Phenethylamine and cathinone precursors

Abstract

The disclosed subject matter generally relates to phenethylamines or cathinones covalently bonded to prodrug-type chemical moieties. The technology described herein allows for slow / sustained / controlled delivery of the parent phenethylamine or cathinone to the blood system in a manner that improves duration of therapeutic effect, ease of application, patient compliance, and / or a combination of these properties, particularly when administered orally. Furthermore, the described technology allows for the sustained release of the parent phenethylamine or cathinone over an extended period of time, thereby eliminating spikes in drug levels that reduce cardiovascular stress, addiction / abuse potential, and / or other common irritating side effects associated with psychoactive compounds.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The disclosed subject matter generally relates to phenethylamines or cathinones covalently bonded to prodrug-type chemical moieties. The technology described herein allows for slow / sustained / controlled delivery of the parent phenethylamine or cathinone to the blood system in a manner that improves duration of therapeutic effect, ease of application, patient compliance, and / or a combination of these properties, particularly when administered orally. Furthermore, the described technology allows for the sustained release of the parent phenethylamine or cathinone over an extended period of time, thereby eliminating spikes in drug levels that reduce cardiovascular stress, addiction / abuse potential, and / or other common irritating side effects associated with psychoactive compounds. [Background technology]

[0002] Methylone (3,4-methylenedioxy-N-methylactinone) belongs to a group of psychoactive synthetic cathinones known as β-ketoamphetamines. It is a synthetic analog of MDMA that differs by the presence of a ketone at the benzyl position. First synthesized in 1996 as an antidepressant and antiparkinsonian, methylone is a recreational street drug. Methylone induces psychostimulant and empathetic effects similar to those of MDMA, with a mechanism of action involving the monoaminergic system.

[0003] MDMA (3,4-methylenedioxymethamphetamine, commonly known as Ecstasy) is a psychoactive drug used primarily for recreational purposes. MDMA works primarily by increasing the activity of the neurotransmitters serotonin, dopamine, and norepinephrine in parts of the brain. In 2017, the U.S. Food and Drug Administration (FDA) approved a limited study of MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), citing preliminary evidence that MDMA may enhance the efficacy of psychotherapy.

[0004] Despite its close structural similarity to MDMA, methylone possesses distinct pharmacological and functional properties. Methylone has been shown to improve PTSD symptoms in 81% of patients in a series of clinical trials involving 21 patients. Currently, only the serotonergic antidepressants sertraline and paroxetine are approved for the treatment of PTSD, so drugs that exhibit antidepressant-like activity should improve PTSD symptoms. Methylone demonstrated the strongest efficacy in the forced swim test, a classic preclinical screen for antidepressant activity. Methylone also demonstrated efficacy in a mouse model of PTSD, improving fear extinction recall after fear conditioning, consistent with the treatment response in this study. These data, combined with the results of a series of clinical cases, strongly support the potential for clinically effective treatment of PTSD.

[0005] Methylone users report a rapid onset of action (15–30 minutes) and a short duration of action (2–3.5 hours). A prospective, observational, naturalistic study comparing self-administration of methylone and MDMA in healthy volunteers (Lourdes et al. (2021) Biology 10:788) found that both drugs significantly increased systolic and diastolic blood pressure, while increases in heart rate were associated only with methylone. Subjects reported stimulant-like effects beginning 1 hour after administration, but most of these effects had largely disappeared by 4 hours.

[0006] Analysis of the parent compound and metabolites in human and rat urine samples demonstrated similar metabolic pathways for methylone and MDMA. Both are extensively biotransformed by the cytochrome p450 isoform 2D6, consistent with their rapid and short duration of action. PK / PD studies in rats demonstrated that methylone was significantly associated with T Max 15 minutes, t 1 / 2 showed rapid kinetics of 1 hour (Elmore et al. (2017) Neuropsychopharmacology 42:649). In the same study, plasma concentrations of methylone appeared to correlate with locomotor activity.

[0007] As an alternative to sustained-release formulations, prodrugs have been used to extend the duration of action and reduce the toxicity and / or side effects associated with the initial rapid rise in drug concentration. Examples of such prodrugs can be found in U.S. Patent No. 7,105,486 B2 and International Publication No. 2022 / 053696, in which the amine functional groups of d-amphetamine and MDMA are covalently linked to amino acids to form amide bonds. In the case of d-amphetamine, the resulting L-lysine-conjugated prodrug, known as lisdexamfetamine, exhibited a longer duration of action (10–12 hours) compared to the 3–6 hours of unconjugated d-amphetamine. Lisdexamfetamine has also been reported to have a more favorable toxicity / tolerance profile compared to unconjugated d-amphetamine, for reasons including, but not limited to, a significant reduction in the pharmacological activity of the prodrug due to structural changes, a natural gating mechanism at the hydrolysis site that limits the release of active amphetamine from the prodrug, and the prodrug's lack of brain permeability.

[0008] Amino groups, such as those found in methylone or MDMA, can be derivatized into different complex prodrugs characterized by the newly formed functional group and its specific transformation process to liberate the active drug. Examples of complex amine prodrugs, such as amide prodrugs, peptide or polypeptide prodrugs, carbamate prodrugs, acyloxyalkoxycarbonyl prodrugs, acyloxymethyl prodrugs, phosphoramide prodrugs, and phosphoryloxyalkyl prodrugs, can be found in Rautio et al. (2018) Nat. Rev. Drug Discov. 17:559.

[0009] It is therefore an object of the present invention to provide psychotropic drugs that exhibit advantageous pharmacokinetic and / or pharmacodynamic profiles for the treatment of CNS disorders such as PTSD.

[0010] It is a further object of the present invention to provide psychotropic agents that exhibit favorable toxicity and / or tolerability profiles for the treatment of CNS disorders such as PTSD.

[0011] It is a further object of the present invention to provide prodrugs of phenethylamines, such as MDMA, or prodrugs of cathinones, such as methylone, that can be hydrolyzed after absorption and converted directly to the therapeutically active form of the parent compound. Summary of the Invention

[0012] The present invention relates to compounds that are prodrug forms of phenethylamine or cathinone precursors. The present invention also provides pharmaceutical compositions comprising an effective amount of a phenethylamine or cathinone precursor and a pharmaceutically acceptable carrier. The present invention also provides methods for treating, in a mammal, conditions such as post-traumatic stress disorder (PTSD), anxiety disorders, attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, cluster headache, cancer-related conditions, loss of motivation, burnout, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea, or vomiting by administering an effective amount of a phenethylamine or cathinone precursor.

[0013] The features and advantages of the subject matter herein will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying drawings. As will be understood, the subject matter disclosed and claimed is capable of modification in various respects without departing from the scope of the claims. Accordingly, the drawings and description are to be regarded as illustrative in nature and not restrictive, the full scope of the subject matter being set forth in the claims. The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [Brief explanation of the drawings]

[0014] [Figures 1A-1D]Methylone improves fear extinction recall in a mouse model of PTSD. (Figure 1A) Schematic of the experimental design. On day 1, one CS-US (tone-shock) pairing was administered, followed by six CS presentations in a novel context (Context B). Methylone or saline vehicle was injected 30 min before extinction training on day 2. On day 3, the CS response time was quantified. (Figure 1B) The CS response time at the first cue on day 3 (extinction recall) was significantly reduced by methylone compared with saline (t(26) = 2.350, p < 0.05). (Figure 1C) The CS response time before each of the six cues on day 3 is shown (to control for the effect of locomotor activity). A significant cue x drug interaction was observed (F(5,130) = 2.409, p < 0.05). (Figure 1D) No changes in locomotion were observed on day 3 (t(26) = 1.073, p > 0.05). Methylone group (30 mg / kg, IP, orange diamonds) N = 12, saline control group (black squares) N = 16. *p < 0.05 DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides prodrugs of phenethylamines or cathinones that exhibit advantageous pharmacokinetic properties and beneficial side effect profiles, making the compounds provided herein particularly suitable for therapeutic use.

[0016] In one aspect, provided herein is a compound of formula (I): [ka] (In the formula, Y is —C(O)— or —CH—; X is (a) an amino acid or peptide, (b)-C(O)R 3 , (c)-C(O)OR 3 , (d)-C(O)OCH(R 4 ) OR 5 , (e)-CH2OC(O)R 3 , (f)-P(O)(OH)2, (g) -CH2OP(O)(OH)2, (h)-C(O)(CH2) n Z a R 5 , [ka] and independently selected from the group consisting of: n is 3 or 4; R 1 and R 2 are each independently -C 1-6 Alkyl or -C 3-6 is cycloalkyl; R 3 -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, [ka] selected from the group consisting of: R 4 , R 7 , R 8 , R 9 and R 10 are independently H, -C 1-6 Alkyl or -C 3-6 is cycloalkyl; R 5 is -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids, and peptides; Z a and Z b are each independently O or NR 4 and; Z c is OC(O)R 3 or OP(O)(OR 4 )2 is selected; R 6 -H, -C 1-6 Alkyl, -C 3-6 selected from the group consisting of cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH, and CF3; R 11 and R 12 are independently H, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl; 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 substituted with haloalkyl, aryl, or heteroaryl), or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments of the foregoing compounds, R 1 and R 2 are each independently methyl or ethyl. In some embodiments, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro, or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12are each independently H or methyl. In some embodiments, R 10 is methyl. In some embodiments, when Y is -CH2-, X is not an amino acid, a peptide, or a -P(O)(OH)2 group.

[0018] According to another embodiment, the compound of formula (I) has formula (III): [ka] (In the formula, X is (a) an amino acid or peptide; (b)-C(O)R 3 , (c)-C(O)OR 3 , (d)-C(O)OCH(R 4 ) OR 5 , (e)-CH2OC(O)R 3 , (f)-P(O)(OH)2, (g) -CH2OP(O)(OH)2, (h)-C(O)(CH2) n Z a R 5 , [ka] and independently selected from the group consisting of: n is 3 or 4; R 1 and R 2 are each independently -C 1-6 Alkyl or -C 3-6 is cycloalkyl; R 3 -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, [ka] selected from the group consisting of: R4 , R 7 , R 8 , R 9 and R 10 are independently H, -C 1-6 Alkyl or -C 3-6 is cycloalkyl; R 5 is -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids, and peptides; Z a and Z b are each independently O or NR 4 and; Z c is OC(O)R 3 or OP(O)(OR 4 )2 is selected; R 6 -H, -C 1-6 Alkyl, -C 3-6 selected from the group consisting of cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH, and CF3; R 11 and R 12 are independently H, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl; 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 substituted with haloalkyl, aryl, or heteroaryl) or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments of the foregoing compounds, R 1 and R 2 are each independently methyl or ethyl. In some embodiments, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro, or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12 are each independently H or methyl. In some embodiments, R 10 is methyl. In some embodiments, X is an amino acid. In some embodiments, the compound is selected from the group consisting of compounds 1-402 in Tables 1, 2 and 3 below.

[0020] According to some embodiments, the compound of formula (I) has formula (IV): [ka] (In the formula, X is (a)-C(O)R 3 , (b)-C(O)OR 3 , (c)-C(O)OCH(R 4 ) OR 5 , (d)-CH2OC(O)R 3 , (e) -CH2OP(O)(OH)2, (f)-C(O)(CH2) n Z a R 5 , [ka] and independently selected from the group consisting of: n is 3 or 4; R 1 and R 2 are each independently -C 1-6 Alkyl or -C 3-6 is cycloalkyl; R 3 -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, [ka] selected from the group consisting of: R 4 , R 7 , R 8 , R 9 and R 10 are independently H, -C 1-6 Alkyl or -C 3-6 is cycloalkyl; R 5 is -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids, and peptides; Z a and Z b are each independently O or NR 4 and; Z c is OC(O)R 3 or OP(O)(OR 4 )2 is selected; R 6 -H, -C 1-6 Alkyl, -C 3-6 selected from the group consisting of cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH, and CF3; R 11 and R 12 are independently H, -C 1-6 Alkyl, -C 1-6Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl; 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 substituted with haloalkyl, aryl, or heteroaryl) or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments of the foregoing compounds, R 1 and R 2 are each independently methyl or ethyl. In some embodiments, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro, or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12 are each independently H or methyl. In some embodiments, R 10 is methyl.

[0022] According to some embodiments, the compound of formula (I) has formula (V): [ka] (In the formula, X is (a) an amino acid or peptide; (b)-C(O)R 3 , (c)-C(O)OR 3 , (d)-C(O)OCH(R 4 ) OR 5 , (e)-CH2OC(O)R 3 , (f)-P(O)(OH)2, (g) -CH2OP(O)(OH)2, (h)-C(O)(CH2) n Z a R 5 , [ka] and independently selected from the group consisting of: n is 3 or 4; R 3 -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, [ka] selected from the group consisting of: R 4 , R 7 , R 8 , R 9 and R 10 are independently H, -C 1-6 Alkyl or -C 3-6 is cycloalkyl; R 5 is -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids, and peptides; Z a and Z b are each independently O or NR 4 and; Z cis OC(O)R 3 or OP(O)(OR 4 )2 is selected; R 6 -H, -C 1-6 Alkyl, -C 3-6 selected from the group consisting of cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH, and CF3; R 11 and R 12 are independently H, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl; 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 substituted with haloalkyl, aryl, or heteroaryl) or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments of the foregoing compounds, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro, or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12are each independently H or methyl. In some embodiments, R 10 is methyl. In some embodiments, X is an amino acid.

[0024] According to some embodiments, the compound of formula (I) has formula (VI): [ka] (In the formula, X is (a)-C(O)R 3 , (b)-C(O)OR 3 , (c)-C(O)OCH(R 4 ) OR 5 , (d)-CH2OC(O)R 3 , (e) -CH2OP(O)(OH)2, (f)-C(O)(CH2) n Z a R 5 , [ka] and independently selected from the group consisting of: n is 3 or 4; R 3 -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, [ka] selected from the group consisting of: R 4 , R 7 , R 8 , R 9 and R 10 are independently H, -C 1-6 Alkyl or -C 3-6 is cycloalkyl; R 5 is -C(O)R 3 , -C(O)OR3 , -P(O)OR 11 (OR 12 ), amino acids, and peptides; Z a and Z b are each independently O or NR 4 and; Z c is OC(O)R 3 or OP(O)(OR 4 )2 is selected; R 6 -H, -C 1-6 Alkyl, -C 3-6 selected from the group consisting of cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH, and CF3; R 11 and R 12 are independently H, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl; 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 substituted with haloalkyl, aryl, or heteroaryl) or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6is H, methyl, methoxy, nitro, or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12 are each independently H or methyl. In some embodiments, R 10 is methyl. In some embodiments, the compound is selected from the group consisting of compounds 403-511 in Table 4 below.

[0026] In some embodiments of the foregoing compounds, the amino acid, dipeptide, tripeptide, or polypeptide may include one or more of the naturally occurring (L-) amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, phenylalanine, serine, tryptophan, threonine, tyrosine, and valine.

[0027] Without intending to be bound by theory, it is believed that prodrugs of cathinones, such as methylone, or phenethylamines, such as MDMA, act as systemic controlled-release systems for the active principle of the parent molecule through bioactivation. Such bioactivation can be achieved by enzymatic or chemical cleavage of the covalently attached promoiety, or a combination of both enzymatic and chemical cleavage of the covalently attached promoiety.

[0028] As used herein, "alkyl" and other groups having the prefix "alk," such as alkoxy, alkanoyl, alkenyl, alkynyl, etc., refer to carbon chains that may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, etc. The terms "alkenyl," "alkynyl," and the like, include carbon chains that include at least one unsaturated C-C bond.

[0029] The term "haloalkyl" refers to an alkyl group having one to nine halo groups attached thereto. Examples include -CHF, -CHF, -CF, -CHCHF, -CHFCHF, -CFCHF, -CFCHF, and -CFCF.

[0030] The term "cycloalkyl" refers to a carbocycle containing no heteroatoms, including mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can contain one ring that is partially or fully unsaturated, such as a benzene ring, to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes fused ring systems such as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl, adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like. Similarly, "cycloalkenyl" refers to a carbocycle containing no heteroatoms and at least one non-aromatic C-C double bond, including mono-, bi-, and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

[0031] The term "cycloalkyloxy", unless specifically stated otherwise, includes a cycloalkyl group attached to the oxy connecting atom.

[0032] The term "alkoxy", unless otherwise stated, includes an alkyl group attached to the oxy connecting atom.

[0033] The term "aryl", unless otherwise specified, includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl.

[0034] The term "aryloxy", unless otherwise specified, includes single ring systems such as phenyl or naphthyl as well as multiple ring systems attached to the bonding site through an oxygen linking atom.

[0035] The term "C0-C6 alkyl" includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. When the alkyl is a terminal moiety, the alkyl with no carbon atoms is a hydrogen atom substituent. When the alkyl is a bridging moiety, the alkyl with no carbon atoms is a direct bond.

[0036] The term "hetero," unless otherwise specified, includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems containing one or more O, S, or N atoms (including mixtures of these atoms). The heteroatoms replace ring carbon atoms. Thus, for example, heterocycloC5 alkyl is a five-membered ring containing 5 to 0 carbon atoms. Examples of heteroaryl include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl.

[0037] The term "heteroaryloxy," unless otherwise stated, means a heteroaryl group attached through an oxygen linking atom to the connecting site. Heteroaryl (C 1-6Examples of alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl, and quinoxalinylmethyl. Heterocyclo C 3-7 Examples of alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

[0038] "N-heterocyclo C 4-7 The term "alkyl" refers to a non-aryl heterocyclic compound having 3 to 6 carbon atoms and one nitrogen atom forming the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, and perhydroazepinyl. Aryl (C 1-6 Examples of alkyl include phenyl (C 1-6 ) alkyl, and naphthyl (C 1-6 ) alkyl. Heterocycle C 3-6 Alkylcarbonyl (C 1-6 Examples of alkyl include azetidinecarbonyl (C 1-6 ) alkyl, pyrrolidinylcarbonyl (C 1-6 ) alkyl, piperidinyl carbonyl (C 1-6 ) alkyl, piperazinyl carbonyl (C 1-6 ) alkyl, morpholinylcarbonyl (C 1-6 ) alkyl, and thiomorpholinylcarbonyl (C 1-6 ) alkyl.

[0039] The term "amine" includes primary, secondary and tertiary amines unless specifically stated otherwise.

[0040] Unless otherwise specified, the term "carbamoyl" includes -NHC(O)OC1-C4 alkyl and -OC(O)NHC1-C4 alkyl.

[0041] The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

[0042] The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl may represent a pentafluorophenyl or phenyl ring. Furthermore, substitution can occur on any group. For example, substituted aryl (C 1-6 ) Alkyl includes substitution on both aryl and alkyl groups.

[0043] The term "oxide" of a heteroaryl group is used in its normal, well-known chemical sense and includes, for example, the N-oxide of a nitrogen heteroatom.

[0044] The compounds described herein contain one or more double bonds and may therefore occur as cis / trans isomers and other conformational isomers, and the present invention includes all such possible isomers and mixtures thereof.

[0045] The compounds described herein may contain one or more asymmetric carbon atoms and thus may give rise to diastereomers and optical isomers. The present invention includes such possible diastereomers, their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above formula (I) is shown without a definite stereochemistry at a specific position. The present invention includes all stereoisomers of formula (I) and their pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included.

[0046] During the course of the synthetic methods used to prepare such compounds, or when using racemization or epimerization methods known to those skilled in the art, the products of such methods may be mixtures of stereoisomers.

[0047] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a salt of a compound described herein.

[0048] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, or co-crystal formers. Crystalline forms may exist as salts, solvates, hydrates, or clathrates. When the compounds of the present invention are acidic, the corresponding salts can usually be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (I and II), iron (III), iron (II), lithium, magnesium, manganese (I and II), potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary amines, secondary amines, tertiary amines, and substituted amines, such as cyclic amines, naturally occurring substituted amines, and synthetic substituted amines. Pharmaceutically acceptable organic non-toxic bases with which salts or co-crystals can be formed include, for example, arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and other ion exchange resins.

[0049] When the compound of the present invention is basic, its corresponding salt or cocrystal can be generally prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, musicic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Particularly preferred are benzenesulfonic acid, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0050] According to some embodiments, pharmaceutical compositions may be prepared containing a compound of formula (I) (or a pharmaceutically acceptable salt or co-crystal thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants.

[0051] According to another embodiment, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier / excipient, a compound of formula (I) or a pharmaceutically acceptable salt / co-crystal, and the corresponding parent psychotropic agent of the compound of formula (I).

[0052] Dosage levels of about 0.0001 mg to about 100 mg per kg of body weight per day may be useful in treating conditions such as post-traumatic stress disorder (PTSD), anxiety disorders, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, cluster headaches, cancer-related conditions, loss of motivation, burnout, boredom, migraines, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea, or vomiting.

[0053] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the therapeutic target and the particular method of administration. For example, formulations intended for oral administration to humans typically contain about 0.5 mg to about 5 g of active ingredient, compounded with an appropriate acceptable amount of "GRAS" ingredients, which can vary from about 5% to about 95% of the total composition. Unit dosage forms typically contain about 0.001 mg to about 5000 mg of active ingredient, typically 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 5.0 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 3000 mg, 5000 mg, or any dose in between.

[0054] Pharmaceutical compositions suitable for use as described herein include compositions containing an effective amount of the active ingredient to achieve its intended purpose. Determining an effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. In general, the compounds disclosed herein are effective over a wide range of dosages. However, it is understood that the specific dosage level for a particular patient will depend on various factors, including age, body weight, overall health, sex, diet, time of administration, route of administration, excretion rate, drug combination, and the severity of the particular disease being treated.

[0055] The composition, shape, and type of the dosage forms provided herein typically vary depending on their intended use. For example, a dosage form used for the acute treatment of a disease may contain a larger amount of one or more active ingredients comprising Formula (I) than a dosage form used for the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain a smaller amount of one or more active ingredients comprising Formula (I) than an oral dosage form used for the same disease. These and other ways in which specific dosage forms provided herein differ from one another will be readily apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton, Pa. (2000). In practice, the compounds of Formula (I) of the present invention, or their pharmaceutically acceptable salts / cocrystals, can be combined as a homogeneously mixed active ingredient with pharmaceutical excipients, carriers, or diluents according to conventional pharmaceutical compounding techniques. The carrier may be, for example, oral, mucosal (e.g., nasal, sublingual, vaginal, inhalation, bladder, rectal, ocular, buccal, or otic), parenteral (including intravenous, intradermal, subcutaneous, bolus injection, intramuscular, or intraarterial), or topical (e.g., transdermal, transcutaneous, eye drops, or other ophthalmic formulations). Thus, pharmaceutical compositions of the present invention may be provided as discrete units suitable for oral administration such as capsules (sustained-release or enteric-coated or coated with a polymer modified for targeted delivery, or uncoated), sachets, or tablets (coated or uncoated, or bilayer or sustained- or delayed-release, including microencapsulation), or tablets each containing a predetermined amount of the active ingredient. Further, compositions may be provided as powders, granules, coated sustained-release particles, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water or water-in-oil liquid emulsions, liposomes, or nanosuspensions. In addition to the common dosage forms listed above, the compounds of formula (I), or pharmaceutically acceptable salts or co-crystals thereof, may also be administered via controlled or modified release formulations and / or delivery devices. The compositions may be prepared by any of the methods of pharmacy.Generally, such methods include the step of bringing into association the active ingredient(s) with excipients or carriers that constitute one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers / excipients or finely divided solid carriers / excipients, or both. The product can then usually be shaped into the desired presentation.

[0056] Thus, pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier / excipient and a compound of formula (I) or a pharmaceutically acceptable salt / co-crystal. The compound of formula (I) or a pharmaceutically acceptable salt / co-crystal may also be included in the pharmaceutical composition in combination with one or more other therapeutically effective compounds.

[0057] The pharmaceutical carriers used can include, for example, fillers such as talc, calcium carbonate, microcrystalline cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, and mixtures thereof, binders such as Kollidon, disintegrants such as croscarmellose sodium, crospovidone, sodium starch glycolate, gelatinized starch, gums and other starches, and mixtures thereof, and lubricants such as calcium stearate, magnesium stearate, syloid silica gel, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, sesame oil, corn oil, soybean oil), ethyl oleate agar, or other lipid formulation lubricants and mixtures thereof, to form oral solid dosage forms such as powders, capsules, tablets, and capsules. Because of their ease of administration, tablets and capsules are the preferred oral dosage units when solid pharmaceutical carriers are used. Each solid oral dosage unit can be further coated with a special polymer that can achieve delayed or sustained release of the dosage unit's contents. Formula (I) can be administered by delayed or sustained release means or by delivery devices known to those skilled in the art. Non-limiting examples of delayed or sustained release include those described in U.S. Pat. Nos. 3,845,770, 3,916,899, 3,536,809, and 5,059,595. Such dosage forms can be used to delay or control the release of one or more ingredients using polymers such as hydroxypropylmethylcellulose, usually in the form of a matrix, such as a gel, permeable membrane, microemulsion, osmotic system, liposome, microsphere, or combination thereof. Controlled-release formulations can protect the dosage unit from exposure to the gastric environment; delay release of the active ingredient into the lower gastrointestinal tract, such as the colon; or delay release of the active ingredient to reduce blood levels of the drug and affect the occurrence of side effects.

[0058] Examples of gaseous carriers include carbon dioxide and nitrogen.

[0059] In preparing oral liquid compositions for oral dosage forms, any convenient pharmaceutical medium may be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., to form oral liquid preparations such as suspensions, elixirs, solutions, etc.

[0060] A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.

[0061] Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Each tablet preferably contains from about 0.001 mg to about 5000 mg of the active ingredient, and each cachet or capsule preferably contains from about 0.001 mg to about 5000 mg of the active ingredient.

[0062] Pharmaceutical compositions of the present invention suitable for parenteral administration (including intravenous, intramuscular, subcutaneous, intraocular, and intraarterial administration) may be prepared as solutions or suspensions of the active compound in an injectable component. Parenteral dosage forms are preferably sterile or can be sterilized prior to administration to a patient. Non-limiting examples of suitable vehicles include water for injection, USP, dextrose injection, sodium chloride injection, lactated Ringer's solution, and the like. A suitable surfactant, such as polysorbate 80, can also be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, ethyl alcohol, polypropylene glycol, and mixtures thereof, in nonaqueous vehicles such as oils (e.g., corn oil, sesame oil, isopropyl myristate). Antioxidants, such as vitamin C palmitate, help stabilize the formulation. Additionally, preservatives can be included to prevent the detrimental growth of microorganisms.

[0063] Furthermore, it may be in the form of a sterile powder for extemporaneous preparation of such a sterile injectable solution or dispersion. In either case, the final injectable form must be sterile, non-irritating even with the addition of an isotonicity agent, and have efficient fluidity for easy syringability. The pharmaceutical composition must be stable under the conditions of manufacture and storage. Therefore, it must preferably be protected from the contaminating action of microorganisms, such as bacteria and fungi, by using, for example, benzalkonium chloride, chlorobutanol, methylparaben, propylparaben, edetate disodium, sorbic acid, or other agents known to those skilled in the art. The pharmaceutical compositions of the present invention can be in a form suitable for topical application to the skin and its appendages, or, for example, various mucous membranes, such as, for example, aerosols, patches, creams, ointments, lotions, powders, emulsions, etc. Usable routes of administration include nasal, sublingual, vaginal, rectal, ocular, oral, or intra-aural administration. Furthermore, the compositions can be in a form suitable for use in transdermal or intradermal microneedle devices. These formulations can be prepared by conventional processing of the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof. For example, a lotion, cream, or ointment can be prepared by mixing a hydrophilic material with water and about 5% to about 30% by weight of the compound to produce a cream, lotion, or ointment with the desired consistency. Typical examples of excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, isopropyl myristate, mineral oil, and mixtures thereof. Moisturizing agents, such as occlusive agents, humectants, and emollients, can also be added to the pharmaceutical composition and, if desired, the dosage form. The pH of the pharmaceutical composition or dosage form can also be adjusted to improve delivery of Formula (I). Suitable dosage forms for treating mucosal tissues in the oral cavity can be formulated as mouthwashes or oral gels.

[0064] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, where the carrier is solid, liquid, or spray.Preferably, the mixture is formed into unit-dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be easily formed by first mixing the composition with the softened or melted carrier, followed by cooling and shaping in molds.

[0065] In addition to the aforementioned carrier components, the above-mentioned pharmaceutical formulations may optionally contain one or more additional carrier components, such as diluents, buffers, binders, surfactants, thickeners, lubricants, and preservatives (including antioxidants). Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. The composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared as a powder or liquid concentrate. The addition of preservatives, such as antioxidants, is widely accepted in the pharmaceutical arts as a means of simulating long-term storage to determine properties such as the shelf life or stability of a formulation over time (see, for example, Jens T. Carstensen, Drug stability: Principles & Practice. 2nd Ed., Marcel Dekker, NY, NY. 1995, pp. 379-80).

[0066] All diseases, conditions, and disorders described herein shall conform to the definitions set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization.

[0067] As used herein, "reduce," "decrease," "lessen," and similar terms mean a reduction of at least about 10%, about 15%, about 20%, about 25%, about 35%, about 50%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, or more.

[0068] As used herein, "improve," "increase," "enhance," and similar terms refer to an increase of at least about 10%, about 15%, about 20%, about 25%, about 50%, about 75%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more.

[0069] In one embodiment, a variety of other therapeutic agents may be used for administration in conjunction with the compositions and methods provided herein.

[0070] In another aspect, provided herein is a method for treating and / or preventing a disease or condition, such as a neuropsychiatric disorder, and / or ameliorating its symptoms, the method comprising administering an effective amount of a compound provided herein to a subject. In some embodiments, the disease or condition is selected from post-traumatic stress disorder (PTSD), anxiety disorder, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, cluster headache, cancer-related conditions, loss of motivation, burnout, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea, or vomiting. In some embodiments, the disease or condition is PTSD. In some embodiments, the disease or condition is an anxiety disorder. In some embodiments, the disease or condition is depression.

[0071] The compounds provided herein can be used for a variety of therapeutic purposes. In one embodiment, the compounds are administered to a subject to treat a neuropsychiatric disorder. In the compositions and methods provided herein, a "subject" includes humans and other animals, preferably mammals, and most preferably humans. Thus, the compounds provided herein are applicable to both human therapy and veterinary medicine. In another embodiment, the subject is a mammal, and in yet another embodiment, the subject is a human. As used herein, "condition," "disease," or "illness" refers to a disorder that may be ameliorated by administration of the compounds provided herein and pharmaceutical compositions thereof.

[0072] The methods and compositions described herein can be used to prevent, as well as ameliorate, the signs and / or symptoms of conditions such as neuropsychiatric disorders. The terms "treating" and "treatment" are used to refer to the treatment of a condition in a subject, including preventing, inhibiting, or ameliorating the condition in a subject, as well as reducing or ameliorating the signs or symptoms of the condition. Treatment goals incorporate endpoints such as improvement on the DSM-5 severity scale to measure whether engagement of the pleasant cognitive-affective valence system results in increased resilience and quality of life with a corresponding decrease in unpleasant affective valence.

[0073] Those skilled in the art will appreciate that methods of treatment and / or prevention comprising administering a compound provided herein for the treatment and / or prevention of one or more of the indications described herein also include: use of a compound provided herein in the manufacture of a medicament for the treatment and / or prevention of one or more of the indications described herein; and use of a compound provided herein for the treatment and / or prevention of one or more of the indications described herein.

[0074] Pharmaceutical compositions are contemplated for the compounds and methods provided herein. Formulations of the compositions and methods provided herein are prepared by mixing the compound of interest with any pharmaceutically acceptable carrier, excipient, or stabilizer to a desired purity and preparing it for storage in the form of a lyophilized formulation or aqueous solution. Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations used and include buffers such as phosphate, citrate, acetate, and other organic acids; antioxidants such as ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol; butyl alcohol or benzyl alcohol; alkylparabens such as methylparaben and propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol; low molecular weight (less than about 10 residues) polypeptides); serum albumin, gelatin, immunoglobulins, etc. The pharmaceutical compositions may contain any of the following: proteins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates such as glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; sweeteners and other flavorings; fillers such as microcrystalline cellulose, lactose, corn, and other starches; binders; additives; colorants; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants or polyethylene glycol (PEG). In another embodiment, the pharmaceutical compositions provided herein are in a water-soluble form, e.g., as pharmaceutically acceptable salts, meaning to include both acid and base addition salts."Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness of the free base and are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. The salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine salts.The preparations used for in vivo administration are preferably sterile.This can be easily achieved by filtration through sterile filtration membranes or other methods.

[0075] Pharmaceutically acceptable excipients for formulation of the compounds provided herein include, but are not limited to, diluents such as microcrystalline cellulose, starch, mannitol, anhydrous calcium hydrogen phosphate, or a co-mixture of silicon dioxide, calcium carbonate, microcrystalline cellulose, and talc; disintegrants such as sodium starch glycolate or croscarmellose sodium; binders such as polyvinylpyrrolidone, copolyvinylpyrrolidone, or hydroxypropyl cellulose; lubricants such as magnesium stearate or sodium stearyl fumarate; glidants such as colloidal silicon dioxide; and film coats such as Opadry II white or PVA-based brown Opadry II.

[0076] The compounds provided herein may be encapsulated in microcapsules prepared by methods including, but not limited to, coacervation techniques, interfacial polymerization (e.g., using hydroxymethylcellulose or gelatin microcapsules, or poly(methyl methacrylate) microcapsules), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), and macroemulsions. Sustained-release formulations may also be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers, which matrices are in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyrate (a microsphere-based delivery system consisting of a desired bioactive molecule incorporated into a matrix of poly-DL-lactide-co-glycolide (PLG)).

[0077] Administration of pharmaceutical compositions containing compounds provided herein can be carried out in a variety of ways, including, but not limited to, oral, subcutaneous, intravenous, nasal, intraaural, transdermal, topical (e.g., gels, ointments, lotions, creams, etc.), intraperitoneal, intramuscular, intrapulmonary, intravaginal, parenteral, rectal, or ocular, for example, in the form of a sterile aqueous solution. As known to those skilled in the art, pharmaceutical compositions can be appropriately formulated depending on the method of introduction.

[0078] In some embodiments, the pharmaceutical formulation is an oral dosage form. In some embodiments, the pharmaceutical formulation is a parenteral dosage form. In some embodiments, the pharmaceutical composition comprises a tablet. In some embodiments, the pharmaceutical composition comprises a capsule. In some embodiments, the pharmaceutical composition comprises a dry powder. In some embodiments, the pharmaceutical composition comprises a solution. In some embodiments, two or more dosage forms are administered to a subject substantially simultaneously. In some embodiments, a subject may receive all of the therapeutic dose in one tablet or capsule. In some embodiments, the therapeutic dose may be divided among multiple tablets or capsules.

[0079] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a molecule" can also include plural molecules.

[0080] The terms "about" and "approximately," used interchangeably herein, mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on the limitations of how the value is measured or determined, i.e., the measurement system. For example, "about" can mean within 1 or more standard deviations, in accordance with practice in the art. Furthermore, as used herein, the term "about," when referring to a measurable value such as dose, time, temperature, etc., is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0081] A reference to a particular value includes at least that particular value unless the context clearly dictates otherwise. When a range of values ​​is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, a reference to values ​​stated in a range includes each and every value within that range. All ranges are inclusive and combinable.

[0082] The phrase "and / or," as used herein, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and discretely present in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present in addition to the elements specifically identified in the "and / or" clause, whether or not those elements are related to the elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can be interpreted in various ways, such as in one embodiment referring to A only (optionally including elements other than B), in another embodiment referring to B only (optionally including elements other than A), and in yet another embodiment referring to both A and B (optionally including other elements).

[0083] As used herein, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one, and also two or more, of a number or list of elements, but optionally including additional items not in the list. Unless a contrary intention is clearly indicated, such as "any one" or "exactly one," or when used in an embodiment, the phrase "consisting of" only refers to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein will be interpreted as indicating exclusive alternatives (i.e., "either / or," "any one," "only one," or "exactly one") only when preceded by terms of exclusive alternatives, such as "either," "any one," "only one," or "exactly one."

[0084] As used herein, the phrase "at least one" refers to a list of one or more elements and should be interpreted to mean at least one element selected from any one or more of the elements in the list of elements, but does not require at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically listed in the list of elements to which the phrase "at least one element" refers. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can mean, in one embodiment, at least one, optionally, two or more As and no Bs (and optionally including elements other than B); in another embodiment, at least one, optionally, two or more Bs and no As (and optionally including elements other than A); in yet another embodiment, at least one, optionally two or more As, and at least one, optionally, two or more Bs (and optionally including other elements); etc.

[0085] It is specifically intended that the various features described herein can be used in any combination unless the context indicates otherwise.

[0086] Any patents, patent application publications, or scientific publications cited herein are hereby incorporated by reference in their entirety.

[0087] The following examples are presented in order to more fully illustrate preferred embodiments of the invention, but they should in no way be construed as limiting the broad scope of the invention.

[0088] Example 1 Synthesis method Compounds of formula (I) of the present invention can be prepared starting from parent molecule II according to the proposed synthetic routes outlined in Schemes 1-17 below: Methylone IIa (Y=CO, R 1 =CH3, R 2 =CH3), Ethylon IIb (Y=CO, R 1 =CH3, R 2 =CH2CH3), Butyrone IIc (Y=CO, R 1 =CH2CH3,R 2 =CH3) and MDMA IId (Y=CH2,R 1 =CH3,R 2 =CH3) can be prepared using procedures such as those described in WO 9639133 A1 (IIa); Heather E. et al. Drug Test. Analysis, 2017, 9, 426 (IIa); Maheux CR et al. Drug Test. Analysis, 2016, 8, 847 (IIb); Maheux CR et al. Drug Test. Analysis, 2012, 4, 17 (IIc) and Milhazes N. et al. Anal. Chem. Act. 2007, 596, 231 (IId).

[0089] Amino acid derived prodrugs of formula Ib and Id can be prepared by coupling the requisite amine II with the appropriate amino acid as shown in Scheme 1 below, where R 11 and R 12are each independently selected from the side chain residues of naturally occurring amino acids. To couple an amino acid with II, one of the amino groups is preferably protected with a protecting group (Pg) before reacting the amino acid with II. Agents and methods for protecting amino groups in reactants are known in the art. Examples of protecting groups that can be used to protect amino groups include, but are not limited to, fluorenylmethoxycarbonyl (Fmoc), t-butyl carbonate (Boc), trifluoroacetic acid (TFA), acetic acid (Ac), benzyloxycarbonyl (CBZ), and the like. Preferably, the carboxylic acid group in the N-protected amino acid is activated with an acid activating agent (sometimes called a coupling reagent) to facilitate the reaction of the N-protected amino acid with II. Examples of acid-activating agents (coupling reagents) well known in the art include, but are not limited to, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazole tetramethyluronium hexafluorophosphate (HBTU), and azabenzotriazole tetramethyluranium hexafluorophosphate (HATU). The use of an appropriate acyl halide or acid anhydride as an activated acylating group in an N-protected amino acid is also contemplated. After coupling using any standard coupling procedure, an intermediate protected prodrug Ia is obtained, which can then be deprotected using standard reagents known in the art to yield the desired prodrug Ib. This amino acid prodrug can be further derivatized to a dipeptide by repeating the coupling procedure to yield prodrug Id, followed by deprotection of the newly added amino group Ic.

[0090] [ka] Alternatively, peptide-derived prodrugs of formula Id may be prepared by coupling the requisite amine II with an appropriate dipeptide, as shown in Scheme 2 below. Such coupling may be achieved under the conditions previously described for intermediate Ia (Scheme 1). The requisite dipeptide is obtained by coupling two amino acids, each independently selected from naturally occurring L-amino acids, using standard peptide coupling protocols well known in the art.

[0091] [ka] Amide prodrugs of formula Ie can be prepared by coupling the requisite amine II with an appropriate acylating agent as shown in Scheme 3 below. Acylation of the amino group of II can be achieved by coupling an acid chloride (Z=Cl) or an acid anhydride (Z=-OC(O)R) in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO3, K2CO3, or 2,6-lutidine in a suitable solvent such as methylene chloride, THF, DMF, acetonitrile, or toluene. 3 or —OC(O)t-butyl). The coupling reaction can also be carried out with carboxylic acids (Z═OH) in the presence of coupling reagents such as N,N-dicyclohexylcarbodiimide (DCC), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazole tetramethyluronium hexafluorophosphate (HBTU), and azabenzotriazole tetramethyluranium hexafluorophosphate (HATU), or other similar reagents known to those skilled in the art.

[0092] [ka] Carbamate prodrugs of formula If can be prepared by coupling the requisite amine II with the appropriate chloroformate as shown in Scheme 4 below. The coupling reaction is carried out in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine, NaOH, NaHCO3, K2CO3, or pyridine in a suitable solvent such as methylene chloride, THF, ethyl acetate, acetonitrile, 1,4-dioxane, or water. Alternatively, the carbamate If can be prepared by sequential addition of triphosgene to amine II in a solvent such as methylene chloride in the presence of a base such as diisopropylethylamine (DIPEA), followed by NaOR 3 It can be prepared by adding an alkoxide such as

[0093] [ka] Acyloxyalkoxycarbonyl prodrugs of Formula Ig (Scheme 5) can be prepared by sequential coupling of the required amine II with 1-chloroethyl chloroformate in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as methylene chloride, followed by the addition of a carboxylate of choice. Such carboxylates can be prepared by the addition of the corresponding carboxylic acid R 3 COH can be generated by reaction with a base such as triethylamine or cesium carbonate in a solvent such as DMF or acetonitrile. Alternatively, the acyloxyalkoxycarbonyl prodrug of Formula Ig can be reacted directly by coupling the requisite amine II with an electrophilic acylating agent such as 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl carboxylate in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as methylene chloride.

[0094] [ka] Acyloxymethyl prodrugs of formula Ih can be prepared by coupling the requisite amine II with the appropriate chloromethyl ester in the presence of a base agent such as triethylamine in a solvent such as acetonitrile (Scheme 6). 3 C(O)OCH2Cl is a compound of formula R 3 It can be prepared according to the procedure of reacting the acyl chloride of COCl with paraformaldehyde.

[0095] [ka] The phosphoramide prodrug of Formula Ii can be prepared according to the procedures described in WO 2020 / 008064. As depicted in Scheme 7 below, PCl5 is added to the required amine II in the presence of a basic agent such as pyridine and a solvent such as methylene chloride. A water / DMSO mixture is then added to hydrolyze the dichlorophosphoramide solution, yielding the phosphoramide prodrug of Formula Ii.

[0096] [ka] Phosphoryloxymethyls of formula Ik can be prepared in a two-step procedure from the requisite amine II, as shown in Scheme 8 below. Following the procedures described in WO 2020 / 008064, a solution of amine II in a solvent such as acetonitrile can be treated with a basic agent such as KCO, NaI, or di-tert-butylchloromethyl phosphate at a controlled temperature of 50° C. to afford the protected phosphonate Ij. Hydrolysis of this intermediate under aqueous acidic conditions affords the phosphoryloxymethyl prodrug Ik.

[0097] [ka] Phosphoryloxyalkoxycarbonyl prodrugs of formula Im (Scheme 9) can be prepared by sequential coupling of the required amine II with a chloroalkyl chloroformate in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as methylene chloride, followed by the addition of dibenzyl phosphate (R 11 and R 12 R can be prepared by adding a suitably protected phosphate, such as (R = benzyl). Such phosphates can be generated by reacting the corresponding phosphonic acid with a base, such as silver carbonate, in a solvent such as DMF or acetonitrile. 11 and R 12 When is benzyl, the phosphate intermediate IL is deprotected using catalytic Pd / C under an atmosphere of H2 in a solvent such as ethyl acetate to give the dihydrogen phosphate Im.

[0098] [ka] Amide prodrugs of formula Ip can be prepared by coupling the requisite amine II with a carboxylic acid Io as shown in Scheme 10 below. a When R is O, NH, or NCH, these carboxylic acids can be substituted with a wide variety of R groups, including alkyl, cycloalkyl, aryl, heteroaryl, and amino acids. 3 The carboxylic acid may be obtained from a commercially available source in which the group may be present. The coupling reaction may be carried out in the presence of a coupling reagent such as N,N-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazole tetramethyluranium hexafluorophosphate (HBTU), azabenzotriazole tetramethyluranium hexafluorophosphate (HATU), or similar reagents known to those skilled in the art. If the carboxylic acid is not commercially available, the amino group (Z) of In may be converted to a carboxylic acid in the presence of a coupling agent as described above.a =NR 4 ) or hydroxy group (Z a Io can be prepared by acylation of an amine In by reacting it with a carboxylic acid (Z=OH). Alternatively, the amine In can be acylated with an acid chloride (Z=Cl) or an acid anhydride (Z=-OC(O)R) in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO3, K2CO3, or 2,6-lutidine in a suitable solvent such as methylene chloride, THF, DMF, acetonitrile, or toluene. 3 Alternatively, it may be reacted with -OC(O)t-butyl.

[0099] [ka] Carbamate prodrugs of formula It can be prepared by coupling the requisite amine II with benzyl alcohol Is as shown in Scheme 11 below. b When R is O, NH, or NCH, benzyl alcohol can be used with a wide variety of R groups, including alkyl, cycloalkyl, aryl, heteroaryl, and amino acids. 3 The coupling reaction can be carried out as described in US Patent Application Publication No. 2017 / 0145044 A1 by sequentially reacting benzyl alcohol with a reagent such as carbonyldiimidazole in a solvent such as dichloromethane, followed by the addition of amine II. If benzyl alcohol is not commercially available, Is can be prepared according to a two-step procedure, in which the required commercially available phenol (Z b =O) or aniline (Z b =NR 4 ) Iq is acylated in a manner similar to that described above for the preparation of Io (Scheme 10), followed by reduction of the benzaldehyde Ir with a reagent such as sodium borohydride in a solvent such as dichloromethane in the presence of an alcohol such as isopropanol.

[0100] [ka] Carbamate prodrugs of Formula Ix can be prepared by coupling the requisite amine II with benzyl alcohol Iw, as shown in Scheme 12 below, and following an assembly sequence similar to that previously described in Scheme 11. b When R is O, NH, or NCH, benzyl alcohol can be used with a wide variety of R groups, including alkyl, cycloalkyl, aryl, heteroaryl, and amino acids. 3 The coupling reaction can be carried out by sequentially reacting benzyl alcohol with a reagent such as carbonyldiimidazole in a solvent such as dichloromethane, followed by the addition of amine II. If benzyl alcohol is not commercially available, Iw can be obtained from commercially available phenols (Z b =O) or aniline (Z b =NR 4 ) Iu can be prepared according to a two-step procedure by acylation in a manner similar to that described above for the preparation of Io (Scheme 10), followed by reduction of the benzaldehyde Iv with a reagent such as sodium borohydride in the presence of an alcohol such as isopropanol in a solvent such as dichloromethane.

[0101] [ka] Phosphonate prodrugs of Formula Iaa can be prepared by coupling the requisite amine II with benzyl alcohol Iz, as shown in Scheme 13 below, and following a combinatorial procedure similar to that described above in Scheme 11. Protected phosphate ester Iy can be obtained by reacting commercially available phenol Iq-1 with a protected phosphate reagent such as di-tert-butylchlorophosphate or di-benzylchlorophosphate in a solvent such as THF or dichloromethane, in the presence of a base such as triethylamine, i-PrNEt, or DBU, and using a catalyst such as DMAP. Treatment of benzaldehyde Iy with a reagent such as sodium borohydride in a solvent such as dichloromethane, in the presence of an alcohol such as isopropanol, affords benzyl alcohol Iz. Carbamate bond formation can be achieved by reacting benzyl alcohol with a reagent such as carbonyldiimidazole in a solvent such as dichloromethane, followed by the addition of amine II. Deprotection of the phosphate to form Iaa can be achieved using reagents such as TFA or aqueous HCl under acidic conditions (Pg=tert-butyl) in solvents such as methylene chloride or THF. 6 is not compatible under reducing conditions, e.g., R 6 Except when = NO2, CN or Br, deprotection can be carried out under hydrogenolysis conditions (Pg = benzyl) using a palladium catalyst (Pd / C) in a solvent such as methanol under a hydrogen atmosphere.

[0102] [ka] Phosphonate prodrugs of formula Idd can be prepared following a combinatorial procedure similar to that described above in Scheme 11, by coupling the requisite amine II with benzyl alcohol Icc, as shown in Scheme 14 below. Protected phosphate Ibb can be obtained by reacting commercially available phenol Iu-1 with a protected phosphate reagent such as di-tert-butylchlorophosphate or di-benzylchlorophosphate in a solvent such as THF or dichloromethane in the presence of a base such as triethylamine, i-PrNEt, or DBU, and a catalyst such as DMAP. Treatment of benzaldehyde Ibb with a reagent such as sodium borohydride in the presence of an alcohol such as isopropanol in a solvent such as dichloromethane provides benzyl alcohol Icc. Carbamate bond formation can be achieved by reacting benzyl alcohol with a reagent such as carbonyldiimidazole in a solvent such as dichloromethane, followed by the addition of amine II. Deprotection of the phosphate to form Iaa can be achieved using reagents such as TFA or aqueous HCl under acidic conditions (Pg=tert-butyl) in solvents such as methylene chloride or THF. 6 is not compatible under reducing conditions, e.g., R 6 Except when = NO2, CN or Br, deprotection can be similarly achieved under reducing conditions (Pg = benzyl) using Pd / C as catalyst in a solvent such as methanol under an H2 atmosphere.

[0103] [ka] Amide prodrugs of formula Ihh can be prepared by coupling the requisite amine II with the carboxylic acid Igg, as shown in Scheme 15 below. Such carboxylic acids can be generated in a three-step procedure starting from the phenol Iee, which can be prepared according to the synthesis reported by Nicolaou M. Gett. al. (J. Org. Chem. 1996, 61, 8636). Acylation of Iee can be carried out by reacting the phenol with a carboxylic acid (Z=OH) in the presence of a coupling reagent such as N,N-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazole tetramethyluranium hexafluorophosphate (HBTU), azabenzotriazole tetramethyluranium hexafluorophosphate (HATU), or other similar reagents known to those skilled in the art. Alternatively, phenol Iee can be converted to an acid chloride (Z=Cl) or an anhydride (Z=-OC(O)R) in a suitable solvent such as methylene chloride, THF, DMF, acetonitrile, or toluene in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO3, K2CO3, or 2,6-lutidine. 3 or -OC(O)t-butyl). Deprotection of Iff can be achieved under mild acidic conditions with a reagent such as PPTS (Pg = TBS) in a solvent such as methanol (Crouch, RD Tetrahedron, 2013, 69, 2383) or under reductive conditions using Pd / C as a catalyst in a solvent such as methanol under an H atmosphere (Pg = benzyl). The corresponding primary alcohol is oxidized with a reagent such as Jones reagent in a solvent such as acetone to give the carboxylic acid Igg. This carboxylic acid Igg can then be coupled with the amine II in the presence of the coupling reagents described above.

[0104] [ka] Phosphonate prodrugs of Formula Ijj can be prepared by coupling the required amine II with a carboxylic acid Iii as shown in Scheme 16 below. Such carboxylic acids can be obtained according to the synthetic method reported by Nicolaou M. Get. et al. (J. Org. Chem. 1996, 61, 8636). Amide bond formation can be achieved by reaction of the required amine II with the carboxylic acid Iii in the presence of a coupling reagent such as N,N-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazole tetramethyluranium hexafluorophosphate (HBTU), and azabenzotriazole tetramethyluranium hexafluorophosphate (HATU), or similar reagents known to those skilled in the art. The phosphonate prodrugs Ijj are obtained by deprotection of the corresponding dibenzyl phosphates under reductive conditions using Pd / C as catalyst in a solvent such as methanol under an atmosphere of H2.

[0105] [ka] Amide prodrugs of formula Inn can be prepared by coupling the requisite amine II with a carboxylic acid Imm, as shown in Scheme 17 below. Such carboxylic acids can be generated in a four-step procedure starting from the phenol Ikk, which can be prepared according to the synthesis reported by Liao Y. and Wang B. (Bioorg. Med. Chem. Lett., 1999, 9, 1795). Acylation of Ikk can be carried out by reaction of the phenol with a carboxylic acid (Z=OH) in the presence of a coupling reagent such as N,N-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazole tetramethyluranium hexafluorophosphate (HBTU), azabenzotriazole tetramethyluranium hexafluorophosphate (HATU), or other similar reagents known to those skilled in the art. Alternatively, phenol Ikk can be converted to an acid chloride (Z=Cl) or an anhydride (Z=-OC(O)R) in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO3, K2CO3, or 2,6-lutidine. 3 or -OC(O)t-butyl) in a suitable solvent such as methylene chloride, THF, DMF, acetonitrile, or toluene. Deprotection of ILL can be achieved using a reagent such as AcOH in a solvent mixture such as THF / HO under mild acidic conditions (Pg = TBS). The corresponding primary alcohol can be oxidized to the carboxylic acid Imm in a two-step procedure. Here, the alcohol is first oxidized to the aldehyde using a reagent such as MnO in a solvent such as dichloromethane, followed by a Claus-type reaction using reagents well known to those skilled in the art. Finally, coupling of the carboxylic acid Imm with the amine II in the presence of the above-mentioned coupling reagents gives the prodrug Inn.

[0106] [ka] Examples of compounds of formula (I) according to the present invention include any of compounds 1 to 402 in Tables 1, 2 and 3 below, and compounds 403 to 511 in Table 4 below (and pharmaceutically acceptable salts of any of these compounds). [Table 1] TIFF2025527481000035.tif247158TIFF2025527481000036.tif237158TIFF2025527481000037.tif236158 TIFF2025527481000038.tif232158TIFF2025527481000039.tif253158TIFF2025527481000040.tif191158 [Table 2] TIFF2025527481000042.tif247158TIFF2025527481000043.tif236158TIFF2025527481000044.tif236158 TIFF2025527481000045.tif231158TIFF2025527481000046.tif252158TIFF2025527481000047.tif190158 [Table 3] TIFF2025527481000049.tif247158TIFF2025527481000050.tif237158TIFF2025527481000051.tif237158 TIFF2025527481000052.tif231158TIFF2025527481000053.tif253158TIFF2025527481000054.tif190158 [Table 4] TIFF2025527481000056.tif241158TIFF2025527481000057.tif245158TIFF20255274810 00058.tif230158TIFF2025527481000059.tif242158TIFF2025527481000060.tif115158

[0107] Compound 1: (2S)-2,6-diamino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylhexanamide. [ka] Compound 1 was prepared by the following procedure. Step 1: Di-tert-butyl ((5S)-6-((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)amino)-6-oxohexane-1,5-diyl)dicarbamate. To a solution of methylone hydrochloride (1.03 g) in 100 mL of CHCl at room temperature, diisopropylethylamine (3.6 mL), HOBT (0.87 g), di-Boc-lysine (1.7 g), EDC (0.9 mL), and DMAP (0.1 g) were added. The reaction was stirred at room temperature overnight, after which 100 mL of CHCl was added. The resulting solution was washed with 200 mL of 1 M HCl, 200 mL of saturated aqueous NaHCO, and 200 mL of saturated aqueous NaCl. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using 30-50% EtOAc in hexanes. The pure fractions were then combined and concentrated to give the desired Boc-protected intermediate as an off-white solid. Step 2: (2S)-2,6-Diamino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylhexanamide. To a solution of di-tert-butyl ((5S)-6-((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)amino)-6-oxohexane-1,5-diyl)dicarbamate from Step 1 in CHCl (10 mL) was added 10 mL of trifluoroacetic acid. The reaction was stirred at room temperature for 4 hours, diluted with 10 mL of CHCl, and brought to pH 1 with 20 mL of 1 M HCl. The layers were separated, and 20% aqueous NaOH was added to the aqueous layer to bring the pH to >10. The resulting basic aqueous layer was extracted twice with 20 mL of CHCl. ​​The combined organic layers were concentrated under reduced pressure to give compound 1 as a solid.

[0108] Compound 2: 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylacetamide. [ka] Compound 2 was prepared by the following procedure: Step 1: tert-Butyl (2-((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)amino)-2-oxoethyl)carbamate. To a solution of methylone hydrochloride (0.5 g) in 50 mL of CHCl at room temperature was added diisopropylethylamine (1.8 mL), Boc-glycine (0.47 g), EDC (0.5 mL), DMAP (0.1 g), and HOBT (0.42 g). The reaction was stirred overnight at room temperature, followed by the addition of 50 mL of CHCl. ​​The resulting solution was washed with 100 mL of 1 M HCl, 100 mL of saturated aqueous NaHCO, and 100 mL of saturated aqueous sodium chloride. The organic layer was concentrated under reduced pressure to give an off-white solid. This crude product was carried on to the next step without purification. Step 2: 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylacetamide. To a solution of tert-butyl (2-((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)amino)-2-oxoethyl)carbamate from Step 1 in CHCl (10 mL) was added 10 mL of trifluoroacetic acid. The reaction was stirred at room temperature for 4 hours, diluted with 30 mL of CHCl, and brought to pH 1 with 20 mL of 1 M hydrochloric acid. The layers were separated, and 20% aqueous NaOH was added to the aqueous layer to bring the pH to >10. The resulting basic aqueous layer was extracted twice with 20 mL of CHCl. ​​The combined organic layers were concentrated under reduced pressure to give compound 2 as a solid.

[0109] Compound 25: N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylacetamide. [ka] Compound 25 was prepared by the following procedure: To a solution of methylone hydrochloride (0.5 g) in 50 mL of CHCl was added diisopropylethylamine (0.9 mL). The solution was stirred at room temperature for 15 minutes, cooled to 0°C, and then acetyl chloride (0.3 mL) was added. After 30 minutes at 0°C, the reaction was warmed to room temperature and stirred overnight. The volatiles were then removed under reduced pressure to give a yellow solid. This solid was dissolved in 150 mL of CHCl. ​​The resulting solution was washed twice with 100 mL of saturated aqueous NaHCO and 100 mL of saturated aqueous sodium chloride. The organic layer was concentrated under reduced pressure to give compound 25 as a solid.

[0110] Compound 45: N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-2,2,2-trifluoro-N-methylacetamide. [ka] Compound 45 was prepared by the following procedure: Methylone hydrochloride (500 mg, 2.05 mmol, 1.0 equiv.) and DCM (4 mL, 8 volumes) were added to a 25 mL round-bottom flask under nitrogen along with DIPEA (1.09 mL, 6.25 mmol, 3 equiv.). After stirring for 10 min, a light brown solution formed. The solution was cooled to 0 °C, and trifluoroacetic anhydride (483 mg, 2.3 mmol, 1.12 equiv.) in DCM (1 mL, 2 volumes) was added dropwise with degassing. A small exotherm from 4 °C to 10 °C was observed. After stirring for 30 min at 0 °C to 10 °C, HPLC monitoring indicated 66% product and 33% starting material. Additional DIPEA (0.44 mL, 1.23 mmol, eq.) and trifluoroacetic anhydride (237 mg, 0.55 equiv.) were added, and the reaction was stirred at ambient temperature overnight. The next day, HPLC analysis showed 95% product with no detectable starting material. The reaction was washed with water (5 mL x 2), and the DCM layer was dried (MgSO) and concentrated to give an orange solid. This solid was purified by column chromatography (10 g silica, 100% DCM) to give 372 mg of compound 45 as a solid.

[0111] Compound 50: 1-(((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamoyl)oxy)ethyl isobutyrate. [ka] Compound 50 was prepared by the following procedure: To a suspension of methylone hydrochloride (1.35 g) in CHCl (10 mL) at 0 °C, triethylamine (1.19 g in 2 mL of CHCl) was added. The resulting beige solution was stirred at 0 °C for 10 min, after which 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl isobutyrate (2.0 g in 4 mL of CHCl) was added dropwise over 5 min. The reaction mixture was stirred at −5 to 5 °C for 1 h, then warmed to room temperature (15–20 °C) and stirred over the weekend (approximately 66 h), resulting in an orange solution. Next, 1 M aqueous acetic acid (7 mL) was added dropwise over 5 min at <25 °C and stirred for 5 min. The phases were separated, and the organic layer was washed with 1 M aqueous KCO (7 mL) and then with 20% aqueous brine (3 × 7 mL). The isolate was concentrated under reduced pressure at 30 °C and then redissolved in ethyl acetate (10 mL). The organics were washed with 1 M aqueous KCO (2 × 7 mL), followed by 20% aqueous brine (7 mL), and then concentrated under reduced pressure at 40 °C. The crude product was purified by silica gel column chromatography, eluting with 1–10% ethyl acetate in heptane. The purified fractions were concentrated under reduced pressure at 40 °C and then stripped from TBME (3 × 20 mL) to give compound 50.

[0112] Compound 71: methyl (1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamate. [ka] Compound 71 was prepared by the following procedure: To a 25 mL round-bottom flask under nitrogen was added methylone hydrochloride (500 mg, 2.05 mmol, 1.0 equiv) along with DCM (4 mL, 8 volumes) and DIPEA (1.09, 6.25 mmol, 3 equiv). The reaction was cooled to 0 °C, and methyl chloroformate (257 mg, 2.7 mmol, 1.3 equiv) in DCM (1 mL, 2 volumes) was added dropwise over 5 min to form a light brown solution. An exotherm from 6 °C to 12 °C was observed. HPLC analysis indicated that the starting material had been consumed. The reaction was worked up by washing with water (5 mL x 2) using a phase separator. The DCM was concentrated to give a clear oil. This oil was purified by column chromatography (10 g silica, 100% DCM) to give 197 mg of compound 71 as a clear oil.

[0113] Compound 77: Pentyl (1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamate. [ka] Compound 77 was prepared by the following procedure: To a solution of methylone hydrochloride (0.5 g) in 50 mL of CHCl was added diisopropylethylamine (0.9 mL) and triethylamine (0.46 mL). The solution was stirred at room temperature for 15 minutes, cooled to 0°C, and amyl chloroformate (0.5 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 90 minutes. The volatiles were removed under reduced pressure to give an off-white solid, which was then dissolved in 100 mL of CHCl. ​​The resulting solution was washed twice with 100 mL of saturated aqueous NaHCO and 100 mL of saturated aqueous NaCl. The organic layer was concentrated under reduced pressure to give compound 77 as a solid.

[0114] Example 2 Evaluation of the effect of prodrugs on the pharmacokinetic properties of methylone. The pharmacokinetic characteristics of methylone after a single intravenous (IV), intraperitoneal (IP), or oral gavage (PO) dose in male Sprague-Dawley rats were measured using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method established and validated for methylone in rats. Rats (n = 3 per group) received a single dose of methylone as follows: 5 mg / kg IV, 15 mg / kg IP, or 15 mg / kg PO. Plasma was collected at 0.083 and 24 hours to measure methylone levels and assess key parameters (C). max , T max , T 1 / 2 The data were analyzed for the following parameters: Ratio of mean mean (RMS), AUC, etc. The results are shown in Table 5. [Table 5]

[0115] Whether the prodrug extends the half-life of methylone or alters other fundamental pharmacokinetic properties (e.g., C max or T maxTo investigate whether prodrugs alter the inflammatory response (e.g., inflammatory bowel disease), rats were administered each prodrug IV, IP, or PO. For each compound, rats were treated in three groups: Group 1, three male Sprague-Dawley rats were administered a single IV bolus dose of 5 mg / kg methylone; Group 2, three male Sprague-Dawley rats were administered a single 15 mg / kg dose of methylone by oral gavage (PO); and Group 3, three male Sprague-Dawley rats were administered a single 15 mg / kg dose of methylone intraperitoneally (IP). In all groups, blood samples were collected from each animal at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose to measure plasma concentrations. Plasma concentrations were quantified by liquid chromatography / tandem mass spectrometry (LC-MS / MS). The bioanalytical assay has been established and validated, with a lower limit of quantitation (LLOQ) of 1 ng / mL and an upper limit of quantitation (ULOQ) of 3000 ng / mL for methylone. Plasma concentration-time data will be analyzed using Phoenix WinNonlin (version 8.3) to characterize the pharmacokinetics of the analyte. A non-compartmental analysis model and linear-logarithmic trapezoidal method will be applied to calculate the PK parameters.

[0116] Behavioral pharmacology studies to address prodrug efficacy Antidepressant effects in the forced swimming test (FST) The forced swim test (FST) has been used for over 40 years and is a classic model for evaluating the antidepressant-like activity of compounds (Porsolt et al. (1977) Nature 266:730-732; Detke et al. (1995) Psychopharmacology 121:66-72). Antidepressants of all types, including selective serotonin reuptake inhibitors, noradrenaline reuptake inhibitors, tricyclic antidepressants, and more recent fast-acting antidepressants such as ketamine, psilocybin, and MDMA, have been shown to reduce immobility in the FST. Methylone has potent dose-dependent antidepressant-like effects in the rat forced swim test (FST). A single dose of 5 mg / kg of methylone reduced immobility by approximately 50% compared to vehicle-treated controls, while a dose of 15 mg / kg reduced immobility by nearly 100%. Changes in climbing and / or swimming behavior reflect the noradrenergic and serotonergic activities of methylone, respectively.

[0117] All FST tests were conducted by experimenters blinded to treatment groups and scored according to standard protocols. Briefly, rats were placed in a circular Plexiglas container filled with water. Water temperature was maintained at 22–25°C and changed for each animal. Day 1 (training) consisted of a 15-minute habituation test, and Day 2 (testing, 24 h later) consisted of a 5-minute test. A time-sampling method was employed, with animals observed every 5 seconds during the test session (60 counts or 5 minutes) and scored for immobility (defined as an inability to struggle), swimming (defined as circular movements around the tank), or climbing (defined as upward escape behavior). Data are expressed as a percentage of the test session (e.g., immobility counts divided by 60). A p-value of less than 0.05 indicates statistical significance after standard statistical analysis (e.g., unpaired t-test or ANOVA).

[0118] To determine whether the prodrugs have antidepressant-like effects and compare them to methylone, rats are treated with each compound 30 minutes prior to testing. Additional tests are performed 24, 72, 168 hours or longer after administration.

[0119] Effects of fear extinction in a model of post-traumatic stress disorder (PTSD) Methylone (30 mg / kg, i.p.) significantly improves fear extinction recall in a mouse model of PTSD (Figure 1). Deficits in fear extinction memory are a hallmark of PTSD in patients (Wicking et al. (2016) Neurobiology of Learning and Memory 136:116). SSRI antidepressants, as well as two medications approved for the treatment of PTSD (paroxetine and sertraline), prevent generalization of fear memories and promote their extinction (Pedraza et al. (2019) Transl Psychiatry 9:53). Enhanced fear extinction may also underlie the beneficial effects of MDMA as a PTSD treatment (Feduccia & Mithoefer (2018) Progress in Neuro-Psychopharmacology & Biological Psychiatry 84(Part A),221-228).

[0120] Effective PTSD treatments disrupt the association between the traumatic memory and the patient's fear response, ensuring that traumatic memory cues no longer trigger fear responses. This is modeled in a three-day fear extinction paradigm in mice. On day 1 (fear conditioning), mice are trained to acquire the "traumatic memory" by associating a conditioned stimulus (CS, a tone) with an unconditioned stimulus (US, an electric foot shock). On day 2 (extinction training), mice are presented with a CS (tone) six times in a novel environment (without a US) to train them to forget the traumatic memory association. On day 3 (extinction recall), mice are "asked" whether the tone still triggers a fear response by measuring the time they remain motionless when the tone is presented. A shorter motionless time indicates better extinction recall. Drugs that improve extinction recall reduce motionless time on day 3 and therefore have potential as a PTSD treatment.

[0121] A study using MDMA demonstrated that administration of MDMA (7.5 mg / kg) 30 minutes after fear conditioning and before extinction training reduced immobility by 35% compared to saline controls, enhancing extinction recall (Young et al. (2015) Transl Psychiatry 5:e634). Recent results using a similar experimental design demonstrated that methylone (30 mg / kg) significantly enhanced fear extinction recall (Figure 1) by nearly 60% compared to saline controls (Figure 1B). Using these methods, prodrugs can be administered to mice and tested for efficacy in fear extinction models to assess their efficacy in treating PTSD and other memory disorders.

[0122] Anxiolytic effects in other behavioral models of anxiety Additional behavioral tests, including thigmotaxis in the elevated plus maze (EPM) and open field test (OFT), are used to assess the anxiolytic effects of methylone and its prodrugs in mice or rats. Methylone (5, 10, or 20 mg / kg, subcutaneously) has been shown to decrease thigmotaxis (the time spent clinging to the perimeter of an open field) in rats (Stefkova et al. (2017) Front Psychiatry 8:232), consistent with anxiolytic effects. These models are described in more detail below. Prodrugs are screened on these behaviors for anxiolytic efficacy of each compound.

[0123] Methylone decreases time spent in the central area compared to the periphery in the OFT, consistent with an anxiolytic-like response; methylone is also a stimulant that increases locomotor activity in this test. Prodrug compounds are screened for effects on both parameters. Briefly, rodents are assessed in a 30-minute OFT using an automated activity monitoring system. Rodents are allowed to acclimate to the room 30 minutes before the start of the test. The following parameters are acquired: horizontal distance traveled, overall walking time, and number of steps. Data on vertical activity (time and number), time spent in the central area compared to the periphery, along with total time, are reported in 5-minute bins.

[0124] The EPM is a classic anxiety model that exploits rodents' aversion to open spaces. The effects of prodrug compounds and methylone are tested in this model. Briefly, rodents are acclimated in the preparation room at least 30 minutes before the start of the experiment. Testing is performed under dim light (40 lux). The elevated plus maze consists of two open arms and two closed arms (arm length: 30 cm, width: 5 cm). The open arms have a 1-cm border, while the closed arms are bordered by a 15-cm wall. At the start of the task, rodents are placed facing the central open arm of the elevated plus maze and video-tracked while exploring the maze for 5 minutes. The time spent in the open and closed arms is measured and analyzed. A greater amount of time spent in the open arms compared to the closed arms is consistent with an anxiolytic effect.

[0125] Example 3 Evaluation of the effect of prodrugs on the pharmacokinetic properties of methylone. Methylone has demonstrated its safety and clinical utility, supported by robust animal and human data, and is undergoing clinical development as a treatment for PTSD. However, the creation of a prodrug of methylone would offer distinct advantages, addressing methylone's short half-life and dose-dependent increases in heart rate and blood pressure. Current clinical protocols for methylone include supervised split dosing (i.e., two smaller effective doses approximately 1 hour apart), frequent blood pressure and heart rate monitoring for 6–8 hours post-dose, and exclusion of patients with a history of cardiovascular disease. Prodrugs may improve the pharmacokinetic properties of methylone (e.g., C max Improvements in methylone's efficacy (lowering blood pressure, prolonging half-life) could reduce or eliminate the need for frequent blood pressure and heart rate monitoring and potentially broaden eligibility criteria, thereby making the clinical benefits of methylone available to more patients.

[0126] Prodrug analogs of methylone have been synthesized. Illustrated below (Scheme 18) is the synthesis of compound 50. This acyloxyalkoxycarbonyl prodrug was efficiently prepared in a single step by direct N-acylation of methylone with 1-4-nitrophenoxycarbonyloxyethyl 2-methylpropanoate. By altering the nature of the ester residue, the rate of bioactivation of the prodrug by esterase hydrolysis can be controlled. Therefore, an alternative approach has also been proposed in U.S. Patent Application Publication No. 2010 / 0160666 (incorporated herein by reference). This strategy allows for the rapid assembly of a series of different ester analogs from a common intermediate.

[0127] [ka] Design, synthesis, and characterization of methylone prodrugs: Methylone is being developed as a treatment for PTSD based on its rapid onset, potent, and long-lasting beneficial effects in animals and humans. Overall, methylone is well tolerated. However, certain aspects of methylone's pharmacological profile are open to improvement. A longer duration of action (wider therapeutic window) and improved C-terminal receptor agonist activity are needed, while maintaining the overall safety and superior beneficial effects of methylone. max Developing alternative treatments with lower toxicity (minimizing cardiovascular effects) could offer significant advantages over the parent methylones and potentially have an even greater impact on PTSD and other patients.

[0128] Methylone can be covalently attached to a variety of promoieties via direct derivatization of the amino group. Prodrug bioactivation is first determined by investigating in vitro chemical, liver, and whole blood stability in rat and human matrices. Based on in vitro cleavage rates to release the methylone active agent, prodrugs are selected and further characterized by rat PK for in vivo validation of the bioactivation process. Complete DMPK profiles are then generated in four model organisms (mouse, rat, dog, and NHP) and humans. Finally, the collected data are used to predict human pharmacokinetics.

[0129] Synthesis of Prodrugs: Methylone prodrugs are synthesized by direct functionalization of the amino group of methylone, as shown in Scheme 19. This approach affords seven different classes of prodrugs defined by the newly created functional group: amide (I), peptide (II), carbamate (III), acyloxyalkoxycarbonyl (IV), phosphoramide (V), acyloxymethyl (VI), and phosphoroxymethyl (VII).

[0130] Although enzymatic biotransformation of each of these functional groups has been clinically validated, it involves primary amines or less N-substituted systems compared to the secondary amine of methylone. Steric hindrance is known to significantly affect the rate of peptide bond hydrolysis. For some methylone prodrugs, such as those in classes I, II, and III, this can potentially inhibit the bioactivation process. Therefore, prodrugs with more "remote" activation sites, such as the acyloxyalkoxycarbonyl group in class IV, which are less dependent on the structural features of the parent molecule, are also being investigated.

[0131] [ka] Potential bioactivation of prodrug candidates: After the prodrugs are synthesized, their potential bioactivation to liberate methylone is evaluated under in vitro conditions. Because the prodrugs are designed to be enzymatically activated by esterases and amidases / peptidases present in blood and / or liver, each prodrug is incubated with human and rat whole blood and hepatocytes. These assays measure the ratio of released parent methylone to remaining prodrug at different time points over a 2-hour period. Chemical stability assessments of each prodrug are also performed under various pH conditions to confirm that the released methylone is the result of enzymatic hydrolysis. Prodrugs that demonstrate in vitro bioactivation are then administered (IV / PO) to rats, and blood samples are collected to evaluate the pharmacokinetic profile of each prodrug.

[0132] For example, the metabolic stability of methylone-releasing prodrug candidates may be assessed in vitro according to the following protocol: Cryopreserved human and rat hepatocytes are thawed in recovery medium and plated in seeding medium to a viable cell density of 1x10 6The cells were diluted to 1000 cells / mL. Viability was determined by trypan blue exclusion. 350 μL of the cell suspension was added to individual strip tubes and pre-incubated at 37°C and 5% CO2 for 10 minutes. After pre-incubation, 350 μL of the prodrug and reference compounds (testosterone and ethoxycoumarin) were added in duplicate at a final concentration of 1 μM to initiate the reaction. 100 μL of this mixture was transferred to a 96-well plate for incubation. At selected time points (0, 10, 30, 60, 90, and 120 minutes), the incubation was stopped with 200 μL of ice-cold acetonitrile (ACN) containing internal standards (glyburide and labetalol at 1 μM). Pre-quench samples of methylone were prepared to calculate the apparent percent active drug at different time points during prodrug incubation. The samples were then centrifuged, and the supernatant was further diluted 1:1 with 25% acetonitrile in water. All samples, including analytical standards, are analyzed by LC-MS / MS to determine the concentration of released methylone and the remaining corresponding prodrug. A 100% recovery is targeted, where the sum of the remaining prodrug and released methylone is 100% with an experimental error of ±20%.

[0133] When compound 50 was incubated with human hepatocytes under the conditions described above, approximately 100% of the prodrug was converted to methylone at t = 60 min, with a total recovery of approximately 100%. As a negative control, incubation of compound 50 in phosphate buffer, pH 6.8, at 37°C for up to 2 h in the absence of hepatocytes did not release the parent methylone.

[0134] DMPK profiling: Based on rat PK data, prodrugs are selected for more extensive evaluation of their DMPK profiles. With the primary goal of predicting human PK, a series of data including PK parameters, whole blood stability, hepatocyte metabolic profile, microsomal clearance, and plasma protein binding are collected for four animal species (mouse, rat, dog, and NHP) and humans (in vitro assays only). Comparison of the human in vitro metabolic profile with the DMPK dataset from preclinical species enables human PK prediction.

[0135] Metabolic resistance to prodrug bioactivation: As previously mentioned, the steric hindrance of methylone's α-substituted secondary amine can slow the rate of hydrolysis of amide prodrugs, potentially resulting in very low levels of the parent compound being released from the system. Alternative prodrugs have been designed that rely on dual activation processes, such as acyloxyalkoxycarbonyl (IV), acyloxymethyl (VI), or phosphoroxymethyl (VII). In this case, the first step in prodrug activation is still an enzymatic hydrolysis step, but it does not involve the amino group of methylone. Chemical autolysis, completely unrelated to the amine structural features of methylone, results in cleavage of the remote functional group.

[0136] Differences between predicted PK in humans and preclinical POC species (rat, mouse): Because the hydrolytic activity of esterases and / or amidases varies significantly between different species, prodrugs with suitable predicted pharmacokinetics in humans may not be usable in preclinical models for evaluation of duration of action due to differences in pharmacokinetics. Therefore, it may be necessary to advance so-called POC molecules with a fit-for-purpose PK profile. These candidates will be added to the lead and back-up candidates.

[0137] Demonstration of prodrug efficacy and improved cardiovascular safety profile in preclinical models: While a longer half-life generally equates to a longer duration of action, the overall impact of this new PK profile on the therapeutic index of methylone needs to be assessed. As with the parent compound, the efficacy of the prodrug will be evaluated in vivo in rats in a forced swim test to assess antidepressant-like activity, and in fear extinction tests in a PTSD model to establish a therapeutic dose range. To assess cardiovascular effects, the tail cuff method will be used to monitor heart rate and blood pressure in rats at effective doses established in behavioral tests and compared to the parent methylone.

[0138] Parent methylone exhibits antidepressant-like activity in the rat forced swim test (Warner-Schmidt et al., 2023) and enhances fear extinction, consistent with its beneficial effects in a mouse model of PTSD (Yu et al., 2022). These three tests are used to evaluate the activity of the prodrug compared to vehicle- or methylone-treated controls. In all studies, groups are compared by ANOVA and appropriate post-hoc tests using Graphpad Prism 9 software. Statistical significance is set at p<0.05. Outliers, defined as individual values ​​more than two standard deviations from the mean, are excluded from analysis.

[0139] Forced swim test: To compare the antidepressant-like effects of methylone prodrugs with parent methylone, male Sprague-Dawley (SD) rats weighing 180–200 g upon arrival are subjected to the FST. Briefly, rats (N = 6–8 per group) perform a 15-minute training swim 24 h before a 5-minute FST test session. Prodrugs (5 doses selected based on PK profile), parent methylone (10 mg / kg), or vehicle control are administered 30 min before the test. Immobility is scored over the duration of the 5-minute test session. A reduction in immobility reflects an antidepressant-like response. The predicted effective dose of the prodrug is identified based on the difference in immobility time between treated and control animals.

[0140] Fear extinction: Fear conditioning is a model of PTSD in which a traumatic memory is formed after a single presentation (e.g., an association between a tone and a painful foot shock). Drugs that promote the extinction of fear conditioning (i.e., unlearning of the traumatic memory) are predicted to be beneficial for the treatment of PTSD. A single administration of methylone (30 mg / kg) has been shown to promote fear extinction in mice. To examine whether a prodrug maintains the beneficial effects of methylone, male C57BL / 6 mice (N = 10–12 per group) are tested in a fear conditioning experiment. Briefly, mice are exposed to cued conditioned fear with a single CS-US presentation in context A on day 1, fear extinction training with six CS presentations in context B on day 2, and extinction testing with six CS presentations in context B on day 3. The prodrug (five doses selected based on its PK profile), parent methylone (10 mg / kg), or vehicle control is administered 30 min before extinction training. Freezing behavior was scored as an index of the mice's memory for the CS-US association. Methylone significantly reduced freezing behavior on day 3, indicating enhanced extinction recall. The effect of the prodrug on the duration of freezing behavior in response to CS presentation on day 3 was compared to vehicle- or methylone-treated controls.

[0141] Heart rate and blood pressure assessment: Male SD rats were orally administered a single dose of the prodrug (3–5 doses determined by the results of the FST), the methylone positive control, or the vehicle negative control. Blood pressure parameters were assessed using a Visitech BP-2000 tail cuff device. The following parameters were obtained or calculated: (1) systolic pressure (SP, primary); (2) diastolic pressure (DP, primary); (3) mean pressure = (SP + DP) / 2; (4) mean arterial pressure (MAP) = DP + (SP - DP) / 3 (estimate); (5) pulse pressure = SP - DP; and (6) heart rate (HR), derived from peak pulse pressure.

[0142] One week before assessing the blood pressure effects of the test substance (prodrug) and positive control (methylone) reagents, animals are trained in the tail cuff apparatus for five sessions over five days. Vehicle or test drug is then administered, and blood pressure is assessed at nine time points (-60, 15, 30, 45, 60, 75, 90, 105, and 120 minutes) post-administration. Differences between vehicle control, methylone, and each prodrug treatment group are determined by one-way ANOVA with Dunnett's multiple comparison test using GraphPad Prism with an alpha threshold of 0.05. Differences between the prodrug and methylone groups are significant, particularly in demonstrating improved cardiovascular effects with the prodrug.

[0143] Conducting preclinical studies required for IND applications for patient administration in clinical trials: The methylone prodrug will be scaled up, purified, and compounded into GMP batches, and a nonclinical toxicology program will be initiated in two species: rats and dogs. A 7-day dose-ranging study will be followed by a 28-day GLP toxicity study to evaluate clinical signs and histopathology at three dose levels in both species. Bioanalytical studies will be conducted in these animals to determine the PK profile in both species. Mutagenicity and genotoxicity will be assessed using the Ames test and chromosomal aberration (in vitro micronucleus) assay. Cardiac safety will be demonstrated in a dog cardiovascular safety study and supported by an in vitro hERG assay. Additional in vivo safety pharmacology studies will include an in vivo micronucleus test and respiratory and CNS studies in rats. These studies will be conducted in accordance with ICH and FDA guidance and are consistent with studies conducted with the methylone parent compound.

[0144] R&D and GMP Batch Formulation: Pisgah Laboratories begins optimizing R&D formulations after identifying prodrug candidates. HPLC, FTIR, proton (1H) nuclear magnetic resonance spectroscopy (NMR), carbon-13 ( 13Identity and structure are confirmed using C) NMR and liquid chromatography-mass spectrometry (LC-MS). A synthetic route that consistently produces prodrug in ≥85% yield and ≥95% purity is selected for scale-up batches. Initial scale-up production is completed under R&D conditions (e.g., 50 g scale for methylone-based). Results from synthesis optimization and initial scale-up batches are used to identify potential impurities and form the basis for stability measures. After successful synthesis of the prodrug during R&D, the material is scaled up to a larger scale (e.g., 500 g for methylone-based) under CGMP conditions. Material manufactured under CGMP conditions is used for research required for IND applications.

[0145] IND-Required Studies: All in vivo studies will use Sprague-Dawley rats or Beagle dogs, consistent with previous IND-required studies conducted with parent methylone. All studies, except for the initial dose-ranging studies in rats and dogs, will be conducted under GLP conditions.

[0146] Model Selection and Rationale: Rats were chosen because they are a commonly used species in nonclinical studies and are an accepted rodent species for nonclinical toxicity evaluation by regulatory agencies. Rodents exhibit reproducible growth rates under laboratory conditions, are relatively free from exogenous diseases, and have low levels of spontaneous abnormalities. The total number of animals is the minimum required to adequately characterize the responses associated with methylone hydrochloride administration and is therefore sufficient to achieve the experimental objectives. No alternative test system has been sufficiently validated to replace the use of live animals in this study. Every effort has been made to maximize information while minimizing the number of animals required for this study. Beagles were chosen because they are a commonly used nonrodent model, have been used to evaluate the toxicity of a variety of test substances, and have an extensive historical database. The total number of animals used in these studies is believed to be the minimum required to adequately characterize the effects of the test substance and is planned to avoid using an unnecessary number of animals to achieve the objectives.

[0147] Toxicological studies: Dose-ranging (DRF) studies in rats and dogs: Four groups of main study animals (five males and five females per group) and corresponding satellite TK study animals (six males and six females per group) will be administered once on day 1 and once on day 8 by oral gavage to determine the tolerability of four different doses of the prodrug, selected based on the results of the pharmacokinetic analysis and the efficacy and cardiovascular studies conducted above. The same study design will be applied to the DRF study in beagle dogs (two males and two females per group for the main study and two males and two females per group for the TK analysis). In-life procedures (mortality / cageside observations, clinical cageside observations, body weight, food consumption, ophthalmology), clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), bioanalytical and toxicokinetic evaluations, and terminal necropsy (gross findings) will be evaluated for all animals according to standard procedures, statistical analysis, and in line with FDA guidance. Results will inform dose selection for all in vivo IND studies.

[0148] 28-Day Toxicity Study in Rats and Dogs: The purpose of this study was to determine the potential toxicity of the prodrug when administered weekly for 4 weeks. The 4-week study, in which the prodrug was administered by oral gavage to rats and dogs with a 14-day recovery period, was conducted according to standard protocols similar to those used in the parent methylone study. Male and female rats were divided into four groups (3 dose levels + vehicle) (10 males and 10 females per group in the main study, and 5 males and 5 females per group in the recovery study), along with corresponding satellite cohorts for TK analysis (3 males and 3 females per group in the vehicle study, and 9 males and 9 females per group in the drug-treated study). The prodrug was administered by oral gavage on days 1, 8, 15, and 22, as in the parent methylone study. A similar experimental design was used in a 28-day study in beagle dogs (4 males and 4 females per group, 2 males and 2 females per group). All procedures were performed under GLP conditions. In-life procedures (mortality / cageside observations, clinical cageside observations, detailed clinical observations, body weights, food consumption, ophthalmology), clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), bioanalytical and toxicokinetic evaluations, and terminal necropsy (tissue collection, organ weights, histopathology, microscopic evaluation) will be evaluated for all animals (main study and recovery) according to standard procedures, statistical analyses, and in line with FDA guidance.

[0149] Ames Test (Bacterial Reverse Mutation Test): The purpose of this test is to evaluate the mutagenic potential of prodrugs to induce reverse mutations in the histidine operon of Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and the tryptophan operon of Escherichia coli strain WP2 uvrA. Prodrugs, appropriate positive controls (ICR, 2NF, SA, NQNO, 2AA), and negative controls (vehicle) are run in triplicate in the presence and absence of metabolic activation mixture S9. In the absence of toxicity or solubility limitations, standard test substance concentrations are 1.0, 5.0, 10, 50, 500, 1000, and 5000 μg / plate. After a 2-day incubation period, plates are evaluated for test substance precipitation and background thinning. The number of revertant colonies is counted and recorded. A test substance is considered positive if the mean number of revertant colonies per concentration increases with increasing test substance concentration and is at least 2-3 times the background frequency in the vehicle control.

[0150] Rat Micronucleus Test: The objective is to determine the potential genotoxicity of the prodrug when administered orally via gavage to rats for 2 days. A dose-ranging study (DRF) will determine tolerability to determine dose levels for definitive testing. The DRF will evaluate tolerability in 3 groups of rats (N=3 per group) treated with 3 doses of the prodrug. In this study, 5 groups of rats (N=5 per group) will be treated with vehicle or 4 doses of the prodrug (based on the results of the micronucleus DRF) once daily for 2 days via oral gavage. Detailed cageside and clinical observations will be conducted pre-dose, post-dose, and daily until 48 hours after the end of dosing. Micronucleus assessment will be performed by peripheral blood flow cytometry using standard protocols. Criteria for a positive response: (1) a statistically significant increase (p≦0.05) in % micronuclei in reticulocytes (MN-RET) in at least one treatment group compared to the negative control group; and (2) the increase is dose-dependent (p≦0.05); and (3) the increase is outside the 95% control interval of the historical negative control data. Criteria for a negative response: (1) no treatment group shows a statistically significant increase in %MN-RET compared to the concurrent negative control; and (2) no dose-dependent increase in %MN-RET; and (3) all results are within the 95% control interval of the historical negative control data; and (4) bone marrow exposure to the test substance is demonstrated to occur.

[0151] Chromosome Aberration (In Vitro Micronucleus) Test: This test evaluates the ability of test substances to break chromosomes and disrupt normal mitotic cell division. The purpose of this test is to evaluate the potential of prodrugs to induce micronuclei in TK6 cells using short- and long-term treatments, with and without an exogenous metabolic activation system. Prodrugs, vehicle controls, or appropriate positive controls (cyclophosphamide monohydrate; mitomycin C; vinblastine sulfate) are evaluated using standard procedures. Target concentrations for the DRF test are 0.977, 1.95, 3.91, 7.81, 15.6, 31.3, 62.5, 125, 250, and 500 μg / mL. All cultures are visually evaluated for signs of cytotoxicity, pH change, and precipitation at the time of dosing, washing, and before harvesting. In the final test, monocultures are treated with vehicle, positive control, and the six highest concentrations of test substance determined by the DRF. The criteria for a positive response are: (1) at least one of the test concentrations shows a statistically significant increase compared to the concurrent negative control, (2) the increase is dose-dependent, and (3) any of the results are outside the 95% control limits of the historical negative control distribution.

[0152] hERG assay: The purpose of this test is to measure the activity of prodrugs in the hERG (human ether-a-go-go-related gene) channel current (I Kr The present study investigated the in vitro effects of hERG on the human ventricular rapid delayed rectifier current (I , a surrogate for the rapidly activating delayed rectifier cardiac potassium current). Kr ) is responsible for Kr This channel was chosen for evaluation because its inhibition is the most common cause of cardiac action potential prolongation by non-cardiac drugs. Prolongation of action potential duration leads to QT interval prolongation and is associated with Torsade de Pointes (TdP), a dangerous ventricular arrhythmia. In this study, the endogenous I KrThe hERG potassium channel is expressed in a non-human embryonic kidney (HEK-293) cell line. The concentration-response relationship of the prodrug's effect on hERG potassium channel currents is assessed at near-physiological temperatures (35-37°C). The percent inhibition at each concentration in the test group is compared with the vehicle control group using one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test. Significant inhibition is defined at a p<0.05 level.

[0153] Core Battery of Safety Pharmacology Studies: Canine Cardiovascular (CV) Study: The objective of this study is to evaluate the potential CV effects of the prodrug in conscious, freely moving beagle dogs following a single dose administered by oral gavage at each dose level using a Latin square design. Four groups (four male dogs per group) will receive three different doses of the prodrug or a vehicle control. Hemodynamic endpoints, temperature, and electrocardiogram (ECG) will be continuously monitored using implanted telemetry devices from at least two hours prior to dosing until at least 24 hours post-dose. Interpretation of results will be based on established safety thresholds per FDA guidance.

[0154] Rat Respiratory Study: The purpose of this study is to evaluate the potential acute respiratory effects of the prodrug in rats. Four groups of male rats (N=8 per group) are studied. Parameters evaluated include respiratory rate, tidal volume, and minute ventilation. Animals are placed in the respiratory monitoring chamber for at least 2.5 hours prior to dosing to allow for acclimation and pre-dose data collection. After at least 2.5 hours in the chamber, animals are briefly removed from the chamber and dosed with prodrug (3 dose levels) or vehicle. Immediately after dosing, animals are returned to the chamber, and respiratory monitoring continues for at least 6 hours. Data are collected continuously, recorded at 1-minute intervals, and reported at 15-minute intervals for the duration of the study. Treatment effects over time are assessed using repeated measures analysis of covariance.

[0155] Rat Central Nervous System Study: The purpose of this study is to evaluate the potential acute neurobehavioral effects of the prodrug. Four groups of male Sprague-Dawley rats (N=8 per group) are treated with either three doses of the prodrug or vehicle. Neurobehavioral assessments (activity, autonomic, excitability, neuromuscular, physiological, and sensorimotor) are performed pre-dose (day -1) and approximately 1.5, 6, and 24 hours post-dose. Each animal is observed for 2 minutes in an opaque open-field observation box.

[0156] Those skilled in the art will appreciate that changes can be made to the above-described embodiments without departing from the broad inventive concept thereof. It is therefore intended that the invention not be limited to the particular embodiments disclosed, but that modifications be included within the spirit and scope of the invention as defined by the appended claims.

Claims

1. Formula (I): 【Chemical 1】 (In the formula, Y is —C(O)— or —CH ２ - and; X is (a) an amino acid or peptide; (b)-C(O)R ３ 、 (c)-C(O)OR ３ 、 (d)-C(O)OCH(R) ４ )(O)R ５ 、 (e)-CH ２ OC(O)R ３ 、 (f)-P(O)(OH) ２ 、 (g)-CH ２ OP(O)(OH) ２ 、 (h)C(O)(CH ２ ) ｎ Z ａ R ５ 、 【Chemistry 2】 and independently selected from the group consisting of: n is 3 or 4; R １ and R ２ are each independently -C １－６ Alkyl or -C ３－６ is cycloalkyl; R ３ is -C １－６ Alkyl, C ３－６ cycloalkyl, —C １－６ haloalkyl, aryl, heteroaryl, 【Chemistry 3】 selected from the group consisting of: R ４ , R ７ , R ８ , R ９ and R １０ are each independently H, —C １－６ Alkyl or C ３－６ is cycloalkyl; R ５ is -C(O)R ３ , -C(O)OR ３ , -P(O)OR １１ (OR １２ ), amino acids, and peptides; Z ａ and Z ｂ are each independently O or NR ４ and Z ｃ is OC(O)R ３ or OP(O)(OR ４ ) ２ Selected from: R ６ is H, -C １－６ Alkyl, —C ３－６ Cycloalkyl, alkoxy, amino, nitro, halo, cyano, —OH and CF ３ selected from the group consisting of: R １１ and R １２ are each independently H, —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ haloalkyl, aryl, or heteroaryl; １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ substituted with haloalkyl, aryl, or heteroaryl; Y is -CH ２ -, X is an amino acid, a peptide, or -P(O)(OH) ２ or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ and each independently is methyl or ethyl.

3. R ４ is H or methyl.

4. 2. The compound of claim 1, wherein Y is —C(O)— and X is an amino acid.

5. X is 【Chemistry 4】 2. The compound of claim 1, wherein:

6. Formula (III): 【Chemistry 5】 (In the formula, n is 3 or 4; X is (a) an amino acid or peptide; (b)-C(O)R ３ 、 (c)-C(O)OR ３ 、 (d)-C(O)OCH(R) ４ )(O)R ５ 、 (e)-CH ２ OC(O)R ３ 、 (f)-P(O)(OH) ２ 、 (g)-CH ２ OP(O)(OH) ２ 、 (h)C(O)(CH ２ ) ｎ Z ａ R ５ 、 【Chemistry 6】 are independently selected from the group consisting of: R １ and R ２ are each independently -C １－６ Alkyl or -C ３－６ is cycloalkyl; R ３ is -C １－６ Alkyl, C ３－６ cycloalkyl, —C １－６ haloalkyl, aryl, heteroaryl, 【Chemistry 7】 selected from the group consisting of: R ４ , R ７ , R ８ , R ９ and R １０ are each independently H, —C １－６ Alkyl or C ３－６ is cycloalkyl; R ５ is -C(O)R ３ , -C(O)OR ３ , -P(O)OR １１ (OR １２ ), amino acids, and peptides; Z ａ and Z ｂ are each independently O or NR ４ and Z ｃ is OC(O)R ３ or OP(O)(OR ４ ) ２ Selected from: R ６ is H, -C １－６ Alkyl, —C ３－６ Cycloalkyl, alkoxy, amino, nitro, halo, cyano, —OH and CF ３ selected from the group consisting of: R １１ and R １２ are each independently H, —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ haloalkyl, aryl, or heteroaryl; １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ substituted with haloalkyl, aryl or heteroaryl) or a pharmaceutically acceptable salt thereof.

7. R １ and R ２ are each independently methyl or ethyl. The compound of claim 6.

8. R ４ is H or methyl.

9. 7. The compound of claim 6, wherein X is an amino acid.

10. X is 【Chemistry 8】 7. The compound of claim 6, wherein:

11. The compound of claim 6, wherein the compound is selected from the group consisting of compounds 1 to 402 in Tables 1, 2 and 3.

12. Formula (IV): 【Chemistry 9】 (In the formula, X is (a)-C(O)R ３ 、 (b)-C(O)OR ３ 、 (c)-C(O)OCH(R) ４ )(O)R ５ 、 (d)-CH ２ OC(O)R ３ 、 (e)-CH ２ OP(O)(OH) ２ 、 (f)C(O)(CH ２ ) ｎ Z ａ R ５ 、 【Chemistry 10】 independently selected from the group consisting of: n is 3 or 4; R １ and R ２ are each independently -C １－６ Alkyl or -C ３－６ is cycloalkyl; R ３ is -C １－６ Alkyl, C ３－６ cycloalkyl, —C １－６ Haloalkyl, aryl, heteroaryl 【Chemistry 11】 selected from the group consisting of: R ４ , R ７ , R ８ , R ９ and R １０ are each independently H, —C １－６ Alkyl or C ３－６ is cycloalkyl; R ５ is -C(O)R ３ , -C(O)OR ３ , -P(O)OR １１ (OR １２ ), amino acids, and peptides; Z ａ and Z ｂ are each independently O or NR ４ and Z ｃ is OC(O)R ３ or OP(O)(OR ４ ) ２ Selected from: R ６ is H, -C １－６ Alkyl, —C ３－６ Cycloalkyl, alkoxy, amino, nitro, halo, cyano, —OH and CF ３ selected from the group consisting of: R １１ and R １２ are each independently H, —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ haloalkyl, aryl, or heteroaryl; １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ substituted with haloalkyl, aryl or heteroaryl) or a pharmaceutically acceptable salt thereof.

13. R １ and R ２ 13. The compound of claim 12, wherein each is independently methyl or ethyl.

14. R ４ is H or methyl.

15. X is 【Chemistry 12】 13. The compound of claim 12, wherein:

16. Formula (V): 【Chemistry 13】 (In the formula, X is (a) an amino acid or peptide; (b)-C(O)R ３ 、 (c)-C(O)OR ３ 、 (d)-C(O)OCH(R) ４ )(O)R ５ 、 (e)-CH ２ OC(O)R ３ 、 (f)-P(O)(OH) ２ 、 (g)-CH ２ OP(O)(OH) ２ 、 (h)C(O)(CH ２ ) ｎ Z ａ R ５ 、 【Chemistry 14】 independently selected from the group consisting of: n is 3 or 4; R ３ is -C １－６ Alkyl, C ３－６ cycloalkyl, —C １－６ Haloalkyl, aryl, heteroaryl 【Chemistry 15】 selected from the group consisting of: R ４ , R ７ , R ８ , R ９ and R １０ are each independently H, —C １－６ Alkyl or C ３－６ is cycloalkyl; R ５ is -C １－６ Alkyl and C ３－６ cycloalkyl, —C(O)R ３ , -C(O)OR ３ , -P(O)OR １１ (OR １２ ), amino acids, and peptides; Z ａ and Z ｂ are each independently O or NR ４ and Z ｃ is OC(O)R ３ or OP(O)(OR ４ ) ２ Selected from: R ６ is H, -C １－６ Alkyl, —C ３－６ Cycloalkyl, alkoxy, amino, nitro, halo, cyano, —OH and CF ３ selected from the group consisting of: R １１ and R １２ are each independently H, —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ haloalkyl, aryl, or heteroaryl; １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ substituted with haloalkyl, aryl or heteroaryl) or a pharmaceutically acceptable salt thereof.

17. R ４ is H or methyl.

18. 17. The compound of claim 16, wherein X is an amino acid.

19. Formula (50): 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

20. Formula (VI): 【Chemistry 17】 (In the formula, X is (a)-C(O)R ３ 、 (b)-C(O)OR ３ 、 (c)-C(O)OCH(R) ４ )(O)R ５ 、 (d)-CH ２ OC(O)R ３ 、 (e)-CH ２ OP(O)(OH) ２ 、 (f)C(O)(CH ２ ) ｎ Z ａ R ５ 、 【Chemistry 18】 independently selected from the group consisting of: n is 3 or 4; R ３ is -C １－６ Alkyl, C ３－６ cycloalkyl, —C １－６ haloalkyl, aryl, heteroaryl, 【Chemistry 19】 selected from the group consisting of: R ４ , R ７ , R ８ , R ９ and R １０ are each independently H, —C １－６ Alkyl or C ３－６ is cycloalkyl; R ５ is -C(O)R ３ , -C(O)OR ３ , -P(O)OR １１ (OR １２ ), amino acids, and peptides; Z ａ and Z ｂ are each independently O or NR ４ and Z ｃ is OC(O)R ３ or OP(O)(OR ４ ) ２ Selected from: R ６ is H, -C １－６ Alkyl, —C ３－６ Cycloalkyl, alkoxy, amino, nitro, halo, cyano, —OH and CF ３ selected from the group consisting of: R １１ and R １２ are each independently H, —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ haloalkyl, aryl, or heteroaryl; １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ The haloalkyl, aryl, or heteroaryl may be unsubstituted or may contain one or more —C １－６ Alkyl, —C １－６ Heteroalkyl, —C ３－６ cycloalkyl, —C １－６ substituted with haloalkyl, aryl or heteroaryl) or a pharmaceutically acceptable salt thereof.

21. R ４ is H or methyl.

22. X is 【Chemistry 20】 21. The compound of claim 20, wherein:

23. 21. The compound of claim 20, wherein the compound is selected from the group consisting of compounds 403-511 in Table 4.

24. A pharmaceutical composition comprising the compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

25. A method of treatment comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

26. 26. The method of claim 25, wherein the treatment is for post-traumatic stress disorder (PTSD), anxiety disorder, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, cluster headache, cancer-related conditions, loss of motivation, burnout, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea, or vomiting.

27. 26. The method of claim 25, wherein the treatment is for post-traumatic stress disorder (PTSD).

28. 26. The method of claim 25, wherein the treatment is for an anxiety disorder.

29. 26. The method of claim 25, wherein the treatment is for depression.

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