Delivery of therapeutic alkaloid compounds

Abstract

Disclosed are compounds that can be converted to mesembrine under biologically relevant conditions, such as acid hydrolysis at body temperature; and related methods for preparing and using these compounds. Stable preparations of isolated mesembrine stereoisomers are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 434,723, filed December 22, 2022, the contents of which are incorporated herein by reference in their entirety. [Technical Field]

[0002] The present disclosure relates to the pharmaceutical field, including the discovery of alkaloid compounds useful for inhibiting the serotonin transporter protein (5-HTT). [Background technology]

[0003] Plants in the Sceletium genus contain biologically active indole alkaloids useful in the treatment of mental health conditions, such as mild to moderate depression. Natural extracts of Sceletium tortuosum, an indigenous herb from South Africa also known as "kougoed," "channa," or "kanna," may contain pharmacologically active alkaloids. Among the alkaloids listed below, mesembrine and mesembrenol are present in Sceletium tortuosum extracts used to treat anxiety, stress, and mental health conditions. Mesembranol is present in lower concentrations in the extracts compared to other alkaloids. [ka]

[0004] Analysis of a standardized commercially available extract of Skeletium tortuosum (obtained under the trade name Zembrin®) was reported in 2011 to have 0.35% to 0.45% total alkaloids, with mesembrenone and mesembrenol accounting for more than 60%, and mesembrine contributing less than 20% (see Non-Patent Documents 1 and 2). The extract demonstrated greater than 80% inhibition of the serotonin (5-HT) transporter, with the potency of isolated alkaloids at the 5-HT transporter being as shown in Table A below (Non-Patent Document 1). Referring to the data in Table A, concentration-dependent inhibition was observed, with mesembrine being the more active compound in the 5-HT transporter assay (i.e., 20-fold more potent than mesembrenone and 87-fold more potent than mesembrenol). A toxicological safety evaluation of this standardized extract was subsequently reported in 2014 (Non-Patent Document 2). TIFF2025541878000002.tif73165

[0005] However, bioactive plant extracts for therapeutic consumption can vary widely both seasonally and among different Skeletium tortuosum plants, making it impossible to provide a sufficiently reproducible and stable phytochemical profile of the desired bioactive components. Skeletium plants and their extracts can vary significantly in total alkaloid content and the chemical nature and relative concentrations of alkaloids from individual Skeletium plants. Furthermore, mesembranol concentrations in Skeletium tortuosum can vary across South African regions and have been reported to be relatively low in most plant extracts tested. Finally, Skeletium alkaloids can be unstable under various conditions that may occur during extraction from plant material and during the storage and formulation of the extracts.

[0006] In Skeletium tortuosum extracts, mesembranol is present in low concentrations compared to the other major alkaloids, and 6-epi-mesembrananol is only detected in trace amounts. The therapeutic use of mesembranol and 6-epi-mesembrananol has been limited by the abundance, variability, and instability of these alkaloids in natural extracts, as well as the instability and pharmacokinetic profiles of these compounds obtained from natural sources. Finally, plasma concentrations of Skeletium tortuosum alkaloids reported in pharmacokinetic studies in rodents have been low. Prodrugs of mesembranol and 6-epi-mesembrananol are needed to improve the oral bioavailability of Skeletium tortuosum alkaloids. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Harvey et al., “Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids”, Journal of Ethnopharmacology 137(2011)1124-1129 2011 [Non-patent document 2] Murbach et.al., “A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin®) in rats,” Food and Chemical Toxicology 74 (2014) 190-199 Summary of the Invention [Means for solving the problem]

[0008] As used herein, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof is disclosed, During the ceremony, R 1 is -C(O)NR 2 R 3 , -P(O)OR 3 OR 4 , -C(O)OR 5 , -C(O)R 6 , or -CH2OC(O)R 7 and; R 2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 3 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 2 and R 3together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and each hydrogen atom in the 4- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 4 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 3 and R 4 are taken together with the -OP(O)-O- to which they are attached to form a 5- to 7-membered heterocycle, and each hydrogen atom in the 5- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 5 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 6 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, -OC(O)C-C alkyl, nitro, -N(C-C alkyl) -, -NH, -N(H)C-C alkyl, C-C haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 7 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; and n is 1 or 2.

[0009] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is as defined herein.

[0010] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 1 is as defined herein.

[0011] In certain embodiments, the compound has formula (II): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 3 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and each hydrogen atom in the 4- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy; and n is 1 or 2.

[0012] In certain embodiments, the compound has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 is as defined herein.

[0013] In certain embodiments, the compound has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 1 and R 3 is as defined herein.

[0014] In certain embodiments, the compound has formula (III): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 3 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 4 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 3 and R 4 are taken together with the -OP(O)-O- to which they are attached to form a 5- to 7-membered heterocycle, and each hydrogen atom in the 5- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy; and n is 1 or 2.

[0015] In certain embodiments, the compound has formula (III-A) or (III-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 is as defined herein.

[0016] In certain embodiments, the compound has formula (III-A) or (III-B): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 3 and R 4 is as defined herein.

[0017] In certain embodiments, the compound has formula (IV): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 5 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0018] In certain embodiments, the compound has formula (IV-A) or (IV-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 5 is as defined herein.

[0019] In certain embodiments, the compound has formula (IV-A) or (IV-B): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 5 is as defined herein.

[0020] In certain embodiments, the compound has formula (V): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 6 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, —OC(O)C-C alkyl, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0021] In certain embodiments, the compound has formula (VA) or (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 6 is as defined herein.

[0022] In certain embodiments, the compound has formula (VA) or (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 6 is as defined herein.

[0023] In certain embodiments, the compound has formula (VI): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 7 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0024] In certain embodiments, the compound has formula (VI-A) or (VI-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 7 is as defined herein.

[0025] In certain embodiments, the compound has formula (VI-A) or (VI-B): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 7 is as defined herein.

[0026] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0027] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0028] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown.

[0029] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0030] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown.

[0031] In certain embodiments, the present disclosure provides a method of treating a psychiatric disorder, comprising administering to a subject a compound of the present disclosure.

[0032] Numerous further embodiments are provided that may be applied to any aspect of the invention described herein. DETAILED DESCRIPTION OF THE INVENTION

[0033] Mesembranol has been found to be a potent inhibitor of the serotonin transporter (SERT). Therefore, the inventors sought to develop the compound as an oral therapeutic agent for mood disorders. Prodrugs of mesembranol have been developed that release mesembranol in vivo with improved oral bioavailability and / or pharmacokinetics compared to the natural product.

[0034] The present invention is based, at least in part, on mesembranol and 6-epi-mesembranol, and their prodrugs. Compounds and compositions are developed and described herein to take advantage of the desirable properties of mesembranol (e.g., (-) mesembranol or (-)6-epi-mesembranol) to improve absorption, distribution, metabolism, and excretion (ADME), which affect pharmacokinetics (PK).

[0035] Exemplary Compounds of the Invention In certain embodiments, compounds described herein can form mesembranol (e.g., (-) mesembranol or (-)6-epi-mesembrananol) under biologically relevant conditions. For example, in some embodiments, compounds disclosed herein (e.g., compounds of Formula (I)) can be hydrolyzed in a highly acidic environment (e.g., a pH of about 2 at room temperature, or the relatively stringent conditions typically encountered within the gastrointestinal tract of a mammal) and / or undergo enzymatic hydrolysis (e.g., in the blood) at a rate favorable to provide a desired bioabsorption (%F) following oral administration by a mammal and to result in a desired pharmacokinetic profile of mesembranol (e.g., -) mesembranol or (-)6-epi-mesembrananol) to the mammal.

[0036] In some embodiments, the compound according to the present disclosure has formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is -C(O)NR 2 R 3 , -P(O)OR 3 OR 4 , -C(O)OR 5 , -C(O)R 6 , or -CH2OC(O)R 7 and; R 2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 3 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and each hydrogen atom in the 4- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 4 is C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 3 and R 4 are taken together with the -OP(O)-O- to which they are attached to form a 5- to 7-membered heterocycle, and each hydrogen atom in the 5- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 5 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 6 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, -OC(O)C-C alkyl, nitro, -N(C-C alkyl) -, -NH, -N(H)C-C alkyl, C-C haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 7 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; and n is 1 or 2.

[0037] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is as defined herein.

[0038] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 1 is as defined herein.

[0039] In certain embodiments, the compound has formula (II): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 3 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and each hydrogen atom in the 4- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy; and n is 1 or 2.

[0040] In certain embodiments, the compound has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 is as defined herein.

[0041] In certain embodiments, the compound has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 1 and R 3 is as defined herein.

[0042] In certain embodiments, the compound has formula (III): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 3 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 4 is C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 3 and R 4 are taken together with the -OP(O)-O- to which they are attached to form a 5- to 7-membered heterocycle, and each hydrogen atom in the 5- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy; and n is 1 or 2.

[0043] In certain embodiments, the compound has formula (III-A) or (III-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 is as defined herein.

[0044] In certain embodiments, the compound has formula (III-A) or (III-B): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 3 and R 4 is as defined herein.

[0045] In certain embodiments, the compound has formula (IV): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 5 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0046] In certain embodiments, the compound has formula (IV-A) or (IV-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 5 is as defined herein.

[0047] In certain embodiments, the compound has formula (IV-A) or (IV-B): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 5 is as defined herein.

[0048] In certain embodiments, the compound has formula (V): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 6 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, —OC(O)C-C alkyl, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0049] In certain embodiments, the compound has formula (VA) or (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 6 is as defined herein.

[0050] In certain embodiments, the compound has formula (VA) or (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 6 is as defined herein.

[0051] In certain embodiments, the compound has formula (VI): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 7 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0052] In certain embodiments, the compound has formula (VI-A) or (VI-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 7 is as defined herein.

[0053] In certain embodiments, the compound has formula (VI-A) or (VI-B): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown and R 7 is as defined herein.

[0054] In certain embodiments, R 1 is -C(O)NR 2 R 3 In some embodiments, R 2 is C1-C6 alkyl (e.g., methyl), C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 In some embodiments, R is cycloalkyl, phenyl, or 5-7 membered heteroaryl. 3 is C1-C6 alkyl (e.g., methyl), phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n In some embodiments, R 3 is H. In some embodiments, R 2 and R 3 Each of R is methyl. 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring.

[0055] In certain embodiments, R 1 is -P(O)OR 3 OR 4 In some embodiments, R 3 and R 4 each independently represents C1-C6 alkyl, phenyl, -(CH2O) n -C(O)OC1-C6 alkyl, or -(CHO) n In some embodiments, R 4 is C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n In some embodiments, R 3 is H. In some embodiments, n is 1, whereby R 1is —CH2O—C(O)OC1-C6 alkyl. In some embodiments, R 3 and R 4 together with the -OP(O)-O- to which they are attached form a 5- to 7-membered heterocycle.

[0056] In certain embodiments, R 1 is -C(O)OR 5 In some embodiments, R 5 is C1-C6 alkyl (e.g., ethyl).

[0057] In certain embodiments, R 1 is -C(O)R 6 In some embodiments, R 6 is C1-C6 alkyl or phenyl. In some embodiments, R 6 is C-C alkyl (e.g., isopropyl, propyl, butyl, or t-butyl). In some embodiments, R 6 is phenyl.

[0058] In certain embodiments, R 1 is -CH2OC(O)R 7 In some embodiments, R 7 is C1-C6 alkyl (e.g., unsubstituted C1-C6 alkyl). In some embodiments, R 7 is isopropyl, propyl, or t-butyl).

[0059] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0060] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the absolute stereochemistry shown.

[0061] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the absolute stereochemistry shown.

[0062] In some embodiments, the compound [ka] wherein each R is independently selected from H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, —(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, and each hydrogen atom of the alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 or two R's taken together with the -OP(O)-O- to which they are attached form a 5-8 membered heterocycle, wherein each hydrogen atom of the 5-8 membered heterocycle is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, C-C 10 Substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0063] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)NR 2 R 3 and;R 2 is C1-C6 alkyl; and R 3 is H or C1-C6. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)NR 2 R 3 and;R 2 is C1-C6 alkyl; and R 3 is C1-C6 alkyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)NR 2 R 3 and;R 2 is C1-C4 alkyl; and R 3 is C1-C4 alkyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)NR 2 R 3 and;R 2 is methyl; and R 3 is methyl.

[0064] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is -P(O)OR 3 OR 4 and;R 3 is H or C1-C6 alkyl, and R 4is H or C1-C6. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -P(O)OR 3 OR 4 and;R 3 is H or C1-C4 alkyl; and R 4 is H or C1-C4 alkyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -P(O)OR 3 OR 4 and;R 3 is H or methyl, and R 4 is H or methyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -P(O)OR 3 OR 4 and;R 3 is H and R 4 is H.

[0065] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)OR 5 and R 5 is C1-C6 alkyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)OR 5 and R 5 is C1-C4 alkyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)OR 5 and R 5is C2-C4 alkyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)OR 5 and R 5 In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)OR 5 and R 5 is ethyl.

[0066] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6 is C1-C6 alkyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6 is n-butyl, isobutyl, or t-butyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6 In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6 is aryl optionally substituted with halo. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6is phenyl optionally substituted with halo. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6 is a 5-membered heteroaryl optionally substituted with halo. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6 is a 6-membered heteroaryl optionally substituted with halo. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6 In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)R 6 and R 6 is pyrimidinyl.

[0067] In certain embodiments, the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH2OC(O)R 7 and R 7 is C1-C6 alkyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH2OC(O)R 7 and R 7 is propyl or butyl. In certain embodiments, the compound has formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH2OC(O)R7 and R 7 is t-butyl, isobutyl, n-butyl, n-propyl, isopropyl, ethyl, or methyl.

[0068] In certain embodiments, the compound has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6 alkyl, and R 3 is H or C1-C6 alkyl. In certain embodiments, the compound has formula (II-A) or (II-B), or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl and R 3 is H or methyl. In certain embodiments, the compound has formula (II-A) or (II-B), or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl and R 3 is methyl.

[0069] In certain embodiments, the compound has formula (III-A) or (III-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 is H or methyl, and R 4 is H or methyl. In certain embodiments, the compound has formula (III-A) or (III-B), or a pharmaceutically acceptable salt thereof, wherein R 3 is H and R 4 is H or methyl. In certain embodiments, the compound is of formula (III-A) or (III-B), or a pharmaceutically acceptable salt thereof, wherein R 3 is H or methyl, and R 4is H. In certain embodiments, the compound has formula (III-A) or (III-B), or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl and R 4 is H. In certain embodiments, the compound is of formula (III-A) or (III-B), or a pharmaceutically acceptable salt thereof, wherein R 3 is H and R 4 In certain embodiments, the compound has formula (III-A) or (III-B), or a pharmaceutically acceptable salt thereof, wherein R 3 is H and R 4 is H.

[0070] In certain embodiments, the compound has formula (IV-A) or (IV-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 5 is C1-C6 alkyl. In certain embodiments, the compound has formula (IV-A) or (IV-B), or a pharmaceutically acceptable salt thereof, wherein R 5 is ethyl.

[0071] In certain embodiments, the compound has formula (VA) or (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 6 is C1-C6 alkyl. In certain embodiments, the compound has formula (IV-A) or (IV-B), or a pharmaceutically acceptable salt thereof, wherein R 6 is C3-C6 alkyl. In certain embodiments, the compound has formula (VA) or (VB), or a pharmaceutically acceptable salt thereof, wherein R 6is C4-C6 alkyl. In certain embodiments, the compound has formula (VA) or (VB), or a pharmaceutically acceptable salt thereof, wherein R 6 is t-butyl, isobutyl, or n-butyl. In certain embodiments, the compound has formula (VA) or (VB), or a pharmaceutically acceptable salt thereof, wherein R 6 In certain embodiments, the compound has formula (VA) or (VB), or a pharmaceutically acceptable salt thereof, wherein R 6 In certain embodiments, the compound has formula (VA) or (VB), or a pharmaceutically acceptable salt thereof, wherein R 6 is pyrimidinyl.

[0072] In certain embodiments, the compound has formula (VI-A) or (VI-B): [ka] or a pharmaceutically acceptable salt thereof, wherein R 7 is C1-C6 alkyl. In certain embodiments, the compound is of formula (VI-A) or (VI-B), or a pharmaceutically acceptable salt thereof, wherein R 7 is C3-C6 alkyl. In certain embodiments, the compound has formula (VI-A) or (VI-B), or a pharmaceutically acceptable salt thereof, wherein R 7 is C3-C4 alkyl. In certain embodiments, the compound is of formula (VI-A) or (VI-B), or a pharmaceutically acceptable salt thereof, wherein R 7 is butyl or propyl.

[0073] In some embodiments, a method of treating a patient suffering from a disease comprises administering to the patient a composition comprising a compound disclosed herein for the treatment or prevention of a mental health disorder. In some embodiments, a method of treating a patient suffering from a disease comprises administering to the patient a composition comprising a compound disclosed herein for the treatment or prevention of a diagnosed condition selected from anxiety and depression. In some embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I)-(VI) for the treatment of depression. In some embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I)-(VI) for the treatment of a condition selected from the group consisting of anxiety associated with depression, anxiety with depression, and mixed anxiety and depression disorder. In some embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I)-(VI) for the treatment of anxiety and hysteria, or anxiety and depression.

[0074] In certain embodiments, the present disclosure provides a method of treating a psychiatric disorder, comprising administering to a subject a compound of the present disclosure (e.g., a compound of Formulas (I)-(VI)).

[0075] In certain embodiments, the disclosure provides a method of inhibiting SERT, comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the prodrug mesembranol. In certain embodiments, the mesembranol is (-)mesembrananol. In certain embodiments, the mesembranol is (-)6-epi-mesembrananol. In certain embodiments, the composition comprises a mesembranol prodrug. In some embodiments, the compound is a compound of Formula (I). In some embodiments, the mesembranol prodrug is a compound of Formula (I) (e.g., a compound of Formula (I), (IA), or (IB)). In some embodiments, the mesembranol prodrug is a compound of Formula (II) (e.g., a compound of Formula (II), (II-A), or (II-B)). In some embodiments, the mesembranol prodrug is a compound of Formula (III) (e.g., a compound of Formula (III), (III-A), or (III-B)). In some embodiments, the prodrug of mesembranol is a compound of formula (IV) (e.g., a compound of formula (IV), (IV-A), or (IV-B)). In some embodiments, the prodrug of mesembranol is a compound of formula (V) (e.g., a compound of formula (V), (V-A), or (V-B)). In some embodiments, the prodrug of mesembranol is a compound of formula (VI) (e.g., a compound of formula (VI), (VI-A), or (VI-B)). In certain embodiments, the pharmaceutical composition contains about 10% or less of an alkaloid selected from (-) mesembrine, mesembrenone, mesembrenol, alone or in combination together. For example, the pharmaceutical composition may contain less than about 10%, less than about 5%, less than about 3%, less than about 2%, or less than about 1% by weight of the combined alkaloids (-) mesembrine and mesembrenone, or the combined alkaloids mesembrenone and mesembrenol, or the combined alkaloids (-) mesembrine, mesembrenone, and mesembrenol. In certain embodiments, the composition is substantially free of (-) mesembrine, mesembrenone, and mesembrenol.

[0076] In some embodiments, the compounds disclosed herein are administered to a patient in a unit dose. In some embodiments, the compounds disclosed herein are prescribed to a patient in an oral unit dose, such as a capsule or tablet, one or more times daily. In some embodiments, the compounds disclosed herein are administered to a patient for the treatment of a disease or condition for which a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) is safe and effective. In some embodiments, a method comprises administering to a patient in need thereof a therapeutically effective amount of a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) for the treatment of anxiety. In some embodiments, a method comprises administering to a patient in need thereof a therapeutically effective amount of a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) for the treatment of a disease selected from the group consisting of mild to moderate depression and major depressive episodes. In some embodiments, a method comprises administering to a patient in need thereof a therapeutically effective amount of a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) for the treatment of a disease selected from the group consisting of psychological and psychiatric disorders in which anxiety is present. In some embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) for the treatment of a major depressive episode. In some embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) for the treatment of a disorder selected from the group consisting of alcohol and drug addiction, bulimia nervosa, and obsessive-compulsive disorder. In some embodiments, an amount of 20 micrograms to 2 milligrams of a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) is orally administered to a patient in need thereof to treat the patient. In some embodiments, an amount of 20 micrograms to 2 milligrams of a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) is orally administered to a patient in need thereof to treat the patient.

[0077] Pharmaceutical Composition In certain embodiments, the present application relates to a pharmaceutical composition comprising an active pharmaceutical ingredient. In certain embodiments, the pharmaceutical composition comprises a compound disclosed herein as an active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients. In some embodiments, the pharmaceutical composition optionally further comprises a therapeutic compound (i.e., a drug) and a pharmaceutically acceptable carrier. The pharmaceutical composition may be a medicament.

[0078] Physiologically acceptable carriers include carriers known in the art.The choice of pharmaceutically acceptable carrier can depend, for example, on the desired route of administration of the composition.Pharmaceutical compositions (preparations) can be administered to subjects by any of many routes, including, for example, parenteral administration (for example, intravenous, subcutaneous or intramuscular), oral administration (for example, tablets and capsules); absorption through oral mucosa (for example, sublingual) or transdermal (for example, as a patch that is applied to the skin), or topical (for example, as a cream, ointment or spray that is applied to the skin).

[0079] In some embodiments, pharmaceutical compositions containing mesembranol prodrugs (e.g., compounds of Formulas (I)-(VI)) or pharmaceutically acceptable salts thereof can be formulated for oral administration. For example, the compounds provided herein can be combined with suitable defined excipients to form an oral unit dosage form, such as a capsule or tablet, containing a target dose of mesembranol prodrugs (e.g., compounds of Formulas (I)-(VI)). The drug product can be prepared by first manufacturing the mesembranol prodrug (e.g., compounds of Formulas (I)-(VI)) as the active pharmaceutical ingredient (API), followed by roller compaction / milling with intragranular excipients and blending with extragranular excipients. The drug product can include mesembranol prodrugs (e.g., compounds of Formulas (I)-(VI)) as API and excipient components in tablets of the desired dosage strength. The blended material can be compressed to form tablets, which can then be film-coated. Excipients may be selected from materials suitable for inclusion in a pharmaceutical composition for its intended purpose and delivery route, including those that provide the pharmaceutical composition with desirable manufacturing and stability characteristics, and / or desirable in vivo or other properties. In some embodiments, the pharmaceutical composition may include a mesembranol prodrug (e.g., a compound of Formulas (I)-(VI)) as the API in combination with a filler (e.g., a form of microcrystalline cellulose), a dry binder, or a disintegrant (e.g., a cross-linked polymer), a flow agent (e.g., colloidal silicon dioxide), and / or a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical composition may include materials, such as sustained-release or disintegrants, that are involved in carrying or transporting the API pharmaceutical from one organ or body part of a subject to another, including materials that desirably control absorption of the API in the intestine.

[0080] The formulations can be conveniently presented in unit dosage form and prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. For use in the methods of the present invention, the active compound can be provided per se, or can be provided as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0081] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0082] To prepare solid dosage forms for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, (2) binders, (3) wetting agents, (4) disintegrants, (5) dissolution retarders, (6) absorption enhancers, (7) wetting agents, (8) absorbing agents, (9) lubricants, (10) complexing agents, and (11) colorants. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain a buffering agent. Similar types of solid compositions may also be used as fillers in soft- and hard-fill gelatin capsules using appropriate excipients. Pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and / or adjuvants. In some embodiments, pharmaceutical compositions according to the present invention may contain conventional carrier agents, including binders, lubricants, and / or flow agents, selected from products and materials commonly used in the pharmaceutical industry to prepare pharmaceutical compositions for the intended route of administration.

[0083] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0084] Liquid dosage forms useful for oral administration comprise a pharmaceutically acceptable carrier and an active ingredient, and are provided as a solid form for reconstitution before administration, or as a liquid (e.g., solution, suspension, or emulsion).In addition to the active ingredient, liquid dosage forms may contain an inert diluent commonly used in the art.For example, the formulation of a pharmaceutically acceptable composition for injection may contain an aqueous solution such as water or physiologically buffered saline, or other solvent or vehicle suitable for the intended route of administration.In some embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0085] The therapeutically effective amount of the pharmaceutical composition can be determined by human clinical trials to determine a safe and effective dose for patients with relevant diagnoses. It is generally understood that the effective amount of the compound may vary depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other types of therapeutic agents administered together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the pharmaceutical composition at a dose and dose interval determined to be safe and effective for the patient.

[0086] The present disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to a compound to form an acid addition salt can be an organic acid or an inorganic acid. The base added to a compound to form a base addition salt can be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt, and in some embodiments, the pharmaceutically acceptable salt is an ammonium salt. For example, pharmaceutically acceptable acid addition salts may exist as various solvates with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be derived from the solvent of crystallization, may be inherent in the solvent of preparation or crystallization, or may be associated with such solvent.

[0087] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0088] The methods and techniques of the present disclosure, unless otherwise indicated, are generally carried out according to conventional methods well known in the art and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", W.H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", W.H. Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000). All of the above, and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0089] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of compounds), a biological macromolecule (e.g., nucleic acids, antibodies containing portions thereof, as well as humanized, chimeric, and human antibodies, and monoclonal antibodies, proteins or portions thereof, e.g., peptides, lipids, carbohydrates), or an extract made from biological material such as bacteria, plants, fungi, or animal (especially mammalian) cells or tissues. Agents include, for example, agents whose structures are known and agents whose structures are unknown.

[0090] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0091] "Treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, diminishment of the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0092] The term "prevention," when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is art-recognized and well understood in the art and includes administration of a composition that reduces the frequency of or delays the onset of symptoms of a medical condition in a subject compared to subjects not administered the composition. Thus, prevention of cancer includes, by way of example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0093] "Administering" or "administration" of a substance, compound, or agent to a subject can be accomplished using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ophthalmically, sublingually, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and transdermally (e.g., by absorption through cutaneous channels). The compound or agent can also be suitably introduced via a rechargeable or biodegradable polymeric or other device, e.g., a patch and pump, or formulation, which provides extended, gradual, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods.

[0094] Suitable methods of administering a substance, compound, or agent to a subject also depend, for example, on the age and / or physical condition of the subject, as well as the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally to the subject, for example, by ingestion. In some embodiments, the orally administered compound or agent is in a sustained- or slow-release formulation or is administered using such a slow- or sustained-release device.

[0095] As used herein, the phrase "co-administration" refers to any administration form of two or more different therapeutic agents in which a second agent is administered while a previously administered therapeutic agent is still effective in the body (e.g., the two agents are effective in a patient simultaneously, which may include a synergistic effect of the two agents). For example, the different therapeutic compounds may be administered in the same formulation or in separate formulations, and may be administered simultaneously or sequentially. Thus, an individual receiving such treatment may benefit from the combined effects of the different therapeutic agents.

[0096] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is an amount of drug or agent that has the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur in a single administration, but may occur only after a series of administrations. Thus, a therapeutically effective amount may be administered in one or more administrations. The exact effective amount required for a subject depends, for example, on the subject's size, health, and age, as well as the nature and extent of the condition being treated, such as cancer or MDS. Those skilled in the art can easily determine the effective amount for a given situation by routine experimentation.

[0097] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes examples of when the event or circumstance occurs and examples of when it does not occur. For example, "optionally substituted alkyl" refers to cases where alkyl can be substituted, as well as cases where alkyl is not substituted.

[0098] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by one skilled in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art, as well as those methods described below. When a substituent is itself substituted with multiple groups, it will be understood that such multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0099] As used herein, the term "optionally substituted" refers to the replacement of 1 to 6 hydrogen radicals in a given structure with the radical of a specified substituent, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH-O-alkyl, -OP(O)(O-alkyl), or -CH-OP(O)(O-alkyl). Preferably, "optionally substituted" refers to the replacement of 1 to 4 hydrogen radicals in a given structure with the above substituents. More preferably, 1 to 3 hydrogen radicals are replaced with the above substituents. It is understood that a substituent may be further substituted.

[0100] As used herein, the term "alkyl" refers to saturated aliphatic groups, including but not limited to, C-C 10 Straight chain alkyl groups, C1-C 10 Examples of "alkyl" include branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. Preferably, the "alkyl" group refers to a C1-C7 straight-chain alkyl group or a C1-C7 branched-chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight-chain alkyl group or a C1-C3 branched-chain alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. The "alkyl" group may be optionally substituted.

[0101] The term "haloalkyl" refers to an alkyl group substituted with at least one hydrogen atom on the carbon replaced by a halogen. Exemplary halogens include fluoro, chloro, bromo, and iodo. Exemplary haloalkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl.

[0102] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0103] "C x-y " or "C x -C y The term "C alkyl" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, means a group containing x to y carbons in a chain. C alkyl indicates a hydrogen when the group is in a terminal position and a bond when the group is internal. 1-6 An alkyl group may, for example, contain 1 to 6 carbon atoms in the chain.

[0104] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0105] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0106] As used herein, the term "amide" refers to the group: [ka] In the formula, R e and R f each independently represents hydrogen or a hydrocarbyl group, or R e and R f together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0107] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0108] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0109] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0110] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Preferably, an "alkyl" group refers to a C1-C7 straight chain alkoxy group or a C1-C7 branched chain alkoxy group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0111] The term "arylaoxy" refers to an aryl group having an oxygen attached thereto. Preferably, an "aryloxy" group is an aryl group having a C-C 10 It refers to an aryloxy group or a 5- to 7-membered heteroaryloxy group. Representative aryloxy groups include phenoxy (C6H5-O-).

[0112] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and their salts, e.g., [ka] wherein R e , R f , and R g each independently represents hydrogen or a hydrocarbyl group, or R e and R ftogether with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0113] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0114] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0115] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring, e.g., phenyl. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0116] The term "carbamate" is art-recognized and includes the following groups: [ka] In the formula, R e and R f independently represent hydrogen or a hydrocarbyl group.

[0117] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0118] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Valence permitting, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0119] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0120] The term "carbonate" is art-recognized and refers to an -OCO2- group.

[0121] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0122] The term "ester" as used herein refers to an ester of -C(O)OR 9 refers to a group, wherein R 9 represents a hydrocarbyl group.

[0123] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0124] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0125] The terms "heteroaryl" and "hetaryl" refer to substituted or unsubstituted aromatic monocyclic ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 1 heteroatom. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, in which at least one of the rings is heteroaromatic, and in which the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0126] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0127] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0128] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring system, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, which ring system contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0129] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom that does not have an =O or =S substituent, typically has at least one carbon-hydrogen bond and a primary carbon backbone, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (which has an =O substituent on the bonded carbon) and ethoxy (which is bonded through an oxygen rather than a carbon) are not considered hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0130] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0131] The term "lower," when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups having 10 or fewer atoms in the substituent, preferably 6 or fewer atoms. For example, "lower alkyl" refers to an alkyl group containing 6 or fewer carbon atoms, preferably 4 or fewer carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether appearing alone or in combination with other substituents (e.g., when counting the carbon atoms of the alkyl substituent, atoms in the aryl group are not counted), such as in descriptions of hydroxyalkyl and aralkyl. The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each ring of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, within the ring.

[0132] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0133] The term “sulfonamide” is art-recognized and refers to a group represented by the general formula: [ka] In the formula, R e and R f independently represent hydrogen or hydrocarbyl.

[0134] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0135] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0136] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0137] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution, subject to the permissible valencies of the substituted atom and substituent, results in a stable compound that does not undergo spontaneous transformation, for example, by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have any permissible substituents of organic compounds described herein that satisfy hydrogen substitution and / or the valencies of the heteroatoms. Substituents can include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or anacil), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0138] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0139] As used herein, the term "thioester" refers to a thioester of -C(O)SR e or -SC(O)R e In the formula, R e represents a hydrocarbyl.

[0140] As used herein, the term "thioether" is the equivalent of an ether where the oxygen has been replaced with a sulfur.

[0141] The term "urea" is art-recognized and may be represented by the general formula: [ka] In the formula, R e and R f independently represent hydrogen or hydrocarbyl.

[0142] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (eg, cell proliferation), as well as enhancing a function or activity.

[0143] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible for the treatment of a patient.

[0144] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any base compound represented by Formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, and sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid. Mono- or di-acid salts may also be formed, and such salts may exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. The selection of suitable salts will be known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be used, for example, in the isolation of compounds of formula I for laboratory use or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0145] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or any of its intermediates. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline or ammonia. The selection of appropriate salts is within the skill of the art.

[0146] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0147] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0148] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intraocular (e.g., intravitreal), intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, or sterile powders that can be reconstituted into a sterile injectable solution or dispersion immediately before use. Many of the compounds useful in the methods and compositions of the present disclosure have at least one asymmetric center in their structure. This stereocenter may exist in either the R or S configuration, and the R and S designations are used in accordance with the conventions set forth in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure contemplates all stereoisomeric forms, such as enantiomers and diastereomers, of the compounds, salts, prodrugs, or mixtures thereof, including all possible mixtures of stereoisomers. See, e.g., WO 01 / 062726.

[0149] Furthermore, certain compounds containing alkenyl groups can exist as Z (Zusammen) or E (Entgegen) isomers. In each case, the present disclosure includes both mixtures and separate individual isomers.

[0150] Some compounds may also exist in tautomeric forms, and such forms, although not explicitly shown in the formulae given herein, are intended to be included within the scope of the present disclosure.

[0151] A "prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized in the host after administration, e.g., hydrolyzed or oxidized, to form mesembrine. Representative examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on a functional group of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to yield the active compound. Examples of prodrugs include the use of esters or phosphoramidates as the biologically labile or cleavable (protecting) group. Prodrugs of the present disclosure are metabolized to produce mesembranol. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs," Ed. H. Bundgaard, Elsevier, 1985.

[0152] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, useful in formulating a drug for pharmaceutical or therapeutic use. As used herein, the terms "logarithm of solubility," "LogS," or "logS" are used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility often results in poor absorption. The LogS value is the unitless logarithm (base 10) of solubility measured in mol / liter.

[0153] Additional Embodiments 1. Compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is -C(O)NR 2 R 3 , -P(O)OR 3 OR 4 , -C(O)OR 5 , -C(O)R 6 , or -CH2OC(O)R 7 and; R 2 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 3 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n-C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and each hydrogen atom in the 4- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 4 is H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 3 and R 4 are taken together with the -OP(O)-O- to which they are attached to form a 5- to 7-membered heterocycle, and each hydrogen atom in the 5- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 5 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 6 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, -OC(O)C-C alkyl, nitro, -N(C-C alkyl) -, -NH, -N(H)C-C alkyl, C-C haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 7 is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; and n is 1 or 2.

[0154] 2. The compound of embodiment 1, wherein the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof.

[0155] 3. The compound of embodiment 1, wherein the compound has formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein said compound has the absolute stereochemistry shown.

[0156] 4.R 1 But -C(O)NR 2 R 3 The compound of any one of embodiments 1 to 3, wherein

[0157] 5.R 2 C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 The compound of embodiment 4, wherein the aryl is cycloalkyl, phenyl, or 5-7 membered heteroaryl.

[0158] 6.R 3 C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) nThe compound of any one of embodiments 4 or 5, wherein the compound is -C(O)C1-C6 alkyl.

[0159] 7.R 3 The compound of any one of embodiments 4 or 5, wherein is H.

[0160] 8.R 2 and R 3 The compound of embodiment 4, wherein each of is C1-C6 alkyl, such as methyl.

[0161] 9.R 2 and R 3 taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle.

[0162] 10.R 1 But -P(O)OR 3 OR 4 The compound of any one of embodiments 1 to 3, wherein

[0163] 11.R 3 and R 4 each independently represents H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n The compound of embodiment 10, wherein the alkyl is -C(O)C1-C6 alkyl.

[0164] 12.R 4 C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n The compound of embodiment 10, wherein the alkyl is -C(O)C1-C6 alkyl.

[0165] 13. The compound according to any one of embodiments 10 to 12, wherein n is 1.

[0166] 14.R 3 and R 4 and n is 0 or 1. The compound of embodiment 10, wherein each of

[0167] 15.R 3 and R 4 taken together with the —OP(O)—O— to which they are attached form a 5- to 7-membered heterocycle.

[0168] 16.In the formula, R 1 -C(O)OR 5 The compound of any one of embodiments 1 to 3, wherein

[0169] 17.R 5 is C1-C3 alkyl.

[0170] 18.R 5 is ethyl.

[0171] 19.In the formula, R 1 -C(O)R 6 The compound of any one of embodiments 1 to 3, wherein

[0172] 20.R 6 is C1-C3 alkyl or phenyl.

[0173] 21.R 6 is C1-C3 alkyl, for example, t-butyl, isopropyl, or propyl.

[0174] 22.R 6 is phenyl.

[0175] 23.In the formula, R 1 -CH2OC(O)R 7 The compound of any one of embodiments 1 to 3, wherein

[0176] 24.R 7 is C1-C6 alkyl.

[0177] 25.R 7 is unsubstituted C1-C6 alkyl.

[0178] 26.R 7 The compound of embodiment 23, wherein is isopropyl, propyl, or t-butyl.

[0179] 27. The compound of embodiment 1, [ka] or a pharmaceutically acceptable salt thereof.

[0180] 28. The compound of embodiment 1, [ka] or a pharmaceutically acceptable salt thereof.

[0181] 29. The compound of embodiment 1, [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown.

[0182] 30. The compound of embodiment 1, [ka] or a pharmaceutically acceptable salt thereof.

[0183] 31. The compound of embodiment 1, [ka] or a pharmaceutically acceptable salt thereof, wherein the compound has the absolute stereochemistry shown.

[0184] 32. Compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 2 C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Each hydrogen atom in the cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C-C alkyl, C-C alkoxy, nitro, —N(C-C alkyl) , —NH , —N(H)C-C alkyl, C-C haloalkyl, —COOH, cyano, phenyl, or phenoxy; R 3 H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and each hydrogen atom in said 4- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy; and The compound wherein n is 1 or 2.

[0185] 33. The compound according to embodiment 32, wherein the compound has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof.

[0186] 34. The compound according to embodiment 32, wherein the compound has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein said compound has the absolute stereochemistry shown.

[0187] 35. Compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 3 H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; R 4 H, C1-C6 alkyl, phenyl, -(CHO) n -C(O)OC1-C6 alkyl, or -(CHO) n -C(O)C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy; Or R 3 and R 4 are taken together with the -OP(O)-O- to which they are attached to form a 5- to 7-membered heterocycle, and each hydrogen atom in the 5- to 7-membered heterocycle is optionally selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C 10 substituted with cycloalkyl, phenyl, 5-7 membered heterocycle, 5-7 membered heteroaryl, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy; and The compound wherein n is 1 or 2.

[0188] 36. The compound according to embodiment 35, wherein the compound has formula (III-A) or (III-B): [ka] or a pharmaceutically acceptable salt thereof.

[0189] 37. The compound according to embodiment 35, wherein the compound has formula (III-A) or (III-B): [ka] or a pharmaceutically acceptable salt thereof, wherein said compound has the absolute stereochemistry shown.

[0190] 38. Compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 5 C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 The compounds wherein each hydrogen atom in the cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C1-C6 alkyl, C1-C3 alkoxy, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0191] 39. The compound according to embodiment 38, wherein the compound has formula (IV-A) or (IV-B): [ka] or a pharmaceutically acceptable salt thereof.

[0192] 40. The compound according to embodiment 38, wherein the compound has formula (IV-A) or (IV-B): [ka] or a pharmaceutically acceptable salt thereof, wherein said compound has the absolute stereochemistry shown.

[0193] 41. Compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 6 C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 The compounds wherein each hydrogen atom in the cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C1-C6 alkyl, C1-C3 alkoxy, -OC(O)C1-C6 alkyl, nitro, -N(C1-C3 alkyl)2, -NH2, -N(H)C1-C3 alkyl, C1-C3 haloalkyl, -COOH, cyano, phenyl, or phenoxy.

[0194] 42. The compound of embodiment 41, wherein the compound has formula (VA) or (VB): [ka] or a pharmaceutically acceptable salt thereof.

[0195] 43. The compound of embodiment 41, wherein the compound has formula (VA) or (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein said compound has the absolute stereochemistry shown.

[0196] 44. Compound of formula (VI): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 7C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C1-C3 alkyl-C3-C 10 cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 The compounds wherein each hydrogen atom in the cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted with halo, hydroxy, C1-C6 alkyl, C1-C3 alkoxy, nitro, —N(C1-C3 alkyl)2, —NH2, —N(H)C1-C3 alkyl, C1-C3 haloalkyl, —COOH, cyano, phenyl, or phenoxy.

[0197] 45. The compound according to embodiment 44, wherein the compound has formula (VI-A) or (VI-B): [ka] or a pharmaceutically acceptable salt thereof.

[0198] 46. ​​The compound according to embodiment 44, wherein the compound has formula (VI-A) or (VI-B): [ka] or a pharmaceutically acceptable salt thereof, wherein said compound has the absolute stereochemistry shown.

[0199] 47. A pharmaceutical composition comprising a compound according to any one of embodiments 1-46 and a pharmaceutically acceptable excipient.

[0200] 48. A method for treating a mental health disorder, comprising administering to a mammal in need thereof an effective amount of a compound according to any one of embodiments 1-46.

[0201] 49. The method of embodiment 48, wherein the mental health disorder is anxiety, stress, or depression.

[0202] 50. The method of embodiment 49, wherein the mental health disorder is anxiety.

[0203] 51. The method of embodiment 49, wherein the mental health disorder is stress.

[0204] 52. The method of embodiment 49, wherein the mental health disorder is depression.

[0205] 53. The method of any one of embodiments 48-52, wherein the mammal is a human. [Example]

[0206] LC / MS spectra were obtained using an Agilent 1200 / G1956A or a SHIMADZU LCMS-2020. Standard LC / MS conditions were as follows (run time 1.55 min): Acidic conditions: Mobile phase A: 0.0375% TFA in water (v / v). Mobile phase B: 0.01875% TFA in acetonitrile (v / v). Column: Kinetex EVO C18 30*2.1mm, 5μm. Basic conditions: Mobile phase A: 0.025% NH₃·H₂O aqueous solution (v / v). Mobile phase B: acetonitrile; Column: Kinetex EVO C18 2.1 x 30 mm, 5 μm. TIFF2025541878000086.tif220165TIFF2025541878000087.tif51165

[0207] TIFF2025541878000088.tif219165

[0208] TIFF2025541878000089.tif55165

[0209] Example 1: Synthesis of (+ / -)-Mesembrine [ka]

[0210] Step 1: Synthesis of 1-(3,4-dimethoxyphenyl)cyclopropane-1-carbonitrile To a solution of 2-(3,4-dimethoxyphenyl)acetonitrile (20 g, 112 mmol) in DMF (93 mL) was added NaH (18.0 g, 451 mmol, 60% purity) in portions. The mixture was stirred at 25 °C for 20 min. 1-Bromo-2-chloroethane (16.1 g, 112 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction was quenched by adding a MeOH / water mixture (1:1; 1000 mL), and the resulting solution was extracted with EtOAc (3 × 500 mL). The combined organic solution was washed with water (4 × 500 mL) and brine (1 × 200 mL), and dried (NaSO). The solution was filtered, and the solvent was evaporated under reduced pressure. The resulting solid was purified by column chromatography (SiO2, petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give 1-(3,4-dimethoxyphenyl)cyclopropane-1-carbonitrile (15 g, 65%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ6.88(s,1H),6.82(d,J=1.2Hz,2H),3.91(s,3H),3.88(s,3H),1.68-1.65(m,2H),1.35(d,J=2.4Hz,2H).

[0211] Step 2: Synthesis of 1-(3,4-dimethoxyphenyl)cyclopropane-1-carbaldehyde To a solution of 1-(3,4-dimethoxyphenyl)cyclopropane-1-carbonitrile (11 g, 54.1 mmol) in THF (160 mL) was added DIBAL-H (1 M in toluene, 81.2 mL). The mixture was allowed to stir at 25 °C for 3 h, and then the reaction was carefully quenched by the addition of 2 M aqueous HCl. The solution was extracted with DCM (3 × 200 mL). The organic solutions were combined, washed with water (2 × 200 mL) and brine (2 × 200 mL), and then dried over NaSO to give 1-(3,4-dimethoxyphenyl)cyclopropane-1-carbaldehyde (9.6 g, 85%) as a yellow oil. LC-MS (ESI+) m / z 207.0 (M+H) + . 1H NMR(400MHz,CDCl3)δ9.26(s,1H),6.94-6.61(m,3H),3.89(d,J=2.8Hz,6H),1.61-1.52(m,2H),1.42-1.37(m,2H)

[0212] Step 3: Synthesis of (Z)-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)-N-methylmethanimine To a solution of 1-(3,4-dimethoxyphenyl)-cyclopropanecarbaldehyde (5.0 g, 24.2 mmol) in DCM (50 mL) was added MeNH (2 M, 121 mL) and NaSO (15.5 g, 109 mmol, 11.0 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give (Z)-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)-N-methylmethanamine (5.1 g, 99%) as a white solid. LC-MS (ESI) + ) m / z 219.9 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.55(q,J=1.2Hz,1H),6.93-6.77(m,3H),3.88(d,J=7.2Hz,6H),3.24(d,J=1.6Hz,3H),1.29-1.23(m,2H),1.18-1.12(m,2H).

[0213] Step 4: Synthesis of 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydro-1H-pyrrole To a solution of (Z)-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)-N-methylmethanimine (5.4 g, 24.6 mmol) in DMF (19 mL) was added NaI (366 mg, 2.44 mmol) and TMSCl (267 mg, 2.46 mmol). The mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic solution was washed with water and brine, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydro-1H-pyrrole (6.25 g, 80%) as a yellow oil. LC-MS (ESI) + ) m / z 220.0 (M+H) + . 1H NMR (400MHz, CDCl3) δ6.90-6.66(m,3H),6.31(t,J=1.6Hz,1H),3.95-3.80(m,6H),3.18-3.11(m,2H),2.79(dt,J=1.2,9.0Hz,2H),2.65(s,3H).

[0214] Step 5: Synthesis of rac-3a-(3,4-dimethoxyphenyl)-1-methyl-1,2,3,3a,7,7a-hexahydro-6H-indol-6-one 4-(3,4-Dimethoxyphenyl)-1-methyl-2,3-dihydro-1H-pyrrole (6.25 g, 28.5 mmol) was dissolved in DCM (100 mL). To this solution was added HCl (1 M in dioxane, 25 mL, 100 mmol). The mixture was evaporated to dryness and then dissolved in ACN (90 mL). To this solution was added (E)-4-methoxybut-3-en-2-one (4.28 g, 42.7 mmol). The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: [water (NH4HCO3-ACN]; B%: 22% to 52%, 20 min). The eluent was acidified with aqueous HCl to give rac-3a-(3,4-dimethoxyphenyl)-1-methyl-1,2,3,3a,7,7a-hexahydro-6H-indol-6-one (3.0 g, 30%) as a white solid. LC-MS (ESI + ) m / z 288.3(M+H) + . 1 H NMR(400MHz,CDCl3)δ6.90-6.88(m,1H),6.87-6.83(m,2H),6.74(dd,J=2.0,10.1Hz,1H),6.11(d,J=10.0Hz,1H),3.89(d,J=4. 0Hz,6H),3.33(dt,J=2.4,8.8Hz,1H),2.69-2.66(m,1H),2.58-2.51(m,2H),2.50-2.41(m,2H),2.33(s,3H),2.27-2.18(m,1H)

[0215] Step 6: Synthesis of rac-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-6H-indol-6-one A mixture of rac-3a-(3,4-dimethoxyphenyl)-1-methyl-1,2,3,3a,7,7a-hexahydro-6H-indol-6-one (12.0 g, 43.9 mmol) and 10% Pd / C (300 mg) in EtOAc (120 mL) was degassed and then purged with H three times. The mixture was stirred at 25 °C under 15 psi of H for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give rac-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-6H-indol-6-one (10 g, 80%) as a brown oil. LC-MS (ESI) + ) m / z 290.4 (M+H) + . 1 H NMR(400MHz,CDCl3)δ6.99-6.89(m,2H),6.89-6.84(m,1H),3.91(d,J=7.6Hz,6H),3.20-3.11(m,1H) ,2.97(t,J=3.6Hz,1H),2.69-2.56(m,2H),2.51-2.31(m,5H),2.27-2.18(m,3H),2.18-2.07(m,2H).

[0216] Example 2: Chiral resolution of rac-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-6H-indol-6-one to give (-) mesembrine 001 [ka] To a solution of rac-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-6H-indol-6-one (28.0 g, 85.1 mmol) in THF (1400 mL) was added (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid (19.7 g, 51.1 mmol). The suspension was stirred at 25 °C for 16 h and then filtered. The solid was dried in vacuo and then triturated with THF three times at 25 °C for 16 h. The resulting solid was filtered and then added to saturated sodium bicarbonate solution (500 mL). The mixture was extracted with EtOAc (500 mL). The organic solutions were combined, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give (-)-mesembrine 001 (7.50 g, 95% ee) as a yellow gum. LC-MS (ESI + ) m / z 290.6(M+H) + . 1 H NMR(400MHz,CDCl3)δ6.89-6.81(m,2H),6.80-6.75(m,1H),3.82(d,J=8.0Hz,6H),3.11-3.03(m,1H),2. 88(t,J=3.6Hz,1H),2.59-2.48(m,2H),2.43-2.32(m,1H),2.31-2.21(m,4H),2.20-2.09(m,3H),2.08(br s,2H).

[0217] Example 3: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yldimethylcarbamate (101) [ka]

[0218] Step 1: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) 001 (2.00 g, 6.91 mmol) and CeCl .To a solution of 7H2O (3.09 g, 8.29 mmol, 788 μL) in MeOH (80 mL) was added NaBH4 (1.57 g, 41.4 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was added to 50 mL of aqueous NH4Cl solution, the organic and aqueous layers were separated, and the aqueous solution was extracted with DCM (50 mL × 3). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH3H2O)-ACN]; B%: 28%-58%, 8 min) to give (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) (730 mg, 37%) as a white oil. 1 H NMR(400MHz,CDCl3)δ6.95-6.88(m,2H),6.86-6.80(m,1H),3.95(s,1H),3.90(d,J=6.8Hz,6H),3.46-3.35(m,1H),2.93(s,1H),2.50(s,3H) ),2.45-2.29(m,2H),2.19(dd,J=2.4,14.9Hz,1H),2.01-1.82(m,2H),1.79-1.72(m,1H),1.70-1.59(m,3H),1.44(tt,J=2.8,13.6Hz,1H).

[0219] Step 2: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yldimethylcarbamate (101) To a solution of 019 (100 mg, 343 μmol) in THF (2 mL) was added t-BuOK (1 M in THF, 686 μL) and N,N-dimethylcarbamoyl chloride (73.8 mg, 686 μmol, 63.0 μL). The reaction mixture was stirred at 25° C. for 1 hour and then concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 8 min) to give 101 (419) (86.7 mg, 72%) as a white oil. LC-MS (ESI+) m / z 363.2 (M+H)+. 1H NMR(400MHz,CDCl3)δ6.94-6.89(m,1H),6.88-6.81(m,2H),4.76(td,J=3.6,7.2Hz,1H),3.89(d,J=10.8Hz,6H),3.52-3.41(m,1H),3.30( t,J=6.8Hz,1H),2.93(s,6H),2.68-2.58(m,1H),2.42(s,3H),2.30-2.11(m,4H),2.05-1.94(m,1H),1.91-1.81(m,1H),1.75-1.62(m,2H).

[0220] Example 4: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl pivalate (102) [ka] To a solution of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) (100 mg, 343 μmol) and 2,2-dimethylpropanoyl chloride (82.7 mg, 686 μmol, 84.4 μL) in DCM (1.0 mL) was added TEA (69.4 mg, 686 μmol, 95.5 μL) and DMAP (4.19 mg, 34.32 μmol). The reaction mixture was stirred at 25 °C for 2 h and then concentrated. The residue was purified by preparative HPLC (Column: Waters xbridge 150 × 25 mm 10 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 54%–84%, 11 min) to give 102 (90.99 mg, 88%) as a brown gum. LC-MS (ESI + ) m / z 376.2(M+H) + . 1H NMR(400MHz,CDCl3)δ6.96-6.87(m,2H),6.87-6.78(m,1H),4.84(t,J=4.4Hz,1H),3.90(d,J=9.2Hz,6H),3.17-3.00 (m,1H),2.84-2.66(m,1H),2.42-2.21(m,5H),2.14-1.98(m,2H),1.96-1.73(m,3H),1.70-1.61(m,2H),1.23(s,9H).

[0221] Example 5: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl butyrate (103) [ka] To a solution of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) (100 mg, 343 μmol) in DCM (1.0 mL) was added DMAP (4.19 mg, 34.3 μmol), TEA (104 mg, 1.03 mmol, 143 μL), and 2-methylpropanoyl chloride (73.1 mg, 686 μmol, 71.7 μL). The reaction mixture was stirred at 25 °C for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (NH3HO)-ACN]; B%: 50% to 80%, 8 min) to give 103 (83.6 mg, 81%) as a yellow gum. LC-MS (ESI + ) m / z 362.1(M+H) + . 1H NMR(400MHz,CDCl3)δ6.97-6.86(m,2H),6.85-6.77(m,1H),4.86(t,J=4.6Hz,1H),3.89(d,J=9.2Hz,6H),3.06(br s,1H),2.76(br s,1H),2.64-2.45(m,1H),2.42-2.17(m,5H),2.13-1.97(m,2H),1.95-1.84(m,2 H),1.82-1.74(m,1H),1.69-1.63(m,1H),1.56-1.49(m,1H),1.28-0.99(m,6H).

[0222] Example 6: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ylbenzoate (104) [ka] A mixture of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) (100 mg, 343 μmol), benzoyl chloride (57.9 mg, 411 μmol, 47.8 μL), and TEA (52.1 mg, 514 μmol, 71.6 μL) in DCM (3.00 mL) was degassed and purged with N three times, and then the reaction mixture was allowed to stir at 25 °C for 5 h under an atmosphere of N. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (FA conditions: column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 8 min) to give 104 (61.70 mg, 45%) as a white gum. LC-MS (ESI+) m / z 396.1 (M+H)+. 1H NMR(400MHz,CDCl3)δ8.14-8.03(m,2H),7.62-7.54(m,1H),7.51-7.42(m,2H), 6.98-6.93(m,1H),6.91-6.86(m,2H),5.17-5.02(m,1H),3.92(d,J=15.6Hz,6H ),3.84-3.71(m,2H),2.84(dt,J=8.4,10.6Hz,2H),2.55(s,3H),2.44-2.36(m, 2H),2.30-2.23(m,2H),2.02-1.89(m,2H),1.81(ddd,J=4.4,8.8,13.0Hz,1H).

[0223] Example 7: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ylpentanoate (105) [ka] To a solution of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) (100 mg, 343 μmol) and pentanoyl chloride (62.0 mg, 515 μmol, 62.4 μL) in DCM (1.0 mL) was added TEA (52.1 mg, 515 μmol, 71.7 μL). The reaction mixture was stirred at 25 °C for 3 h and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 11% to 41%, 10 min) to give 105 (57.4 mg, 31%) as a yellow gum. LC-MS (ESI) + ) m / z. 376.3 (M+H) + . 1H NMR(400MHz,CDCl3)δ6.93-6.87(m,2H),6.84-6.80(m,1H),4.87(m,1H),3.88(d,J=9.2Hz,6H),3.08( t,J=7.6Hz,1H),2.84-2.75(m,1H),2.39-2.28(m,6H),2.24-2.17(m,1H),2.08-1.94(m,3H),1.93-1.8 7(m,2H),1.82-1.77(m,1H),1.68-1.62(m,2H),1.62-1.51(m,2H),1.38(m,2H),0.93(t,J=7.2Hz,3H).

[0224] Example 8: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl butyrate (106) [ka] A mixture of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) (400 mg, 1.37 mmol), chloromethyl butanoate (375 mg, 2.75 mmol), and t-BuONa (264 mg, 2.75 mmol) in THF (5 mL) was degassed and purged with N2 three times. The mixture was stirred at 25 °C under N2 for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions: column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B%: 17%-37%, 58 min) to give 106 (169 mg, 34%) as a gray oil. LC-MS (ESI) + ) m / z 362.3(M+H) + 1H NMR(400MHz,CDCl3)δ=6.93-6.81(m,3H),4.91-4.84(m,1H),3.89(d,J=10.0Hz,6H),3.47-3.37(m,1H),3.22(t,J=6.4Hz,1H),2.60(q,J=9.2Hz,1H) ),2.42(s,3H),2.32(t,J=7.2Hz,2H),2.25-2.09(m,4H),2.00(td,J=7.2, 14.4Hz, 1H), 1.91-1.82 (m, 1H), 1.72-1.60 (m, 4H), 0.96 (t, J=7.2Hz, 3H).

[0225] Example 9: Synthesis of (((3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)oxy)methyl pivalate (107) [ka] To a solution of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol in THF (1.0 mL) was added t-BuOK (1 M, 823 μL). The mixture was stirred at 0° C. for 10 min, and then chloromethyl 2,2-dimethylpropanoate (124 mg, 823 μmol, 119 μL) was added. The reaction mixture was stirred at 25° C. for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 8 min) to give 107 (14.62 mg, 8%) as a yellow gum. LC-MS (ESI + ) m / z 406.2(M+H) + ; 1H NMR(400MHz,CDCl3)δ6.87-6.78(m,2H),6.77-6.70(m,1H),5.35-5.24(m,2H),3.81(d,J=9.6Hz,6H),3.73-3.60(m,1H),3.17-3 .00(m,1H),2.69(s,1H),2.33(s,3H),2.18-2.08(m,1H),2.03-1.78(m,5H),1.76-1.68(m,2H),1.48-1.37(m,1H),1.14(s,9H).

[0226] Example 10: Synthesis of (((3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)oxy)methyl isobutyrate (108) [ka] A mixture of chloromethyl 2-methylpropanoate (210 mg, 1.54 mmol), (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) (150 mg, 514 mmol), and t-BuOK (1 M in THF, 1.54 mL) in THF (1 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 2 h under an atmosphere of N2. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 12%-42%, 8 min) to give 108 (18.29 mg, 20%) as a white solid. LC-MS (ESI + ) m / z 392.5(M+H) + . 1H NMR(400MHz,CDCl3): δ6.74-7.01(m,3H),4.73(br dd,J=6.4,4.8Hz,1H),3.93-3.97(m,1H),3.91(s,3H),3.88(s,3H),3.32-3.55(m,2H),2.55-2.96(m,1H),2.48( s,1H),2.46(s,2H),2.25-2.33(m,2H),2.07-2.21(m,3H),1.96-2.04(m,2H),1.89-1.91(m,1H),1. 85-1.93(m,5H),1.37-1.39(m,1H),1.23-1.37(m,1H),1.34(s,1H),0.98(s,2H),0.94-1.02(m,1H).

[0227] Example 11: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ylethylcarbamate (109) [ka] To a solution of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019) in THF (1.0 mL) was added t-BuOK (1 M, 686 μL). The mixture was stirred at 0° C. for 30 minutes, and then ethyl carbonochloridate (74.5 mg, 686 μmol, 65.3 μL) was added to the mixture at 0° C. The reaction mixture was stirred at 25° C. for 2 hours and then poured into aqueous NaHCO (50 mL). The mixture was extracted with ethyl acetate (50 mL). The combined organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 7%-37%, 8 min) to give 109 (17.7 mg, 17%) as an off-white gum. LC-MS (ESI + ) m / z 364.3(M+H) + . 1H NMR(400MHz,CDCl3)δ6.94-6.85(m,2H),6.85-6.81(m,1H),4.78-4.70(m,1H),4.29-4.11(m,2H),3.89(d,J=10.4Hz,6H),3.44-3.38(m,1 H),3.26(t,J=6.4Hz,1H),2.70-2.59(m,1H),2.43(s,3H),2.28-2.02(m,5H),1.93-1.82(m,1H),1.79-1.66(m,2H),1.33(t,J=7.2Hz,3H).

[0228] Example 12: Synthesis of (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (018, (-)-mesembranol) [ka] A mixture of 001 (200 mg, 691 μmol) and PtO2 (20.0 mg, 88.0 μmol) in IPA (4 mL) was degassed and purged with N2 three times. The mixture was stirred at 25 °C under an atmosphere of N2 for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by recrystallization from EtOH (1 mL) at 25 °C to give (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (018, (-)-mesembranol) (100 mg, 49%) as a white solid. LC-MS (ESI) + ) m / z 292.4 (M+H). 1 H NMR(400MHz,CDCl3)δ6.86-6.78(m,2H),6.77-6.71(m,1H),3.86(s,1H),3.81( d,J=6.8Hz,6H),3.30(dt,J=6.8,9.6Hz,1H),2.83(s,1H),2.40(s,3H),2.33-2 .20(m,1H),2.09(dd,J=2.8,14.8Hz,1H),1.90-1.82(m,2H),1.78(dd,J=6.8,1 1.6Hz, 1H), 1.67-1.62 (m, 2H), 1.57 (td, J=2.8, 14.8Hz, 1H), 1.39-1.30 (m, 2H).

[0229] Example 13: Synthesis of (((3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)oxy)methyl isobutyrate (110) [ka] Compound 019 is reacted with chloromethyl butyrate in the presence of a base such as tBuOK in a solvent such as THF to give 110.

[0230] Example 14: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yldimethylcarbamate (201) [ka] To a solution of 018 in THF (4 mL) was added t-BuOK (1 M, 1.37 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, and then N,N-dimethylcarbamoyl chloride (147 mg, 1.37 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B%: 1%-31%, 10 min) to give 201 (108 mg, 54%) as a colorless gum.

[0231] Example 15: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl pivalate (202) [ka] To a solution of 018 (100 mg, 343 μmol) and 2,2-dimethylpropanoyl chloride (82.7 mg, 686 μmol, 84.4 μL) in DCM (1.0 mL) was added TEA (69.4 mg, 686 μmol, 95.5 μL) and DMAP (4.19 mg, 34.3 μmol). The mixture was stirred at 25°C for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 48% to 78%, 8 min) to give 202 (86.44 mg, 83%) as an off-white solid. LC-MS (ESI) + ) m / z 376.3(M+H) + . 1 H NMR(400MHz,CDCl3)δ6.90-6.73(m,3H),5.00(s,1H),3.82(d,J=6.0Hz,6H),3.39-3.10(m,1H),2.9 5-2.62(m,1H),2.34(s,4H),2.18-1.98(m,3H),1.92-1.67(m,3H),1.31-1.16(m,2H),1.07(s,9H).

[0232] Example 16: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl butyrate (203). [ka] To a solution of 018 (10 mg, 343 μmol) and 2-methylpropanoyl chloride (73.1 mg, 686 μmol, 71 μL) in DCM (1.0 mL) was added TEA (69.4 mg, 686 μmol, 95 μL) and DMAP (4.19 mg, 34.3 μmol). The mixture was stirred at 25°C for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42% to 72%, 8 min) to give 203 (71.8 mg, 71%) as a yellow gum. LC-MS (ESI) +) m / z 362.4(M+H) + . 1 H NMR(400MHz,CDCl3)δ=6.91-6.70(m,3H),5.07-4.87(m,1H),3.82(d,J=6.8Hz,6H),3.16(d,J=1.2Hz,1H),2.71(d,J=2.4Hz,1H),2.37(td,J= 7.2,14.0Hz,1H),2.33-2.18(m,4H),2.16-1.93(m,4H),1.89-1.79(m, 1H),1.77-1.67(m,2H),1.25-1.19(m,1H),1.04(dd,J=3.2,6.8Hz,6H).

[0233] Example 17: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ylbenzoate (204) [ka] To a solution of 018 (100 mg, 343 μmol) and DMAP (4.19 mg, 34.3 μmol) in DCM (1.0 mL) was added TEA (104 mg, 1.03 mmol, 143 μL) and benzoyl chloride (57.9 mg, 412 μmol, 47.8 μL). The mixture was stirred at 25°C for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 12% to 42%, 8 min) to give 204 (73.2 mg, 72%) as a yellow gum. LC-MS (ESI + ) m / z 396.2(M+H) + . 1H NMR(400MHz,CDCl3)δ8.04-7.95(m,2H),7.58-7.51(m,1H),7.46-7.37(m,2H) ,6.97-6.91(m,1H),6.90-6.83(m,2H),5.56-5.40(m,1H),3.90(d,J=3.2Hz,6H ),3.81-3.70(m,1H),3.38(t,J=4.0Hz,1H),2.75-2.62(m,4H),2.52-2.40(m,1 H),2.27-2.14(m,3H),2.14-2.07(m,1H),2.07-1.95(m,2H),1.64-1.50(m,1H)

[0234] Example 18: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ylpentanoate (205) [ka] To a solution of 018 and DMAP (4.19 mg, 34.3 μmol) in DCM (1.0 mL) was added TEA (104 mg, 1.03 mmol, 143 μL) and pentanoyl chloride (49.6 mg, 412 μmol, 49.9 μL). The reaction mixture was stirred at 25°C for 1 h and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 10% to 40%, 10 min) to give 205 (77.6 mg, 78%) as a colorless oil. LC-MS (ESI + ) m / z 376.2(M+H) + . 1H NMR(400MHz,CDCl3)δ6.94-6.80(m,3H),5.23-5.16(m,1H),3.90(d,J=7.0H z,6H),3.77-3.67(m,1H),3.28(t,J=3.8Hz,1H),2.71-2.55(m,4H),2.38-2. 27(m,1H),2.24(t,J=7.6Hz,2H),2.19-2.09(m,3H),2.08-1.99(m,1H),1.9 0-1.78(m,2H),1.64-1.53(m,2H),1.43-1.26(m,3H),0.89(t,J=7.2Hz,3H).

[0235] Example 19: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl butyrate (206) [ka] To a solution of butanoyl butanoate (108 mg, 686 μmol, 112 μL) in DCM (2 mL) was added TEA (69.4 mg, 686 μmol, 95.5 μL), 018 (100 mg, 343 μmol), and DMAP (4.19 mg, 34.3 μmol). The reaction mixture was stirred at 25°C for 2 h and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 39%-79%, 14 min) to give 206 (47.7 mg, 48%) as a gray solid. LC-MS (ESI + ) m / z 362.2(M+H) + ; 1H NMR(400MHz,CDCl3)δ=6.96-6.79(m,3H),5.16-5.00(m,1H),4.02-3.83(m,6H),3.31-3.15(m,1H),2.86-2.69(m,1H),2.42-2.35(m,3H),2.31(br dd,J=5.4,6.4Hz,1H),2.25-2.16(m,3H),2.16-2.02(m,2H),1.99-1.87(m,1H),1.84-1.76(m,2H) ),1.82-1.75(m,1H),1.68-1.60(m,3H),1.66-1.55(m,7H),1.39-1.22(m,2H),1.00-0.83(m,3H).

[0236] Example 20: Synthesis of (((3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)oxy)methyl pivalate (207) [ka] To a solution of 018 (150 mg, 515 μmol) in THF (4 mL) was added t-BuOK (1 M in THF, 1.03 mL). To the reaction mixture was added chloromethyl 2,2-dimethylpropanoate (310 mg, 2.06 mmol, 298 μL). The reaction mixture was stirred at 25° C. for 2 hours and then filtered. The eluate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C). 18 Purification by LC-MS (ESI 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 10% to 40%, 8 min) gave 207 (55 mg, 28%) as a colorless oil. + ) m / z 406.6(M+H) + 。 1H NMR(400MHz,CDCl3)δ=6.89-6.76(m,3H),5.39-5.32(m,1H),5.28(d,J=6.4Hz,1H),4.24-4.05(m,1H),3.89(d,J=6.8Hz,6H),3.85 -3.76(m,1H),3.46-3.14(m,1H),2.63(s,4H),2.27(s,1H),2.21-2.00(m,4H),1.96-1.80(m,2H),1.39-1.27(m,1H),1.21(s,9H).

[0237] Example 21: Synthesis of (((3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)oxy)methyl isobutyrate (208) [ka] To a solution of 018 (150 mg, 514 μmol) in THF (4 mL) was added t-BuOK (1 M in THF, 1.03 mL). To the reaction mixture was added chloromethyl 2-methylpropanoate (281 mg, 2.06 mmol). The reaction mixture was stirred at 25° C. for 2 hours and then filtered. The eluate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters xbridge 150×25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 8 min) to give 208 (15 mg, 8%) as a yellow gum. LC-MS (ESI + ) m / z 392.1(M+H) + . 1 H NMR(400MHz,CDCl3)δ=6.88-6.67(m,3H),5.40-5.14(m,2H),3.81(d,J=6.4Hz,7H),3.33-3.02(m,1H),2.67(d,J=4.0Hz,1H),2. 53-2.43(m,1H),2.42-2.05(m,5H),1.99(s,2H),1.92-1.67(m,3H),1.35-1.14(m,2H),1.12(d,J=1.6Hz,3H),1.11-1.08(m,3H)

[0238] Example 22: Synthesis of (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ylethylcarbamate (209) [ka] To a solution of 018 (150 mg, 514 μmol) in THF (2 mL) at 0° C., t-BuOK (1 M, 1.03 mL) was added over 0.5 h, followed by ethyl carbonochloridate (111 mg, 1.03 mmol, 98.0 μL). The reaction mixture was stirred at 25° C. for 2 h and then filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 5% to 35%, 8 min) to give 209 (27.6 mg, 18%) as a gray gum. LC-MS (ESI + ) m / z 364.0(M+H) + ; 1 H NMR(400MHz,CDCl3)δ7.14-6.70(m,3H),4.13-3.99(m,1H),3.98-3.83(m,6H),3.24(dt,J=4.4,9.2Hz,1H),2.77(br s,1H),2.39(s,2H),2.30-2.28(m,1H),2.27-2.17(m,1H),2.13-2.04(m,2H),1.9 9-1.89(m,1H),1.88-1.76(m,2H),1.74-1.67(m,1H),1.58-1.51(m,1H),1.20(br s,1H),1.43-1.15(m,1H).

[0239] Example 23: Synthesis of (((3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)oxy)methyl isobutyrate (210) [ka] To a solution of 018 (150 mg, 515 μmol) in THF (4 mL) was added t-BuOK (1 M in THF, 1.03 mL). To the reaction mixture was added chloromethyl butanoate (281 mg, 2.06 mmol). The reaction mixture was stirred at 25° C. for 2 hours and filtered. The eluate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Waters xbridge 150×25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42% to 72%, 8 min) to give 210 (18.0 mg, 10%) as a yellow gum. LC-MS (ESI + ) m / z 392.1(M+H) + . 1 H NMR(400MHz,CDCl3-d)δ=7.02-6.60(m,3H),5.46-5.19(m,2H),3.89(d,J=6.0Hz,7H),3.20(d,J=9.2Hz,1H),2.91-2.66(m,1H),2 .54-2.25(m,6H),2.24-2.13(m,1H),2.10-2.00(m,2H),1.98-1.75(m,3H),1.74-1.62(m,3H),1.26(s,1H),0.96(t,J=7.4Hz,3H).

[0240] Example 24: Synthesis of (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indole-6-dihydrogen phosphate (211) [ka]

[0241] Step 1: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl dimethyl phosphate To a solution of 018 (100 mg, 343 μmol) in THF (2.0 mL) was added t-BuOK (1 M in THF, 686 μL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, and then [chloro(methoxy)phosphoryl]oxymethane (148 mg, 1.03 mmol, 111 μL) was added. The reaction mixture was stirred at 25° C. for 2 hours and then filtered. The filtrate was concentrated in vacuo to give the title compound (110 mg, 67%) as a brown oil. LC-MS (ESI + ) m / z 400.2 (M+H) + .

[0242] Step 2: Synthesis of (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indole-6-dihydrogen phosphate (211) To a solution of (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yldimethylphosphate (100 mg, 250 μmol) in DCM (1.0 mL) was added TMSBr (114 mg, 751 μmol, 97 μL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours and then filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 μm; mobile phase: [water (NH3H2O)-ACN]; B%: 0% to 28%, 10 min) to give 211 (9.55 mg, 9%) as a white solid. LC-MS (ESI + ) m / z 372.2 (M+H) + ; 1 H NMR(400MHz,CDCl3)δ6.92-6.66(m,3H),4.80-4.49(m,2H),3.90-3.77(m,6H),3.62 (s,1H),3.08-2.73(m,4H),2.71-2.54(m,1H),2.25-1.64(m,6H),1.37-1.05(m,1H).

[0243] Example 25: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indole-6-dihydrogen phosphate (111) [ka]

[0244] Step 1: Synthesis of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl dimethyl phosphate To a solution of 019 (300 mg, 1.03 mmol) in THF (6 mL) was added t-BuOK (1 M, 2.06 mL) followed by [chloro(methoxy)phosphoryl]oxymethane (297 mg, 2.06 mmol) at 0° C. The reaction mixture was allowed to stir at 25° C. for 4 hours and then concentrated to give the title compound (300 mg, 45%, 62% purity) as a white solid.

[0245] Step 2: Synthesis of (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl dihydrogen phosphate (111) To a solution of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yldimethylphosphate (300 mg, 751 μmol) in DCM (5 mL) was added TMSBr (459 mg, 3.00 mmol, 389 μL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 1% to 25%, 10 min) to give 111 (40.5 mg, 20%) as a white solid. LC-MS (ESI + ) m / z 372.2 (M+H) + ; 1 H NMR(400MHz,CD3OD)δ=7.05-6.93(m,3H),4.50-4.42(m,1H),4.03-3.93(m,1H),3.92-3.82(m,7H),3.30-3 .21(m,1H),3.13-3.03(m,3H),2.71-2.61(m,1H),2.33-2.08(m,4H),2.03-1.87(m,2H),1.47-1.35(m,1H).

[0246] Assay procedure Example A1: Plasma stability assay The stability of compounds in rat and human plasma was measured by incubating the compounds with rat or human plasma at 37°C for consecutive time points in microwell plates and monitoring the disappearance of the prodrug and the appearance of metabolites (mesembranol or 6-epi-mesembranol). A 2 mM stock solution of the test compound was prepared by dissolving the appropriate amount of compound in DMSO. The 2 mM stock was further diluted 200-fold with rat or human plasma to obtain a final concentration of 10 μM, respectively (0.5% DMSO). Fifty-microliter aliquots of the positive control and test compound spiked into rat or human plasma (n=2) were added to a prewarmed plate (37°C) and shaken at 50 rpm. At each time point, the reaction was stopped by adding 500 μL of acetonitrile containing internal standards (100 nM aprozolam, 200 nM caffeine, 100 nM tolbutamide). All samples were vortexed for 10 minutes, followed by centrifugation at 3,220 g for 30 minutes to precipitate proteins. 100 μL of the supernatant was transferred to a new plate. The supernatant was diluted with ultrapure water according to the LC-MS signal response and peak shape. LC-MS / MS was used to quantify the concentrations of the test compound and positive control in the test samples. Results were reported as the % of prodrug compound remaining at each time point and the % of metabolite (mesembranol or 6-epi-mesembranol) accumulated at each time point. The data are shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0247] Example B1: SERT Inhibition Assay SERT inhibition was measured using a neurotransmitter transport fluorescence assay. Briefly, stable 5HTT HEK293 cells were prepared in a 384-microwell plate. Compounds were prepared at a maximum concentration of 1 μM in assay buffer (20 mM HEPES, 0.1% BSA in HBSS). Ten doses of test compound (3-fold serial dilutions) were added to the plated cells and incubated at 37°C for 30 minutes. 25 μL of dye solution (Molecular Devices Neurotransmitter Transporter Uptake Assay Kit) was added per well and incubated at 37°C for 30 minutes. The plate was then read on a plate reader. The results are shown in Table 2 (n=6±SD). [Table 2]

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ is -C(O)NR ２ R ３ , -P(O)OR ３ OR ４ , -C(O)OR ５ , -C(O)R ６ , or -CH ２ O.C.(O.)R. ７ and R ２ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C １０ Cycloalkyl, C １ -C ３ Alkyl-C ３ -C １０ cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C １０ Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally replaced by halo, hydroxy, C １ -C ６ Alkyl, C １ -C ３ Alkoxy, nitro, -N(C １ -C ３ alkyl) ２ , -NH ２ , -N(H)C １ -C ３ Alkyl, C １ -C ３ substituted with haloalkyl, —COOH, cyano, phenyl, or phenoxy; R ３ is H, C １ -C ６ Alkyl, phenyl, -(CH ２ O) ｎ -C(O)OC １ -C ６ Alkyl, or -(CH ２ O) ｎ -C(O)C １ -C ６ alkyl, where C １ -C ６ Each hydrogen atom in an alkyl may optionally be replaced by halo, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C ３ -C １０ Cycloalkyl, phenyl, 5- to 7-membered heterocycle, 5- to 7-membered heteroaryl, nitro, —N(C １ -C ３ alkyl) ２ , -NH ２ , -N(H)C １ -C ３ Alkyl, C １ -C ３ substituted with haloalkyl, —COOH, cyano, phenyl, or phenoxy; Or R ２ and R ３ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and each hydrogen atom in said 4- to 7-membered heterocycle is optionally selected from halo, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C ３ -C １０ Cycloalkyl, phenyl, 5- to 7-membered heterocycle, 5- to 7-membered heteroaryl, nitro, —N(C １ -C ３ alkyl) ２ , -NH ２ , -N(H)C １ -C ３ Alkyl, C １ -C ３ substituted with haloalkyl, —COOH, cyano, phenyl, or phenoxy; R ４ is H, C １ -C ６ Alkyl, phenyl, -(CH ２ O) ｎ -C(O)OC １ -C ６ Alkyl, or -(CH ２ O) ｎ -C(O)C １ -C ６ alkyl, where C １ -C ６ Each hydrogen atom in an alkyl may optionally be replaced by halo, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C ３ -C １０ Cycloalkyl, phenyl, 5- to 7-membered heterocycle, 5- to 7-membered heteroaryl, nitro, —N(C １ -C ３ alkyl) ２ , -NH ２ , -N(H)C １ -C ３ Alkyl, C １ -C ３ substituted with haloalkyl, —COOH, cyano, phenyl, or phenoxy; Or R ３ and R ４ are taken together with the —O—P(O)—O— to which they are attached to form a 5- to 7-membered heterocycle, and each hydrogen atom in the 5- to 7-membered heterocycle is optionally selected from halo, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C ３ -C １０ Cycloalkyl, phenyl, 5- to 7-membered heterocycle, 5- to 7-membered heteroaryl, nitro, —N(C １ -C ３ alkyl) ２ , -NH ２ , -N(H)C １ -C ３ Alkyl, C １ -C ３ substituted with haloalkyl, —COOH, cyano, phenyl, or phenoxy; R ５ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C １０ Cycloalkyl, C １ -C ３ Alkyl-C ３ -C １０ cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C １０ Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally replaced by halo, hydroxy, C １ -C ６ Alkyl, C １ -C ３ Alkoxy, nitro, -N(C １ -C ３ alkyl) ２ , -NH ２ , -N(H)C １ -C ３ Alkyl, C １ -C ３ substituted with haloalkyl, —COOH, cyano, phenyl, or phenoxy; R ６ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C １０ Cycloalkyl, C １ -C ３ Alkyl-C ３ -C １０ cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C １０ Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally replaced by halo, hydroxy, C １ -C ６ Alkyl, C １ -C ３ Alkoxy, —OC(O)C １ -C ６ Alkyl, nitro, -N(C １ -C ３ alkyl) ２ , -NH ２ , -N(H)C １ -C ３ Alkyl, C １ -C ３ substituted with haloalkyl, —COOH, cyano, phenyl, or phenoxy; R ７ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C １０ Cycloalkyl, C １ -C ３ Alkyl-C ３ -C １０ cycloalkyl, phenyl, or 5- to 7-membered heteroaryl, where C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C １０ Each hydrogen atom in cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally replaced by halo, hydroxy, C １ -C ６ Alkyl, C １ -C ３ Alkoxy, nitro, -N(C １ -C ３ alkyl) ２ , -NH ２ , -N(H)C １ -C ３ Alkyl, C １ -C ３ substituted with haloalkyl, —COOH, cyano, phenyl, or phenoxy; and The compound, wherein n is 1 or 2.

2. Compounds of formula (IA) or (IB): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

3. Compounds of formula (II-A) or (II-B): 【Transformation 3】 or a pharmaceutically acceptable salt thereof, wherein R ２ and R ３ are independently H or C １ -C ６ The compound of claim 2, wherein the compound is alkyl.

4. R ２ and R ３ The compound of claim 3 , wherein each of is independently methyl.

5. R ２ and R ３ The compound of claim 3, wherein, together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocycle.

6. Compounds of formula (III): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein R ３ and R ４ each independently represents H, C １ -C ６ Alkyl, phenyl, -(CH ２ O) ｎ -C(O)OC １ -C ６ Alkyl, or -(CH ２ O) ｎ -C(O)C １ -C ６ The compound of claim 1 , wherein the compound is alkyl.

7. 7. The compound of claim 6, wherein n is 1.

8. R ３ and R ４ 7. The compound of claim 6, wherein each of

9. R ３ and R ４ taken together with -O-P(O)-O- to which they are attached form a 5- to 7-membered heterocycle.

10. Compound of formula (IV): 【Transformation 5】 or a pharmaceutically acceptable salt thereof, wherein R ５ is C １ -C ６ The compound of claim 1 , wherein the compound is alkyl.

11. R ５ The compound of claim 10, wherein is ethyl.

12. Compound of formula (V): 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

13. R ６ But C １ -C ６ 13. The compound of claim 12, which is alkyl or phenyl.

14. R ６ But C １ -C ３ The compound of claim 12, wherein the alkyl is t-butyl, isopropyl, or propyl.

15. Compound of formula (V): 【Transformation 7】 or a pharmaceutically acceptable salt thereof, wherein R ６ The compound of claim 1 , wherein is phenyl.

16. Compound of formula (VI): 【Transformation 8】 or a pharmaceutically acceptable salt thereof, wherein R ７ is C １ -C ６ The compound of claim 1 , wherein the compound is alkyl.

17. R ７ is unsubstituted C １ -C ６ 17. The compound of claim 16, wherein the compound is alkyl.

18. R ７ The compound of claim 16, wherein is isopropyl, propyl, or t-butyl. 【Request Item 19】 【Chemistry 9】 or a pharmaceutically acceptable salt thereof. 【Request Item 20】 【Chemistry 10】 or a pharmaceutically acceptable salt thereof. 【Request Item 21】 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, and having the absolute stereochemistry shown. 【Request Item 22】 【Chemistry 12】 or a pharmaceutically acceptable salt thereof. 【Request Item 23】 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, and having the absolute stereochemistry shown.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 and a pharmaceutically acceptable excipient.

25. 26. A method for treating a mental health disorder, comprising administering an effective amount of a compound according to any one of claims 1 to 23 to a mammal in need thereof.

26. 26. The method of claim 25, wherein the mental health disorder is anxiety, stress, or depression.

27. 26. The method of claim 25, wherein the mental health disorder is anxiety.

28. 26. The method of claim 25, wherein the mental health disorder is stress.

29. 26. The method of claim 25, wherein the mental health disorder is depression.

30. The method of any one of claims 25 to 29, wherein the mammal is a human.

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