg of protein (Sigma) were dissolved in 0.70 mL hydrochloric acid and enough water to make 100 mL. This test solution had a pH of approximately 1.2. The prepared SGF solution was used for in vitro studies to evaluate prodrug stability.

[0508] Procedure for simulated gastric fluid stability assay: 20 μL from a 100 mM test compound (CBD prodrug) stock solution in acetonitrile was added to 980 μL SGF and incubated at 37° C. At specified time intervals, aliquots (100 μL) were removed and added to pre-chilled 100% acetonitrile (200 μL, spiked with ISTD) and mixed thoroughly by vortex mixing for 2 min. The mixture was centrifuged at 13000 rpm for 15 min at 4° C. The supernatant was transferred to an HPLC vial and analyzed using LC-MS / MS to check the amount of remaining unchanged CBD prodrug and to obtain its half-life. The results of the SGF stability assay are summarized in Table 1. Example 10 Liver microsome stability assay

[0509] General Experimental: Human and mouse liver microsomes were purchased from Xenotech at 20 mg / mL. NADPH (Sigma-Aldrich) 10 mM stock was prepared in deionized water.

[0510] Liver microsome stability assay procedure: Test compounds and positive controls were dissolved in 100% DMSO to make 10 mM stock solutions. Verapamil (Sigma-Aldrich) and diphenhydramine (Sigma-Aldrich) were used as positive controls for both human liver microsomes (HLM) and mouse liver microsomes (MLM). 10 mM stock solutions of test compounds and control compounds were further diluted to 500 μM with potassium phosphate buffer (100 mM, pH 7.4) to ensure that the organic solvent content was less than 0.2%. Liver microsome (HLM or MLM) assays were prepared in 1.5 mL Eppendorf tubes in a final volume of 1100 μL to be performed in duplicate. Each reaction contained phosphate buffer (928.4 μL), liver microsomes (55 μL), and test compound (6.6 μL of 500 μM), resulting in a final test compound concentration of 3 μM. The reaction was initiated with 110 μL of 10 mM NADPH. Aliquots (100 μL) were removed in duplicate at 0, 5, 10, 15, and 30 min and quenched with 100 mL of 100% cold methanol containing an internal standard (ISTD: d5-7-ethoxycoumarin 2 μM). Aliquots were centrifuged at 12,000 g for 5 min and the supernatant was transferred to an LC-MS vial. Each time point was assessed by LC-MS / MS and the m / z area under the curve (AUC) was integrated with respect to the ISTD based on the MRM transition. Positive controls were run in a final volume of 550 μL so that one could be run per time point. Negative controls without NADPH were run with the test and control compounds, respectively, in a final volume of 150 μL and measured at the longest time point. The control compounds were treated and analyzed similarly to the test compounds. At each time point, LC-MS / MS was performed in triplicate with an intervening blank wash to avoid carryover and to equilibrate the column following LC-MS / MS. 1 / 2 ) was calculated using the data obtained from LC-MS / MS by plotting ln(% parent prodrug remaining) versus time and performing linear regression to determine the slope. For first order kinetics, slope = -k and T 1 / 2 = 0.693 / k. The results of the HLM and MLM stability assays are summarized in Tables 1-3. Example 11 Plasma stability assay

[0511] General Experimental: Procaine and procainamide were purchased from Sigma-Aldrich. Human plasma was obtained from BioIVT (catalog number HUMANPLLHP2N) and 1× Dulbecco's PBS (pH 7.4, Gibco) was obtained from Thermos Fischer. Stock solutions were prepared in 100% DMSO and appropriate dilutions of target analytes were prepared in methanol for method development.

[0512] Plasma stability assay procedure: Test compounds were dissolved in DMSO to make 10 mM stock solutions and then diluted to 500 μM with buffer (or 70% MeOH). Human plasma was thawed at ambient temperature and aliquots (994.0 μL) were taken in duplicate for each compound in 1.5 mL Eppendorf tubes (A and B). Plasma was incubated at 37° C. for 10 min in an incubator shaker at 150 rpm and the reaction was started by adding test compound (6.0 μL) and vortex mixing. The total reaction volume was 1000 μL and the final concentration of organic solvents was 0.6% MeOH and 0.03% DMSO. Spiked plasma samples were incubated at 37° C. for 4 h. At 0, 15, 30, 60, 120, 180, and 240 min, 100 μL aliquots were taken from the test incubation mixture and immediately quenched in ice-cold acetonitrile (150 μL, containing 2 μM ISTD) containing the internal standard, followed by rapid vortex mixing to terminate the reaction. In addition, a matrix blank was prepared by adding acetonitrile solution containing ISTD to a plasma sample that did not contain either the analyte or the control compound. Additional tubes were also made to measure the degradation of the compound in PBS buffer. Samples were centrifuged at 15000 rpm for 25 min at 4° C. The supernatant was transferred to an LC-MS vial for analysis by LC / MS-MS. Each time point was run in duplicate, with blank washes in between to avoid carryover and to equilibrate the column following the run. Half-life (T 1 / 2) was calculated using the data obtained from LC-MS / MS by plotting ln(% parent prodrug remaining) versus time and performing linear regression to determine the slope. For first order kinetics, slope = -k and T 1 / 2 = 0.693 / k. The results of the human plasma stability assay are summarized in Tables 1-3.

[0513] Procaine (low plasma stability) and procainamide (good plasma stability) were used as positive controls at a final concentration of 3 μM. These positive controls were run in parallel to test the system for suitability.

[0514] **1.5 mL conical polypropylene microcentrifuge tubes were labeled in duplicate for 0, 15, 30, 60, 120, 180, and 240 minutes for each compound being tested.** Example: Number of tubes prepared for test compound (TC): Test Compound 1: 994 μL human plasma + 6.0 μL TC1 (Vial A) 994 μL human plasma + 6.0 μL TC1 (vial B) Positive control: 596 μL human plasma + 3.6 μL (procaine + procainamide) Matrix blank: 500 μL PBS buffer + 100 μL human plasma Negative control: 142 μL PBS buffer + 0.9 μL TC1 Quench mixture: 150 μL of acetonitrile containing ISTD (2 μM) or 70% MeOH:HO (containing ISTD) Final volume after quench: 250 μL (100 μL from incubation mixture and 150 μL from quench mixture, ISTD concentration 1.2 μM) Example 12 Hepatocyte cellular uptake and stability assays

[0515] General Experiment: Fresh mouse hepatocytes (seeded on 24-well culture plates containing Matrigel) were obtained from BioIVT. INVITROGRO HI medium and Torpedo antibiotic mix were obtained from BioIVT.

[0516] Hepatocyte Cellular Uptake and Stability Assay Procedure: Complete INVITROGRO HI medium (i.e., growth medium) was prepared by adding 1.0 mL of TORPEDO antibiotic mix to 45 mL of INVITROGEN HI medium. Transport medium was removed from a 24-well plate of fresh mouse hepatocytes seeded with 175K viable cells and replaced with growth medium described above (1.0 mL / well). Plates were incubated overnight at 37° C. in 5% CO2. 40 mM stock solutions of test compounds were prepared in 100% DMSO. The 40 mM stock solutions were then diluted to 20 μM in 50 mL of growth medium. For compound-treated plates, blank growth medium was removed and replaced with compound-containing medium described above (compound concentration 20 μM). A separate plate of cells in blank growth medium (no test compound added) was used as a control and T0. Compound-treated plates were incubated at 37°C in 5% CO2 for the following time points: 0 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 24 h. Non-treated plates were sampled at 0 h. After incubation at the desired time points, cells were washed twice with 1.0 mL of DPBS. Cells were then extracted by adding 500 μL of 70% MeOH:H2O spiked with an internal standard (ISTD). ISTD was d5-ethoxycoumarin at a concentration of 2 μM. After mixing, samples were transferred to pre-labeled microcentrifuge tubes and centrifuged at 15000 for 10 min at 4°C. After centrifugation, 300 μL of the supernatant was transferred to labeled HPLC vials and measured by LC-MS / MS. Each time point was performed in duplicate. Standard curves for each test compound and its metabolites were constructed separately to quantify their concentrations in the samples. The results of hepatocyte cellular uptake assays for compounds 7b, 8, and 14a are shown in Figures 8-10. (Example 13) Brain homogenate stability assay

[0517] General Experiment: DPBS (1x) (Gibco) and Pierce BCA Assay Kit (Thermo Fischer) for protein quantification were purchased. Frozen mouse brain homogenates were provided by Dr. Scott Myers, Emory University School of Medicine (C57BL / 6J adult male mice (Jackson Laboratory), 239 days (34 weeks) old). Briefly, each mouse was euthanized by an overdose of isoflurane, and immediately after respiratory arrest, the chest cavity was opened and the left ventricle was punctured with a 21G needle, then the vena cava was clipped and the body was perfused with cold PBS (pH 7.35) for 2 minutes. The brain was then removed (on ice) and the forebrain was separated from the cerebellum. The wet weight of the forebrain was recorded and placed in 3 mL of ice-cold HBSS (Hank's Balanced Salt Solution, pH 7.4), then homogenized at 3 / 4 maximum setting for 10 seconds. The tubes of brain homogenate were then capped and rapidly frozen on dry ice. The amount of protein in mouse brain homogenates was quantified using the Pierce BCA assay kit before performing the stability assay.

[0518] Brain homogenate stability assay procedure: 10 mM stock solutions were prepared in 100% DMSO for each test compound. The stock solutions were then diluted to 500 μM in DPBS or 50% MeOH:DPBS solution (for compounds with low water solubility). Each test sample was prepared in duplicate, i.e., in two 1.5 mL Eppendorf tubes labeled as A and B. Each Eppendorf tube contained the following components: 580 μL DPBS + 20 μL test compound solution (from the 500 μM batch described above) + 400 μL brain homogenate. A negative control was run in parallel without brain homogenate, i.e., only DPBS containing test compound (TC). The assay was initiated by adding the test compound to each Eppendorf tube, followed by vortex mixing and incubation at 37° C. at 185 rpm on a shaker. Small aliquots (100 μL) were taken from the Eppendorf tubes at different time points (0, 10, 30, 60, 120, 240, 360, and 1440 min) and quenched with 200 μL of cold ACN spiked with 2 μM ISTD. The t=0 sample was taken immediately after the TC solution was added to its corresponding Eppendorf tube. Each sample aliquot was vortexed thoroughly and centrifuged at 12000 rpm for 5 min at 4° C. The supernatant was transferred to an HPLC vial and measured by LC-MS / MS. The half-life (T 1 / 2 ) was calculated using the data obtained from LC-MS / MS by plotting ln(% parent prodrug remaining) versus time and performing linear regression to determine the slope. For first order kinetics, slope = -k and T 1 / 2 =0.693 / k. The results of the brain homogenate stability assay for compound 7b are shown in FIG. Example 14 CYP Inhibitor Panel Results

[0519] General Experiment: Cytochrome P450 enzyme (CYP) inhibition assays were performed by SAI Life Sciences Limited. The objective of the study was to evaluate the potential of CBD and compound 7b to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. This was accomplished by determining the inhibitory effect of the test compounds on the metabolism of phenacetin, coumarin, bupropion, amodiaquine, diclofenac, S-mephenytoin, bufuralol, and midazolam to acetaminophen, 7-OH coumarin, OH-bupropion, N-desethylamodiaquine, 4-OH diclofenac, 4-OH mephenytoin, OH-bufuralol maleate, and 1-OH midazolam, respectively, in human liver microsomes. All metabolites were analyzed using an ultra-high performance LC-MS / MS Waters ACQUITY™. Substrates and inhibitors were purchased from Sigma Aldrich (Germany), pooled human liver microsomes (50 donors) were purchased from Gibco (USA), and NADPH was purchased from SRL (India).

[0520] Preparation of reagents: 50 mM potassium phosphate buffer (pH 7.4) was prepared by adding 0.647 g potassium phosphate monobasic (KH2PO4) and 3.527 g potassium phosphate dibasic (K2HPO4) to 400 mL Milli-Q water and bringing the volume up to 500 mL. Microsomes (20 mg / mL) were diluted with 50 mM potassium phosphate buffer (pH 7.4) buffer to prepare a concentration of 0.2 mg / mL. For CYP2C19, a concentration of 1 mg / mL was prepared. Stock solutions of test compounds were prepared at concentrations of 10 mM and 1 mM in DMSO. A stock solution of 35 mM phenacetin was prepared in DMSO. A standard stock of 140 μM was prepared by diluting the stock with incubation buffer. A stock solution of 20 mM bufuralol was prepared in DMSO. A 20 μM standard stock was prepared by diluting the stock with incubation buffer. A 10 mM stock solution of midazolam was prepared in DMSO. A 10 μM standard stock was prepared by diluting the stock with incubation buffer. A 20 mM stock solution of diclofenac was prepared in DMSO. A 40 μM standard stock was prepared by diluting the stock with incubation buffer. A 50 mM stock solution of S-mephenytoin was prepared in DMSO. A 120 μM standard stock was prepared by diluting the stock with incubation buffer. A 50 mM stock solution of bupropion was prepared in DMSO. A 200 μM standard stock was prepared by diluting the stock with incubation buffer. A 2 mM stock solution of coumarin was prepared in DMSO. A 8 μM standard stock was prepared by diluting the stock with incubation buffer. A stock solution of 10 mM amodiaquine was prepared in DMSO. An 8 μM standard stock was prepared by diluting the stock in incubation buffer. 10 mM fluvoxamine, sulfaphenazole, tranylcypromine, and ticlopidine stock solutions were prepared in DMSO. 1 mM ketoconazole and quinidine stock solutions were prepared in DMSO. A stock solution of 30 mM quercetin was prepared in DMSO. A stock solution of 3 mM ticlopidine was prepared in DMSO. A 4 mM stock solution was prepared by dissolving the appropriate amount of NADPH in 50 mM potassium phosphate buffer, pH 7.4.

[0521] CYP Inhibition Assay Procedure: Human liver microsomes were harvested from -80°C. Microsomes were then thawed on ice bath for 30 min. For 3A4, 2D6, 2B6, 1A2, 2A6, 2C8, and 2C9, 0.2 mg / mL microsome standard solutions were prepared in 50 mM potassium phosphate buffer (pH 7.4). For 2C19, 1 mg / mL microsome standard solutions were prepared in 50 mM potassium phosphate buffer (pH 7.4). 0.3 μL of test compound / positive control and vehicle control (DMSO) were spiked into 150 μL microsome standard solution per isoform. From the above microsome mixture, 50 μL aliquots (n=2) were transferred to separate plates and 25 μL of marker substrate (specific for isoform) was added and pre-incubated at 37°C for 5 min. The reactions were started by adding 25 μL of 4 mM NADPH (Note: in the final reaction, the NADPH concentration was 1 mM and the protein concentration was 0.1 mg / mL for 3A4, 2D6, 2B6, 1A2, 2A6, 2C8, 2C9, and 1 mg / mL for CYP 2C19). The reaction mixtures were incubated at 37 °C for 5-20 min depending on the CYP enzyme. The reaction mixtures were terminated by adding 100 μL of stop solution. All samples were vortexed for 10 min and centrifuged at 4000 rpm for 10 min. After centrifugation, 100 μL of the supernatant was transferred to the LCMS loading plate for analysis. The samples were monitored by identifying the substrate metabolites using LC-MS / MS in MRM mode. The peak area ratio, i.e., PAR (metabolite relative to internal standard), should be used to calculate the % inhibition. Activity % = PA ratio in the presence of test compound / PA ratio of DMSO control × 100. % Inhibition=100-% Activity. The % Inhibition for selected positive controls (against specific CYP isoforms) and test compounds is shown graphically in FIG. Example 15 In vivo pharmacokinetic study of prodrugs 7c, 29a, 32, and 38c

[0522] General Experimental: In vivo pharmacokinetic studies of 7c, 29a, 32, and 38c were performed by SAI Life Sciences Limited. The objective of this study was to determine the pharmacokinetics and brain tissue distribution of CBD released from 7c, 29a, 32, and 38c in male C57BL / 6 mice after a single oral administration of the prodrugs at a dose equivalent to CBD of 50 mg / kg. Plasma and brain sampling was performed in triplicate at 0.5, 2, and 4 hours. The prodrugs were formulated as 10 v / v% PEG-300, 10 v / v% Solutol HS-15, and 80 v / v% saline. The doses of 7c, 29a, 32, and 38c were 84 mg / kg, 82 mg / kg, 82 mg / kg, and 84 mg / kg, respectively, in a dose volume of 10 mL / kg. In vivo pharmacokinetic study procedure: Nine male C57BL / 6 mice were orally administered solution formulations of each prodrug at the doses mentioned above. Blood samples (approximately 60 μL) were collected from a set of three mice at 0.5, 2, and 4 hours under light isoflurane anesthesia. Blood samples were collected at each time point into labeled microcentrifuge tubes containing 6 μL of stabilizer (5×Halt (5 μL) + 1000 μM PMSF + 1000 μM paraoxon) and K2EDTA as anticoagulant. Plasma was collected by centrifugation of blood and stored at −70±10° C. until analysis. Animals were anesthetized immediately after blood collection, and brain samples were collected from each mouse at each time point. Brain samples were homogenized using ice-cold phosphate buffered saline (pH 7.4) containing stabilizers (5xHalt+1000μM PMSF+1000μM paraoxon) and homogenates were stored below -70±10°C until analysis. The total homogenate volume was 3 times the brain weight. Brain samples were diluted (1 part tissue: 2 parts buffer) and homogenized. Homogenates were submitted for bioanalysis and received concentrations (ng / mL) were corrected by the dilution factor (3x) and final concentrations reported were expressed in ng / g. Plasma and brain concentration-time data of CBD and prodrugs were used for calculations. Plasma and brain samples were quantified by a purpose-built LC-MS / MS method. Extraction procedures for plasma samples and spiked plasma calibration standards were performed on ice bath (PMSF+HALT inhibitor stabilized plasma and brain were used for preparation of calibration standards). 20 μL of study sample plasma or spiked plasma calibration standards were added to individual pre-labeled microcentrifuge tubes, followed by 200 μL of internal standard (Cetirizine + Bicalcutamide, 50 ng / mL) prepared in 0.1% formic acid in methanol, except for the blank, which was spiked with 200 μL of 0.1% formic acid in methanol. Samples were vortexed for 5 minutes. Samples were centrifuged at a speed of 4000 rpm for 10 minutes at 4° C. After centrifugation, 200 μL of clear supernatant was transferred to a 96-well plate and analyzed using LC-MS / MS. The results of these studies are shown graphically in FIG. 13. (Example 16) In vivo anticonvulsant efficacy study of CBD, 7a, and 7b

[0523] General Experiment: CBD and prodrugs 7a and 7b were screened for their ability to block psychomotor seizures induced by low frequency (6 Hz), long duration (3 s) stimulation delivered through corneal electrodes. Mice were stimulated 2 hours after IP injection administration of CBD and prodrugs 7a and 7b. Doses ranged from 25-200 mg / kg for the compounds. CBD and prodrugs were formulated as 10 v / v% ethanol, 10 v / v% Cremaphor and 80 v / v% saline. Test results were quantified using a modified Racine score to determine seizure severity and seizure protection in the epilepsy electroshock model.

[0524] Procedure for in vivo anticonvulsant efficacy study: Male albino CF-1 mice (18-25 g, Charles River, Kingston, NY) were used as experimental animals. All animals had free access to both food (Prolab RMH 3000) and water, except when removed from their cages for experimental procedures. All mice were housed, fed, and handled in a manner consistent with the recommendations of the National Research Council publication, "Guide for the Care and Use of Laboratory Animals" and approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Utah. Mice were approximately 12 weeks old and were visually examined to be healthy, with no skin problems or signs of aggression. CBD was administered to mice at various dose concentrations in the above formulations at a dose volume of 10 ml / kg by intraperitoneal (IP) route. Two hours after IP injection, 6 Hz stimulation was given through corneal electrodes. Prior to stimulation, an electrolyte solution containing an anesthetic was administered to the eye (0.5% tetracaine HCl). Mice were challenged with a current of 22 mA (a convulsive current that induces seizures in 97% of CF1 mice). Seizures were characterized by an initial momentary faint followed immediately by forelimb clonus, whisker jerking, and Straub's tail reaction, the absence of these behaviors being the criterion for a "protected mouse." Mice were scored by a modified Racine score (score 2 being no seizure protection and 0 being completely seizure protected). The results of these studies are shown graphically in FIG. 14. (Example 17) Bioanalysis results

[0525] The following tables and Figures 8-11 detail the bioanalytical results of exemplary compounds of the present disclosure. [Table 1] [Table 2-1] [Table 2-2]

Table 3

Table 4

Claims

1. Formula (I) 【Chemical 336】 and pharmaceutically acceptable salts thereof, wherein: R １ teeth, 【Hua340】 is selected from the group Z is a divalent C １～１８ Alkyl and divalent C １～１８ haloalkyl groups, wherein the divalent C １～１８ Alkyl and divalent C １～１８ The haloalkyl group is C ６～１８ Aryl, C １～１３ Heteroaryl, C ２～１２ Heterocyclyl, —OC １～１８ Alkyl, -SC １～１８ Alkyl, -N(T ２ ) C １～１８ Alkyl, and -N(T ２ ) optionally substituted with one or more groups independently selected from AA groups; ２ is H and C １～８ alkyl groups, and AA is selected from amino acid residues and is attached to the nitrogen through its C-terminal carbonyl group; X and Y may be the same or different and may be H, Q, C １～１８ Alkyl, C １～１８ Haloalkyl, C ６～１８ Aryl, C １～１３ Heteroaryl, C ７～１９ Aryl alkyl, C ２～１４ Heteroarylalkyl, -(CH ２ CH ２ O) ｎ CH ３ , 【Chemical 338】 are independently selected from the group Each T ３ , T ４ , and T ５ may be the same or different, H and C １～８ independently selected from alkyl groups, each Q is independently selected from a pharmaceutically acceptable cation; each n is independently selected from an integer ranging from 1 to 12; each m is independently selected from an integer ranging from 1 to 8; R ２ is C １～８ alkyl groups].

2. Z is a divalent C １～１８ 10. At least one compound according to claim 1 selected from alkyl groups.

3. Zが、-CH ２ -、-(CH ２ ) ２ -、-(CH ２ ) ３ -、-(CH ２ ) ４ -、-(CH ２ ) ５ -、-(CH ２ ) ６ -、-(CH ２ ) ７ -、-(CH ２ ) ８ -、-(CH ２ ) ９ -、-(CH ２ ) １０ -、 【Chemical 344】 3. At least one compound according to claim 2 selected from:

4. Z is -(CH ２ ) ２ 4. At least one compound according to claim 3, wherein:

5. Z is -(CH ２ ) ３ 4. At least one compound according to claim 3, wherein:

6. Z is, 【Chemical 345】 4. At least one compound according to claim 3, wherein:

7. Z is, 【Chemical 346】 4. At least one compound according to claim 3, wherein:

8. Z is a divalent C １～１８ 10. At least one compound according to claim 1 selected from haloalkyl groups.

9. Z is, 【Chemical 347】 9. At least one compound according to claim 8, wherein:

10. Z is C ６～１８ a divalent C substituted with at least one group selected from an aryl group; １～１８ 10. At least one compound according to claim 1 selected from alkyl groups.

11. Z is, 【Chemical 348】 11. At least one compound according to claim 10, wherein:

12. Z is, 【Chemical 349】 11. At least one compound according to claim 10, wherein:

13. Z is C １～１３ a divalent C substituted with at least one group selected from a heteroaryl group; １～１８ 10. At least one compound according to claim 1 selected from alkyl groups.

14. Z is, 【Hua350】 14. At least one compound according to claim 13 selected from:

15. Z is C ２～１２ a divalent C substituted with at least one group selected from a heterocyclyl group; １～１８ 10. At least one compound according to claim 1 selected from alkyl groups.

16. Z is, 【Chemistry 351】 16. At least one compound according to claim 15 selected from:

17. Z is -OC １～１８ a divalent C substituted with at least one group selected from alkyl groups; １～１８ 10. At least one compound according to claim 1 selected from alkyl groups.

18. Z is, 【Chemical 352】 18. At least one compound according to claim 17 selected from:

19. Z is -SC １～１８ a divalent C substituted with at least one group selected from alkyl groups; １～１８ 10. At least one compound according to claim 1 selected from alkyl groups.

20. Z is, 【Chemical 353】 20. At least one compound according to claim 19 selected from:

21. Z is -N(T ２ ) C １～１８ a divalent C substituted with at least one group selected from alkyl groups; １～１８ 10. At least one compound according to claim 1 selected from alkyl groups.

22. Z is, 【Chemical 354】 22. At least one compound according to claim 21 selected from:

23. Z is -N(T ２ ) a divalent C substituted with at least one group selected from the AA group; １～１８ 10. At least one compound according to claim 1 selected from alkyl groups.

24. Z is, 【Chemical 355】 24. At least one compound according to claim 23 selected from the group:

25. 24. At least one compound according to claim 23, wherein AA is selected from natural L-amino acid residues.

26. 10. At least one compound according to claim 1, wherein X is H.

27. 10. At least one compound according to claim 1, wherein X is Q.

28. 28. At least one compound according to claim 27, wherein Y is H.

29. 28. At least one compound according to claim 27, wherein Y is Q.

30. 30. At least one compound according to claim 29, wherein each Q is independently selected from (substituted and unsubstituted) ammonium cations.

31. 31. At least one compound according to claim 30, wherein each Q is an unsubstituted ammonium cation.

32. R ２ But C ２～６ 10. At least one compound according to claim 1 selected from alkyl groups.

33. 10. At least one compound according to claim 1, wherein the carbon of Z adjacent to the carbonyl group does not have a hydrogen atom.

34. 10. At least one compound according to claim 1, wherein the carbon of Z adjacent to the carbonyl group has one hydrogen atom.

35. 10. At least one compound of claim 1, wherein the carbon of Z adjacent to the carbonyl group is substituted.

36. At least one compound of claim 33, wherein X and Y are each an unsubstituted ammonium cation.

37. At least one compound according to claim 34, wherein X and Y are each an unsubstituted ammonium cation.

38. R ２ 37. At least one compound according to claim 36, wherein is selected from n-pentyl and n-propyl.

39. R ２ 38. At least one compound of claim 37, wherein is selected from n-pentyl and n-propyl.

40. A composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.

41. 41. The composition of claim 40, wherein the composition is an oral formulation.

42. 42. The composition of claim 41, wherein the oral formulation is a solid form selected from tablets, capsules, pills, and granules.

43. 42. The composition of claim 41, wherein the oral formulation is in a liquid form selected from a solution, a suspension, and an emulsion.

44. A composition for the treatment and / or prevention of at least one disease, disorder, and / or condition in a subject in need thereof, for which treatment with an anxiolytic, analgesic, an antiemetic, a mood stabilizer, and / or an antipsychotic is useful, said composition comprising at least one compound of claim 1.

45. A composition for the treatment and / or prevention of at least one psychiatric disease, disorder, and / or condition in a subject in need thereof, the composition comprising at least one compound described in claim 1.

46. 46. The composition of claim 45, wherein the at least one psychiatric disease, disorder, and / or condition is selected from depression, anxiety, dementia, bipolar disorder, schizophrenia, addiction, and nausea.

47. 47. The composition of claim 46, wherein the at least one psychiatric disease, disorder, and / or condition is selected from depression and anxiety.

48. A composition for the treatment and / or prevention of pain in a subject in need thereof, comprising at least one compound described in claim 1.

49. 49. The composition of claim 48, wherein the pain is chronic pain.

50. 49. The composition of claim 48, wherein the pain is neuropathic pain.

51. 51. The composition of claim 50, wherein the neuropathic pain results from a pathological event in the peripheral and / or central nervous system.

52. 51. The composition of claim 50, wherein the neuropathic pain is selected from diabetic peripheral neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, rheumatoid arthritis, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic lower back pain, HIV neuropathic pain, trigeminal neuralgia and / or central post-stroke pain.

53. A composition for the treatment and / or prevention of at least one neurological disease, disorder, and / or condition in a subject in need thereof, the composition comprising at least one compound described in claim 1.

54. 54. The composition of claim 53, wherein the at least one neurological disease, disorder, and / or condition is selected from depression, autism, postpartum depression, attention deficit disorder, schizophrenia, anxiety, various psychoses, and epilepsy.

55. A composition for the treatment and / or prevention of at least one symptom associated with epilepsy and / or similar seizure disorders in a subject in need of such treatment and / or prevention of at least one symptom associated with epilepsy and / or similar seizure disorders, the composition comprising at least one compound described in claim 1.

56. A composition for the treatment and / or prevention of at least one symptom associated with Lennox-Gastaut syndrome, Dravet syndrome, developmental epileptic encephalopathy, and / or tuberous sclerosis complex in a subject in need of such treatment and / or prevention, the composition comprising at least one compound described in claim 1.

57. A composition for reducing the frequency of seizures associated with epilepsy and / or rare genetic disorders / diseases in a subject in need thereof, the composition comprising at least one compound described in claim 1.

58. A composition for reducing the severity and / or intensity of seizures associated with epilepsy and / or rare genetic disorders / diseases in a subject in need thereof, the composition comprising at least one compound described in claim 1.

59. A composition for treating traumatic brain injury in a subject in need thereof, comprising at least one compound described in claim 1.

60. A composition for treating a sleep disorder in a subject in need thereof, comprising at least one compound described in claim 1.

61. A composition for treating high blood pressure and / or hypertension in a subject in need thereof, comprising at least one compound described in claim 1.

62. The composition of any one of claims 44 to 61, wherein the subject is a human.

63. 63. The composition of claim 62, wherein the human is under 18 years of age.

64. 63. The composition of claim 62, wherein at least one compound of claim 1 is administered orally.

65. The at least one compound, 【Chemical 377】 2. At least one compound according to claim 1 selected from:

66. At least one compound according to claim 65, wherein Z is selected from divalent C 1-18 alkyl groups.

67. Z is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 -, 【Chemical 344】 67. At least one compound according to claim 66 selected from:

68. At least one compound according to claim 67, wherein each Q is independently selected from (substituted and unsubstituted) ammonium cations.

69. At least one compound according to claim 67, wherein each Q is an unsubstituted ammonium cation.

70. The at least one compound, 【Chemical 378】 10. At least one compound according to claim 1 selected from: and pharmaceutically acceptable salts thereof.

71. The at least one compound: 【Chemical 379】 10. At least one compound according to claim 1 selected from: and pharmaceutically acceptable salts thereof.

72. The at least one compound: 【Hua380】 2. At least one compound according to claim 1, wherein:

73. The at least one compound: 【Chemical 381】 2. At least one compound according to claim 1, wherein:

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