Phenylethylamine and cathinone precursors

Abstract

The disclosed subject matter relates generally to phenylethylamine or cathinone covalently bound to a chemical moiety in the form of a prodrug. The techniques described herein allow for slow / sustained / controlled delivery of the maternal phenylethylamine or cathinone into the blood system when administered, in particular oral administration, which increases the duration of therapeutic effect, ease of application, patient compliance, and / or a combination of these characteristics. Furthermore, the techniques allow for the gradual release of the parent phenylethylamine or cathinone over an extended period of time, thereby eliminating a rise in drug levels, reducing cardiovascular stress, the likelihood of addiction / abuse, and / or other common stimulant side effects associated with psychoactive compounds.

Description

Technical Field

[0001] The disclosed subject matter generally relates to phenethylamines or cathinones covalently bound to a chemical moiety in prodrug form. The techniques described herein allow for the slow / continuous / controlled delivery of the parent phenethylamine or cathinone into the bloodstream when administered, particularly orally, in a manner that increases the duration of the therapeutic effect, ease of application, patient compliance, and / or a combination of these features. Additionally, the techniques allow for the gradual release of the parent phenethylamine or cathinone over an extended period of time, thereby eliminating drug level spikes and reducing cardiovascular stress, likelihood of addiction / abuse, and / or other common stimulant side effects associated with psychoactive compounds. Background Art

[0002] Methylone (3,4-methylenedioxy-N-methylcathinone) belongs to a group of psychoactive synthetic cathinones known as β-ketophenethylamines. It is a synthetic analogue of MDMA, differing in that there is a ketone at the benzyl position. Methylone was first synthesized in 1996 as an antidepressant and antiparkinsonian agent and is an illicit street drug. It induces psycho-stimulant and empathogenic effects similar to MDMA, and its mechanism of action involves the monoaminergic system.

[0003] MDMA (3,4-methylenedioxymethamphetamine), commonly known as ecstasy, is a psychoactive drug primarily used for recreational purposes. MDMA acts mainly by increasing the activity of the neurotransmitters serotonin, dopamine, and norepinephrine in a part of the brain. In 2017, the US Food and Drug Administration (FDA) approved a limited study of MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), and some preliminary evidence suggests that MDMA may enhance the effects of psychotherapy.

[0004] Although structurally very similar to MDMA, methylone has different pharmacological and functional properties. In a clinical case series of 21 individuals, methylone showed improvement in the symptoms of PTSD in 81% of the patients. Currently, the only drugs approved for the treatment of PTSD are the serotonergic antidepressants sertraline and paroxetine, so drugs showing similar antidepressant activity should improve PTSD symptoms. Methylone may have the strongest effects in preclinical screening for classical antidepressant activity (forced swim test). Methylone also showed benefits in a mouse model of PTSD, improving fear extinction recall after conditioned fear, which is consistent with the treatment response in this test. Together with the results of the clinical case series, these data strongly support the possibility of a clinically effective treatment for PTSD.

[0005] Users of methylone reported a rapid onset of 15 - 30 minutes and a short duration of 2 - 3.5 hours. In a prospective naturalistic observational study comparing self - administration of methylone and MDMA in healthy volunteers (Lourdes et al. (2021) Biology 10:788), a significant increase in both systolic and diastolic blood pressure was observed for both drugs, while only methylone was associated with an increase in heart rate. Subjects reported stimulant - like effects starting 1 hour after dosing, and most of these effects had almost disappeared 4 hours later.

[0006] Analysis of the parent and metabolites in human and rat urine samples showed that the metabolic pathways of methylone and MDMA were similar. They are both extensively biotransformed by cytochrome p450 isoform 2D6, which is consistent with their rapid kinetics and short duration of action. In a rat PK / PD study, methylone showed rapid kinetics, with a T Max of 15 min and a t 1 / 2 of 1 h (Elmore et al. (2017) Neuropsychopharmacology 42:649). In the same study, it was shown that the plasma concentration of methylone was associated with locomotor activation.

[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 climb in drug levels. Examples of such prodrugs can be found in US 7,105,486 B2 and WO2022 / 053696, in which the amino 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, called dextroamphetamine, showed a longer duration of action of 10 - 12 hours, compared to 3 - 6 hours for the unconjugated form of d - amphetamine. It was reported that the toxicity / tolerance of dextroamphetamine was more favorable compared to the unconjugated form of d - amphetamine, which can be attributed to, but is not limited to, a significant reduction in the pharmacological activity of the prodrug due to structural modification, a natural gating mechanism at the hydrolysis site limiting the release of active amphetamine from the prodrug, and a lack of brain permeability of the prodrug.

[0008] Amino groups (such as those present in methylone or MDMA) can be derivatized into different conjugated prodrugs, characterized by the newly formed functional groups and their specific processes of converting to release the active drug. Examples of conjugated amine prodrugs, such as amide prodrugs, peptide or polypeptide prodrugs, carbamate prodrugs, acyloxyalkoxycarbonyl prodrugs, acyloxymethyl prodrugs, phosphoramide prodrugs, and phosphonyloxyalkyl prodrugs, can be found in Rautio et al. (2018) Nat. Rev. Drug Discov. 17:559.

[0009] Accordingly, it is an object of the present invention to provide a psychoactive agent that exhibits favorable pharmacokinetic and / or pharmacodynamic characteristics for the treatment of CNS disorders such as PTSD.

[0010] Another object of the present invention is to provide a psychoactive agent that exhibits favorable toxicity and / or tolerance characteristics for CNS disorders such as PTSD.

[0011] Another object of the present invention is to provide a phenethylamine prodrug (such as MDMA) or a cathinone prodrug (such as methylethcathinone) that can be hydrolyzed and directly converted to the parent compound in its therapeutically active form after absorption. SUMMARY OF THE INVENTION

[0012] The present invention relates to phenethylamine or cathinone precursor compounds in prodrug form. The present invention also provides a pharmaceutical composition comprising an effective amount of a phenethylamine or cathinone precursor and a pharmaceutically acceptable carrier. The present invention also provides a method of treatment in a mammal, such as post-traumatic stress disorder (PTSD), anxiety disorder, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, cluster headache, conditions associated with cancer, hypomotility, burn-out, bore-out, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorder, nausea or vomiting, by administering an effective amount of a phenethylamine or cathinone precursor.

[0013] As shown in the accompanying drawings, the features and advantages of the subject matter of the present invention will become more apparent from the following detailed description of the selected embodiments. It should be recognized that the subject matter disclosed and claimed is capable of modification in various aspects, all of which do not depart from the scope of the claims. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive, and the full scope of the subject matter is set forth in the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The following drawings form a part of this specification and are included to further illustrate certain aspects of the present disclosure. The subject matter of the present invention may be better understood by reference to one or more of these drawings in conjunction with the detailed description of the specific embodiments presented herein.

[0015] Figure 1 A - 1D: Methylethcathinone improves fear extinction recall in a mouse model of PTSD. ( Figure 1 A) Schematic of the experimental design. A single CS-US (tone - shock) pairing was conducted on Day 1, followed by 6 CS presentations in a novel context (Context B). Thirty minutes prior to extinction training on Day 2, methylethcathinone or saline vehicle was injected. On Day 3, the time spent freezing to the CS was quantified. ( Figure 1B) Compared with saline, methyl ketone significantly reduced the immobility time during the first cue (extinction recall) on day 3 (t (26) = 2.350, p < 0.05).( Figure 1 C) Shows the immobility time during the period before each of the 6 cues on day 3 (to control for motor effects). There was a significant cue x drug interaction (F (5,130) = 2.409, p < 0.05).( Figure 1 D) No motor changes were observed on day 3 (t (26) = 1.073, p > 0.05). Methyl ketone group, N = 12 (30 mg / kg, IP, orange diamond), and saline control group, N = 16 (black square). *p < 0.05. DETAILED DESCRIPTION

[0016] The present invention provides phenethylamine or cathinone prodrugs that exhibit favorable pharmacokinetic properties and beneficial side effect profiles, making the compounds provided herein particularly suitable for therapeutic use.

[0017] In one aspect, the present invention provides a compound represented by formula (I):

[0018]

[0019] or a pharmaceutically acceptable salt thereof, wherein:

[0020] Y is -C(O)- or -CH 2 -;

[0021] X is independently selected from the group consisting of:

[0022] (a) an amino acid or a peptide;

[0023] (b) -C(O)R 3 ;

[0024] (c) -C(O)OR 3 ;

[0025] (d) -C(O)OCH(R 4 )OR 5 ;

[0026] (e) -CH 2 OC(O)R 3 ;

[0027] (f) -P(O)(OH) 2 ;

[0028] (g) -CH 2 OP(O)(OH) 2 ;

[0029] (h)-C(O)(CH 2 ) n Z a R 5 ;

[0030] (i)

[0031] (j)

[0032] (k) and

[0033] (l)

[0034] wherein:

[0035] n is 3 or 4;

[0036] R 1 and R 2 are each independently -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0037] R 3 is selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0038]

[0039] R 4 , R 7 , R 8 , R 9 and R 10 are each independently H, -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0040] R 5 is selected from the group consisting of: -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids and peptides;

[0041] Z a and Z b are each independently O or NR 4 ;

[0042] Z c is selected from: OC(O)R 3 or OP(O)(OR 4) 2 ;

[0043] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ;

[0044] 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, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

[0045] 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 NO 2 or N 3 . 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, when Y is -CH 2 -, X is not an amino acid, a peptide or a -P(O)(OH) 2 group.

[0046] According to another embodiment, the compound of formula (I) is a compound having the structure of formula (III):

[0047]

[0048] or a pharmaceutically acceptable salt thereof, wherein:

[0049] X is independently selected from the group consisting of:

[0050] (a) an amino acid or a peptide;

[0051] (b) -C(O)R 3 ;

[0052] (c) -C(O)OR 3 ;

[0053] (d) -C(O)OCH(R 4 )OR 5 ;

[0054] (e) -CH 2 OC(O)R 3 ;

[0055] (f) -P(O)(OH) 2 ;

[0056] (g) -CH 2 OP(O)(OH) 2 ;

[0057] (h) -C(O)(CH 2 ) n Z a R 5 ;

[0058] (i)

[0059] (j)

[0060] (k) and

[0061] (l)

[0062] wherein:

[0063] n is 3 or 4;

[0064] R 1 and R 2 are each independently -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0065] R 3Selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0066]

[0067] R 4 、R 7 、R 8 、R 9 and R 10 are each independently H, -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0068] R 5 is selected from the group consisting of: -C(O)R 3 、-C(O)OR 3 、-P(O)OR 11 (OR 12 )、amino acids and peptides;

[0069] Z a and Z b are each independently O or NR 4 ;

[0070] Z c is selected from: OC(O)R 3 or OP(O)(OR 4 ) 2 ;

[0071] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ;

[0072] 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, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted with one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C1-6 Substituted with a haloalkyl, aryl or heteroaryl group.

[0073] 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 NO 2 or N 3 . 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 of Tables 1, 2 and 3 below.

[0074] According to some embodiments, the compound of formula (I) is a compound having the structure of formula (IV):

[0075]

[0076] or a pharmaceutically acceptable salt thereof, wherein:

[0077] X is independently selected from the group consisting of:

[0078] (a) -C(O)R 3 ,

[0079] (b) -C(O)OR 3 ,

[0080] (c) -C(O)OCH(R 4 )OR 5 ,

[0081] (d) -CH 2 OC(O)R 3 ,

[0082] (e) -CH 2 OP(O)(OH) 2 ,

[0083] (f)-C(O)(CH 2 ) n Z a R 5 ,

[0084] (g)

[0085] (h)

[0086] (i) and

[0087] (j)

[0088] wherein:

[0089] n is 3 or 4;

[0090] R 1 and R 2 are each independently -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0091] R 3 is selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0092]

[0093] R 4 , R 7 , R 8 , R 9 and R 10 are each independently H, -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0094] R 5 is selected from the group consisting of: -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids, and peptides;

[0095] Z a and Z b are each independently O or NR 4 ;

[0096] Z c is selected from: OC(O)R 3 or OP(O)(OR 4) 2 ;

[0097] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ;

[0098] 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, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

[0099] 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 NO 2 or N 3 . 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.

[0100] According to some embodiments, the compound of formula (I) is a compound having the structure of formula (V):

[0101]

[0102] or a pharmaceutically acceptable salt thereof, wherein:

[0103] X is independently selected from the group consisting of:

[0104] (a) an amino acid or a peptide;

[0105] (b) -C(O)R 3 ;

[0106] (c) -C(O)OR 3 ;

[0107] (d) -C(O)OCH(R 4 )OR 5 ;

[0108] (e) -CH 2 OC(O)R 3 ;

[0109] (f) -P(O)(OH) 2 ;

[0110] (g) -CH 2 OP(O)(OH) 2 ;

[0111] (h) -C(O)(CH 2 ) n Z a R 5 ;

[0112] (i)

[0113] (j)

[0114] (k) and

[0115] (l)

[0116] wherein:

[0117] n is 3 or 4;

[0118] R 3 is selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0119]

[0120] R 4 、R 7 、R 8, R 9 and R 10 are each independently H, –C 1-6 alkyl or –C 3-6 cycloalkyl;

[0121] R 5 is selected from the group consisting of: -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids, and peptides;

[0122] Z a and Z b are each independently O or NR 4 ;

[0123] Z c is selected from: OC(O)R 3 or OP(O)(OR 4 ) 2 ;

[0124] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH, and CF 3 ;

[0125] 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, where -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl.

[0126] 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 N 3 . 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.

[0127] According to some embodiments, the compound of formula (I) is a compound having the structure of formula (VI):

[0128]

[0129] or a pharmaceutically acceptable salt thereof, wherein:

[0130] X is independently selected from the group consisting of:

[0131] (a) -C(O)R 3 ,

[0132] (b) -C(O)OR 3 ,

[0133] (c) -C(O)OCH(R 4 )OR 5 ,

[0134] (d) -CH 2 OC(O)R 3 ,

[0135] (e) -CH 2 OP(O)(OH) 2 ,

[0136] (f) -C(O)(CH 2 ) n Z a R 5 ,

[0137] (g)

[0138] (h)

[0139] (i) and

[0140] (j)

[0141] wherein:

[0142] n is 3 or 4;

[0143] R 3 is selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0144]

[0145] R 4 、R 7 、R 8 、R 9 and R 10 are each independently H, -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0146] R 5 is selected from the group consisting of: -C(O)R 3 、-C(O)OR 3 、-P(O)OR 11 (OR 12 )、amino acids and peptides;

[0147] Z a and Z b are each independently O or NR 4 ;

[0148] Z c is selected from: OC(O)R 3 or OP(O)(OR 4 ) 2 ;

[0149] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ;

[0150] 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, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6The haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

[0151] 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 NO 2 or N 3 . 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, the compound is selected from the group consisting of compounds 403 - 511 of Table 4 below.

[0152] For some embodiments of the foregoing compounds, the amino acid, dipeptide, tripeptide or polypeptide may comprise 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.

[0153] Without being bound by theory, prodrugs of cathinone (such as methyl ketones) or prodrugs of phenethylamine (such as MDMA) are thought to act as a system for the controlled systemic release of the principal active ingredient of the parent molecule through in vivo bioactivation. This bioactivation can be achieved by enzymatic or chemical cleavage of a covalently bound promoiety, or by a combination of enzymatic and chemical cleavage of a covalently bound promoiety.

[0154] As used herein, "alkyl" and other groups having the prefix "alk" (such as alkoxy, alkanoyl, alkenyl, alkynyl, etc.) refer to carbon chains, which can be straight-chain, branched-chain or a combination thereof. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, etc. "Alkenyl", "alkynyl" and other similar terms include carbon chains containing at least one unsaturated C-C bond.

[0155] The term "haloalkyl" refers to an alkyl group to which 1-9 halo groups are attached. Examples include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CHFCH 2 F, -CF 2 CH 2 F, -CF 2 CHF 2 and -CF 2 CF 3 .

[0156] The term "cycloalkyl" means a carbocyclic ring that does not contain heteroatoms and includes monocyclic, bicyclic and tricyclic saturated carbocyclic rings, as well as fused ring systems. Such fused ring systems can include a ring that is partially or completely unsaturated (such as a benzene ring) to form a fused ring system (such as a benzo-fused carbocyclic ring). Cycloalkyl includes fused ring systems, such as spiro-fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl, adamantyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthyl, etc. Similarly, "cycloalkenyl" means a carbocyclic ring that does not contain heteroatoms and contains at least one non-aromatic C-C double bond, and includes monocyclic, bicyclic and tricyclic partially saturated carbocyclic rings, as well as benzo-fused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, etc.

[0157] Unless otherwise specifically stated, the term "cycloalkoxy" includes a cycloalkyl group attached to an oxygen-bonded atom.

[0158] Unless otherwise specifically stated, the term "alkoxy" includes an alkyl group attached to an oxygen-bonded atom.

[0159] Unless otherwise specifically stated, the term "aryl" includes polycyclic systems as well as monocyclic systems, such as phenyl or naphthyl.

[0160] Unless otherwise specifically stated, the term "aryloxy" includes polycyclic systems as well as monocyclic systems, such as phenyl or naphthyl attached to the attachment site through an oxygen-bonded atom.

[0161] The term "C 0 -C 6"Alkyl" includes alkyl groups containing 6, 5, 4, 3, 2, 1 carbon atoms or no carbon atoms. When the alkyl group is a terminal moiety, the alkyl group with no carbon atoms is a hydrogen atom substituent. When the alkyl group is a bridging moiety, the alkyl group with no carbon atoms is a direct bond.

[0162] Unless otherwise specifically stated, the term "hetero" 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) in the ring. The heteroatoms replace ring carbon atoms. Thus, for example, heterocyclic C 5 Alkyl is a five-membered ring containing 5 carbon atoms to no carbon atoms. Examples of heteroaryl include pyridyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

[0163] Unless otherwise specifically stated, the term "heteroaryloxy" describes a heteroaryl group attached to a point of attachment through an oxygen atom linker. Heteroaryl(C 1-6 )alkyl examples include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazoylethyl, isoxazolylmethyl, thiazolylmethyl, thiazoylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazoylethyl, thiadiazolylmethyl, thiadiazoylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazoylethyl, pyridylmethyl, pyridylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl. Heterocyclic C 3-7 Examples of alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl, tetrahydrofuryl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one and thiomorpholinyl.

[0164] The term "N-heterocyclic C 4-7 alkyl" describes a non-aromatic heterocyclic compound having 3 - 6 carbon atoms and one nitrogen atom forming the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl and perhydroazepinyl. Aryl(C 1-6 )alkyl examples include, for example, phenyl(C 1-6 )alkyl and naphthyl(C 1-6 )alkyl. Heterocyclic C 3-6 alkylcarbonyl(C 1-6 )alkyl examples include, for example, azetidinylcarbonyl(C 1-6 )alkyl, pyrrolidinylcarbonyl(C 1-6) Alkyl, piperidinylcarbonyl (C 1-6 ) Alkyl, piperazinylcarbonyl (C 1-6 ) Alkyl, morpholinylcarbonyl (C 1-6 ) Alkyl and thiomorpholinylcarbonyl (C 1-6 ) Alkyl.

[0165] Unless otherwise specifically stated, "amine" includes primary, secondary, and tertiary amines.

[0166] Unless otherwise stated, the term "carbamoyl" includes -NHC(O)OC 1 -C 4 Alkyl and -OC(O)NHC 1 -C 4 Alkyl.

[0167] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms.

[0168] The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl can represent pentafluorophenyl or a phenyl ring. Additionally, substitution can occur at any group. For example, substituted aryl(C 1-6 ) Alkyl includes substitution on the aryl and substitution on the alkyl.

[0169] The "oxide" of the term heteroaryl is used in the generally well-known chemical sense and includes, for example, the N-oxide of a nitrogen heteroatom.

[0170] The compounds described herein contain one or more double bonds and can thus give rise to cis / trans isomers as well as other conformational isomers. The present invention includes all such possible isomers and mixtures of such isomers.

[0171] The compounds described herein can contain one or more asymmetric centers and can thus give rise to diastereoisomers and optical isomers. The present invention includes all such possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. The above formula (I) is shown with no defined stereochemistry at certain positions. The present invention includes all stereoisomers of formula (I) and their pharmaceutically acceptable salts. Additionally, mixtures of stereoisomers and isolated specific stereoisomers are included.

[0172] During the course of the synthetic procedures used to prepare such compounds, or in the racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be mixtures of stereoisomers.

[0173] In another aspect, the present invention provides 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.

[0174] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids or co-crystal formers. The crystalline forms can exist as salts, solvates, hydrates or inclusion compounds. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases (including inorganic bases and organic bases). Salts derived from such inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts (cupric and cuprous salts), iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts (manganic and manganous salts), potassium salts, sodium salts, zinc salts, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines (such as naturally occurring and synthetically substituted amines). Other pharmaceutically acceptable organic non-toxic bases or co-crystals that can form salts or co-crystals include ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, homatropine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0175] When the compound of the present invention is basic, its corresponding salt or co-crystal can be conveniently prepared from pharmaceutically acceptable non-toxic acids (including inorganic acids 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, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic 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.

[0176] According to some embodiments, a pharmaceutical composition can be prepared comprising a compound represented by formula (I) (or a pharmaceutically acceptable salt or co-crystal thereof) as an active ingredient and a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.

[0177] According to another embodiment, the pharmaceutical composition of the present invention can 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).

[0178] Dose levels of from about 0.0001 mg / kg to about 100 mg / kg 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 headache, conditions associated with cancer, hypomotility, burnout, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea or vomiting.

[0179] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the target being treated and the specific mode of administration. For example, a formulation intended for oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, formulated with a suitable and acceptable amount of "GRAS" material, which can vary from about 5% to about 95% of the total composition. Unit dosage forms will generally contain an active ingredient between about 0.001 mg and about 5000 mg, 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 therebetween.

[0180] Suitable pharmaceutical compositions as described herein include those that contain an effective amount of the active ingredient to achieve its intended purpose. Determination of the effective amount is entirely within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the present disclosure are effective over a wide range of doses. However, it is understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health, gender, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated.

[0181] The composition, shape, and type of the dosage forms provided herein will generally vary according to their use. For example, a dosage form used in the acute treatment of a disease may contain a greater amount of one or more active ingredients including those of formula (I) than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain a smaller amount of one or more active ingredients including those of formula (I) than an oral dosage form used to treat the same disease. These and other ways in which the specific dosage forms provided herein differ from one another will be readily understandable to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing, Easton, Pa (2000). In practice, the compounds of formula (I) or their pharmaceutically acceptable salts / cocrystal combinations of the present invention can be combined as the active ingredient in an essential mixture with pharmaceutical excipients, carriers, or diluents according to conventional pharmaceutical compounding techniques. The carrier can take many forms, depending on the form of the preparation required for administration, such as oral, mucosal (e.g., nasal, sublingual, vaginal, inhaled, cystic, rectal, ophthalmic, buccal, or otic), parenteral (including intravenous, intradermal, subcutaneous, bolus, intramuscular, or intraarterial), or topical (e.g., transdermal, percutaneous, eye drops, or other ophthalmic preparations). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration, such as capsules (with or without polymer coating, sustained release or enteric coated or modified for targeted delivery), sachets, or tablets (coated or uncoated or bilayer or sustained release or delayed release, including microencapsulated) or tablets containing spray-dried intermediates, each containing a predetermined amount of the active ingredient. In addition, the compositions can be presented as powders, granules, coated sustained release granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, water-in-oil emulsions, or oil-in-water liquid emulsions, liposomes, nanosuspensions. In addition to the above common dosage forms, the compounds of formula (I) or their pharmaceutically acceptable salts or cocrystals can also be administered by controlled release or modified release formulations and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Generally speaking, such methods include the step of combining the active ingredient with excipients or carriers that constitute one or more necessary ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier / excipient or a subdivided solid carrier / excipient or both. The product can then be conveniently formed into the desired appearance.

[0182] Accordingly, the pharmaceutical compositions of the present invention can comprise a pharmaceutically acceptable carrier / excipient and a compound of formula (I) or a pharmaceutically acceptable salt / cocrystal. The compound of formula (I) or its pharmaceutically acceptable salt / cocrystal can also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0183] The pharmaceutical carriers employed can, for example, form oral solid preparations such as powders, capsules, and tablets, including fillers such as talc, calcium carbonate, microcrystalline cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, and mixtures thereof; binders such as Kollidon; disintegrants such as sodium carboxymethylcellulose cross-linked, crospovidone, sodium starch glycolate, pregelatinized starch, gums, and other starches and mixtures thereof; lubricants such as calcium stearate, magnesium stearate, syloid silica gel, mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (such as peanut oil, sesame oil, corn oil, or soybean oil), ethyl oleate agar, or other lipid-formulated lubricants and mixtures thereof. Tablets and capsules are the preferred oral dosage units using solid pharmaceutical carriers due to ease of administration. Each solid oral dosage unit can be further coated with a specialized polymer so that the release of the contents of the dosage unit can be delayed or sustained. Formula (I) can be administered by delayed-release or sustained-release means or by delivery devices well known to those of ordinary skill in the art. Non-limiting examples of delayed-release or sustained-release include those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 5,059,595. Such dosage forms can be used to slowly release or control the release of one or more components using, for example, polymers such as hydroxypropylmethylcellulose, which are typically in the form of matrices such as gels, osmotic membranes, microemulsions, osmotic systems, liposomes, microspheres, or combinations thereof. Controlled-release formulations can be used to protect the dosage unit from exposure to the gastric environment; delay the release of the active ingredient to the lower gastrointestinal tract (such as the colon); or slow the release of the active ingredient so that the blood level of the drug can be reduced and the occurrence of side effects can be affected.

[0184] Examples of gaseous carriers include carbon dioxide and nitrogen.

[0185] In preparing oral liquid compositions for oral dosage forms, any convenient pharmaceutical medium can be employed. For example, water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. can be used to form oral liquid preparations such as suspensions, elixirs, and solutions.

[0186] Tablets containing the compositions of the present invention can be prepared by compressing or molding them, optionally together with one or more accessory ingredients or adjuvants.

[0187] Compressed tablets can be prepared by compressing an active ingredient in free-flowing form, such as a powder or granule, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of a powdery 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 active ingredient, and each cachet or capsule preferably contains from about 0.001 mg to about 5000 mg of active ingredient.

[0188] The pharmaceutical compositions of the present invention suitable for parenteral administration, including intravenous, intramuscular, subcutaneous, ophthalmic and intra-arterial, can be prepared as a solution or suspension of the active compound in injectable ingredients. The parenteral dosage forms are preferably sterile or capable of being sterilized before administration to the patient. Non-limiting examples of suitable vehicles include Water for Injection USP, Dextrose Injection, Sodium Chloride Injection and Lactated Ringer's Injection. Suitable surfactants, such as polysorbate 80, can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, ethanol, polypropylene glycol and mixtures thereof in non-aqueous vehicles such as oils (e.g., corn oil, sesame oil, isopropyl myristate). Antioxidants, such as vitamin C palmitate, to help stabilize the formulation. In addition, preservatives can be included to prevent the harmful growth of microorganisms.

[0189] In addition, the composition can be in the form of a sterile powder for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile, non-irritating, isotonic, and must be a fluid effective for easy injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; thus, preservatives are preferably included to prevent the contaminating action of microorganisms such as bacteria and fungi, such as benzalkonium chloride, chlorobutanol, methylparaben, propylparaben, disodium edetate, sorbic acid, or other agents known to those of skill in the art. The pharmaceutical compositions of the present invention can be in forms suitable for topical application to the skin and its appendages or to various mucous membranes, such as, for example, aerosols, patches, creams, ointments, lotions, powders, emulsions, and the like. Routes of administration that can be used include nasal, sublingual, vaginal, rectal, ocular, buccal, or otic. In addition, the composition can be in a form suitable for a transdermal or intradermal microneedle device. These formulations can be prepared by conventional processing methods using the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention. For example, lotions, creams, or ointments are prepared by mixing hydrophilic materials and water and about 5 wt% to about 30 wt% of the compound to produce a cream, lotion, or ointment having the desired consistency. Examples of typical excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, isopropyl myristate, mineral oil, and mixtures thereof. If desired, humectants (such as occlusives, moisturizers, emollients) can also be added to the pharmaceutical composition and dosage form. The pH of the pharmaceutical composition or dosage form can also be adjusted to improve delivery of formula (I). Dosage forms suitable for treating oral mucosal tissue can be formulated as mouthwashes or oral gels.

[0190] The pharmaceutical compositions of the present invention can be in a form suitable for rectal administration, wherein the carrier is solid or liquid or a spray. Preferably the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with the softened or melted carrier, followed by cooling and molding in a mold.

[0191] In addition to the foregoing carrier components, the pharmaceutical formulations described above may, where appropriate, include one or more other carrier components such as diluents, buffers, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Further, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by formula (I) or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or a liquid concentrate. The addition of preservatives such as preservatives is widely accepted in the pharmaceutical field as a means of simulating long-term storage to determine characteristics such as shelf life or the stability of the formulation over time (see, for example, Jens T. Carstensen, Drug stability: Principles & Practice. 2nd Edition, Marcel Dekker, NY, NY. 1995, pp. 379-80).

[0192] All diseases, conditions, and disorders listed herein are defined as described 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 (WHO).

[0193] As used herein, the terms "reduce", "lower", "mitigate", 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.

[0194] As used herein, the terms "improve", "increase", "enhance", and similar terms indicate 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.

[0195] In one embodiment, a plurality of other therapeutic agents may be used in combination with the compositions and methods provided herein.

[0196] On the other hand, the present disclosure provides methods for treating and / or preventing a disease or condition (such as neuropathic pain) and / or improving the symptoms of a subject in need thereof, which comprise administering to the subject an effective amount of a compound provided herein. 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, conditions associated with cancer, hypomotility, burnout, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorder, nausea or vomiting. In some embodiments, the disease or condition is PTSD. In some embodiments, the disease or condition is anxiety disorder. In some embodiments, the disease or condition is depression.

[0197] The compounds provided herein can be used for various therapeutic purposes. In one embodiment, a compound is administered to a subject to treat neuropathic pain. For the purposes of the compositions and methods provided herein, "subject" includes humans and other animals, preferably mammals and most preferably humans. Thus, the compounds provided herein are suitable for human therapy and veterinary applications. In another embodiment, the subject is a mammal, and in another embodiment, the subject is a human. As used herein, "condition", "disease" or "ailment" refers to a disorder that can be improved by administering the compounds provided herein and their pharmaceutical compositions.

[0198] The methods and compositions described herein can be used for preventing as well as improving the signs and / or symptoms of a condition such as neuropathic pain. The terms "treating" and "treatment", as used to refer to treating a subject's condition, include: preventing, inhibiting or improving the subject's condition, and reducing or improving the signs or symptoms of the condition. Treatment goals can include endpoints such as improvement in the DSM-5 severity scale, measurement of increased resilience and quality of life, engagement of the positive cognitive valence system, and corresponding reduction of negative valence.

[0199] Those skilled in the art will understand that methods for treating and / or preventing, including administering a compound provided herein for the treatment and / or prevention of one or more indications as described herein, further include: using a compound provided herein in the manufacture of a medicament for the treatment and / or prevention of one or more indications as described herein; and using a compound provided herein for the treatment and / or prevention of one or more indications as described herein.

[0200] Pharmaceutical compositions for the compounds and methods provided herein are contemplated. The compositions and methods provided herein are formulated for storage in the form of lyophilized formulations or aqueous solutions by mixing the compound having the desired purity with optional pharmaceutically acceptable carriers, excipients, or stabilizers. Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed and include buffers such as phosphates, citrates, acetates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoic acid such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; sweetening agents and other flavoring agents; fillers such as microcrystalline cellulose, lactose, corn, and other starches; binders; additives; coloring agents; 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 water-soluble form, such as present as pharmaceutically acceptable salts, which means including acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness of the free base and are not biologically or otherwise undesirable, and these salts are formed with inorganic acids and organic acids, such as inorganic acids like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; 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, salicylic acid, etc. "Pharmaceutically acceptable base addition salts" include those salts derived from the following inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and 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. Formulations for in vivo administration are preferably sterile.This can be easily achieved by filtration through a sterile filtration membrane or other methods.

[0201] Pharmaceutically acceptable excipients for the formulations of the compounds provided herein include, but are not limited to: diluents such as microcrystalline cellulose, starch, mannitol, anhydrous calcium hydrogen phosphate or silica, calcium carbonate, co-mixtures of microcrystalline cellulose and talc; disintegrants such as sodium starch glycolate or croscarmellose sodium; binders such as povidone, copovidone or hydroxypropyl cellulose; lubricants such as magnesium stearate or sodium stearyl fumarate; glidants such as colloidal silica; and film coatings such as white Opadry II or PVA-based brown Opadry II.

[0202] The compounds provided herein can also be encapsulated in microcapsules (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 coarse emulsions prepared by methods including but not limited to coacervation techniques, interfacial polymerization. Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers, which are in the form of shaped articles (e.g., membranes) or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), poly(lactide), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (which are injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprorelin acetate), and poly-D-(-)-3-hydroxybutyric acid), which is a microsphere-based delivery system composed of the desired bioactive molecule incorporated into a poly-DL-lactide-co-glycolide (PLG) matrix.

[0203] Administration of the pharmaceutical compositions containing the compounds provided herein (e.g., in the form of a sterile aqueous solution) can be carried out in a variety of ways, including but not limited to oral, subcutaneous, intravenous, intranasal, intra-aural, transdermal, topical (e.g., gels, ointments, lotions, creams, etc.), intraperitoneal, intramuscular, intralung, transvaginal, parenteral, rectal or intraocular. As is known in the art, the pharmaceutical compositions can be formulated correspondingly according to the mode of introduction.

[0204] 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 tablets. In some embodiments, the pharmaceutical composition comprises capsules. In some embodiments, the pharmaceutical composition comprises a dry powder. In some embodiments, the pharmaceutical composition comprises a solution. In some embodiments, more than one dosage form is administered to the subject substantially simultaneously. In some embodiments, the entire therapeutic dose can be administered to the subject in the form of one tablet or capsule. In some embodiments, the therapeutic dose can be divided into multiple tablets or capsules.

[0205] Unless the context clearly dictates otherwise, as used herein, the singular forms "a," "an," and "the" include plural referents. For example, the term "molecule" can also include multiple molecules.

[0206] The terms "about" or "approximately" are used interchangeably herein and mean that a particular value determined by a person of ordinary skill in the art is within an acceptable error range, which will depend in part on how the value is measured or determined, i.e., the limitations of the measuring system. For example, according to the practice in the art, "about" can mean within 1 or more standard deviations. In addition, as used herein, the term "about" when referring to a measurable value (such as a dose, time, temperature, etc.) means encompassing variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0207] Unless the context clearly indicates otherwise, a reference to a particular numerical value includes at least that particular value. When expressing a range of values, another embodiment includes from one specific value and / or to another specific value. In addition, a reference to a value stated in a range includes each value within that range. All ranges include the end values and are combinable.

[0208] As used herein, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., elements that coexist in some cases and do not coexist in other cases. Multiple elements listed with "and / or" should be interpreted in the same way, i.e., "one or more" of such combined elements. Other elements can optionally be presented, whether or not related to those elements specifically identified, different from the elements specifically identified by the "and / or" clause. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" can, in one embodiment, refer to only A (optionally including elements other than B); in another embodiment, refer to only B (optionally including elements other than A); in yet another embodiment, refer to A and B (optionally including other elements); and so on.

[0209] As used herein, "or" shall 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" shall be interpreted inclusively, i.e., including at least one of the elements or list of elements, and including more than one of them, and optionally, additional unlisted items. Only terms clearly indicating the contrary, such as "only one of... " or "exactly one of... ", or when used in an embodiment, "consisting of... " shall refer to exactly one of the elements of a particular group or list of elements. Generally, the term "or" as used herein when preceded by an exclusive term such as "any one of", "one of... ", "only one of... " or "only one among... " shall be interpreted only as indicating an exclusive alternative (i.e., "one or the other, but not both").

[0210] As used herein, the phrase "at least one" in reference to a list of one or more elements shall be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each element specifically listed in the list of elements, and not excluding any combination of the elements in the list. This definition also allows for the optional presence of elements other than those specifically identified within the list of elements referred to by the phrase "at least one", whether or not related to those specifically identified elements. 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") in one embodiment may refer to at least one, optionally including more than one, of A, where B is absent (and optionally including elements other than B); in another embodiment, it may refer to at least one, optionally including more than one, of B, where A is absent (and optionally including elements other than A); in yet another embodiment, it may refer to at least one, optionally including more than one, of A and at least one, optionally including more than one, of B (and optionally including other elements); and so on.

[0211] Unless the context otherwise indicates, it is expressly intended that the various features described herein may be used in any combination.

[0212] Any patent, patent application publication or scientific publication cited herein is hereby incorporated by reference in its entirety.

[0213] The following examples are provided to more fully illustrate the preferred embodiments of the present disclosure. However, they should in no way be construed as limiting the broad scope of the invention.

[0214] Example 1

[0215] Synthesis method

[0216] The compound of formula (I) of the present invention can be prepared starting from the parent molecule II according to the proposed synthetic routes outlined in Schemes 1-17 below. Methyl ketone IIa (Y = CO, R 1 = CH 3 , R 2 = CH 3 ), ethyl ketone IIb (Y = CO, R 1 = CH 3 , R 2 = CH 2 CH 3 ), butyl ketone IIc (Y = CO, R 1 = CH 2 CH 3 , R 2 = CH 3 ) and MDMA IId (Y = CH 2 , R 1 = CH 3 , R 2 = CH 3 ) can be prepared using procedures such as those described in WO9639133A1 (IIa); Heather E. et al. Drug Test. Analysis, 2017, 9, 426 (IIa); Maheux C.R. et al. Drug Test. Analysis, 2016, 8, 847 (IIb); Maheux C.R. et al. Drug Test. Analysis, 2012, 4, 17 (IIc); and Milhazes N. et al. Anal. Chem. Act. 2007, 596, 231 (IId).

[0217] The amino acid-derived prodrugs of formula Ib and Id can be prepared by coupling the required amine II with the appropriate amino acid, as presented in Scheme 1 below, where R 11 and R 12Side chain residues each independently selected from naturally occurring amino acids. To couple an amino acid with II, it is preferred to protect one amino group with a protecting group (Pg) before the amino acid reacts with II. Agents and methods for protecting amino groups in the reactants are known in the art. Examples of protecting groups that can be used to protect amino groups include, but are not limited to, fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), trifluoroacetate (TFA), acetate (Ac), and benzyloxycarbonyl (CBZ). Preferably, the carboxylic acid group in the N-protected amino acid is activated by an acid activator (sometimes also referred to as a coupling reagent) to facilitate the reaction of the N-protected amino acid with II. Examples of acid activators (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), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (HBTU), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU). The use of appropriate acyl halides or acid anhydrides as the activated acylating group in the N-protected amino acid is also contemplated. After coupling by any standard coupling procedure to obtain the intermediate protected prodrug Ia, deprotection can be carried out with standard reagents known in the art to obtain the desired prodrug Ib. After deprotecting the newly added Ic amino group, this amino acid prodrug can be further derivatized to a dipeptide by repeating the coupling procedure to obtain prodrug Id.

[0218] Scheme 1

[0219]

[0220] Alternatively, a peptide-derived prodrug of formula Id can be prepared by coupling the requisite amine II and an appropriate dipeptide, as presented in Scheme 2 below. This conjugation can be accomplished under the conditions previously described for intermediate Ia (Scheme 1). The requisite dipeptide is provided by the coupling of two amino acids, each independently selected from naturally occurring L-amino acids using standard peptide coupling protocols known in the art.

[0221] Scheme 2

[0222]

[0223] The amide prodrug 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 carried out in the presence of a base (such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO 3 、K 2 CO 3In the case of 2,6-lutidine, it is achieved by reacting with an acyl chloride (Z = Cl) or an acid anhydride (Z = -OC(O)R or -OC(O)tert-butyl) in a suitable solvent such as dichloromethane, THF, DMF, acetonitrile or toluene. The coupling reaction can also be carried out 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), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (HBTU) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other similar reagents well-known to those skilled in the art. 3 The carbamate prodrug of formula If can be prepared by coupling the desired amine II with a suitable 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, NaHCO, K, CO or pyridine in a suitable solvent such as dichloromethane, THF, ethyl acetate, acetonitrile, 1,4-dioxane or water. Alternatively, the carbamate If can be prepared by sequentially adding triphosgene to amine II in a solvent such as dichloromethane in the presence of a base such as diisopropylethylamine (DIPEA), and then adding an alcoholate such as NaOR.

[0224] Scheme 3

[0225]

[0226] The acyl-oxyalkoxycarbonyl prodrug of formula Ig (Scheme 5) can be prepared by sequentially coupling the desired amine II with chloroethyl chloroformate in a solvent such as dichloromethane in the presence of a base such as triethylamine or diisopropylethylamine, and then adding a selected carboxylic acid ester. Such a carboxylic acid ester can be prepared by reacting the corresponding carboxylic acid RCO with... 3 、K 2 CO 3 or pyridine) in a suitable solvent (such as dichloromethane, THF, ethyl acetate, acetonitrile, 1,4-dioxane) or in water. Alternatively, the carbamate If can be prepared by sequentially adding triphosgene to amine II in a solvent (such as dichloromethane) in the presence of a base (such as diisopropylethylamine (DIPEA)), and then adding an alcoholate (such as NaOR 3 ) to prepare the carbamate If.

[0227] Scheme 4

[0228]

[0229] The acyl-oxyalkoxycarbonyl prodrug of formula Ig (Scheme 5) can be prepared by sequentially coupling the desired amine II with chloroethyl chloroformate in a solvent such as dichloromethane in the presence of a base such as triethylamine or diisopropylethylamine, and then adding a selected carboxylic acid ester. Such a carboxylic acid ester can be prepared by reacting the corresponding carboxylic acid R 3 CO 2H reacts with a base (such as triethylamine or cesium carbonate) in a solvent (such as DMF or acetonitrile) to generate. Alternatively, the acyloxyalkoxycarbonyl prodrug of formula Ig can be directly obtained by coupling the required amine II with an electrophilic acylating agent (such as 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl carboxylate) in a solvent (such as dichloromethane) in the presence of a base (such as triethylamine or diisopropylethylamine).

[0230] Scheme 5

[0231]

[0232] The acyloxymethyl prodrug of formula Ih can be prepared by coupling the required amine II with an appropriate chloromethyl ester in a solvent (such as acetonitrile) in the presence of a basic agent (such as triethylamine) (Scheme 6). The chloromethyl ester R 3 C(O)OCH 2 Cl can be prepared according to the procedures described in US20150274670A1 and US20070155729A1, in which the acyl chloride of formula R 3 COCl reacts with paraformaldehyde.

[0233] Scheme 6

[0234]

[0235] The phosphoramidate prodrug of formula Ii can be prepared according to the procedures described in WO 2020 / 008064. As shown in Scheme 7 below, PCl 5 is added to the required amine II in the presence of a basic agent (such as pyridine) and in a solvent (such as dichloromethane). Then a mixture of water / DMSO is added to hydrolyze the dichlorophosphoramidate solution to obtain the phosphoramidate prodrug of formula Ii.

[0236] Scheme 7

[0237]

[0238] The phosphonyloxymethyl of formula Ik can be prepared from the required amine II in a two-step sequence, as presented in Scheme 8 below. According to the procedures found in WO 2020 / 008064, the solution of amine II in a solvent (such as acetonitrile) can be treated with a basic agent (such as K 2 CO 3 ), NaI and di-tert-butyl chloromethylphosphonate) at a controlled temperature of 50 °C to obtain the protected phosphonate Ij. This intermediate is hydrolyzed under aqueous acidic conditions to obtain the phosphonyloxymethyl prodrug Ik.

[0239] Scheme 8

[0240]

[0241] Phosphoryloxyalkoxycarbonyl prodrugs of formula Im (Scheme 9) can be prepared according to the procedure described in Safadi M. et al., Pharm Res, 1993, 10(9), 1350 by sequentially coupling the required amine II with a chloroalkyl chloroformate in a solvent such as dichloromethane in the presence of a base such as triethylamine or diisopropylethylamine, and then adding a suitably protected phosphate such as dibenzyl phosphate (R 11 and R 12 = benzyl). Such a phosphate can be generated by reacting the corresponding phosphonic acid with a base such as silver carbonate in a solvent such as DMF or acetonitrile. When R 11 and R 12 are benzyl, the phosphate intermediate IL can be deprotected in a solvent such as ethyl acetate under an H 2 atmosphere using a catalytic amount of Pd / C to obtain dihydrogen phosphate Im.

[0242] Scheme 9

[0243]

[0244] Amide prodrugs of formula Ip can be prepared by coupling the required amine II with carboxylic acid Io, as presented in Scheme 10 below. When Z a is O, NH or NCH 3 , those carboxylic acids are commercially available, where a variety of R 3 groups such as alkyl, cycloalkyl, aryl, heteroaryl and amino acids can be found. The coupling reaction can 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), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (HBTU) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other similar reagents well known to those skilled in the art. If the carboxylic acid is not commercially available, it can be prepared by acylation of In with an amino group (Z a = NR 4 ) or a hydroxyl group (Za = O) with a carboxylic acid (Z = OH) in the presence of the above coupling agent. Alternatively, it can also be carried out in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO 3 , K 2 CO 3In the case of 2,6-lutidine), in a suitable solvent (such as dichloromethane, THF, DMF, acetonitrile or toluene), the amine In is reacted with an acyl chloride (Z = Cl) or an acid anhydride (Z = -OC(O)R 3 or -OC(O)tert-butyl).

[0245] Scheme 10

[0246]

[0247] The carbamate prodrug of formula It can be prepared by coupling the desired amine II with benzyl alcohol Is, as presented in Scheme 11 below. When Z b is O, NH or NCH 3 the benzyl alcohol is commercially available, where a variety of R 3 groups can be found, such as alkyl, cycloalkyl, aryl, heteroaryl and amino acids. The coupling reaction can be carried out as described in US2017 / 0145044A1, by sequentially reacting the benzyl alcohol with a reagent (such as carbonyldiimidazole) in a solvent (such as dichloromethane), and then adding amine II. If the benzyl alcohol is not commercially available, Is can be prepared in a two-step sequence, where the desired commercially available phenol (Z b = O) or aniline (Z b = NR 4 ) Iq is acylated in a similar manner as described above for the preparation of Io (Scheme 10), and then the benzaldehyde Ir is reduced with a reagent (such as sodium borohydride) in a solvent (such as dichloromethane) in the presence of an alcohol (such as isopropanol).

[0248] Scheme 11

[0249]

[0250] The carbamate prodrug of formula Ix can be prepared by coupling the desired amine II with benzyl alcohol Iw, as presented in Scheme 12 below, and following a similar assembly sequence as described in Scheme 11 above. When Z b is O, NH or NCH 3 the benzyl alcohol is commercially available, where a variety of R 3 groups can be found, such as alkyl, cycloalkyl, aryl, heteroaryl and amino acids. The coupling reaction can be carried out by sequentially reacting the benzyl alcohol with a reagent (such as carbonyldiimidazole) in a solvent (such as dichloromethane), and then adding amine II. If the benzyl alcohol is not commercially available, Iw can be prepared in a two-step sequence, where the desired commercially available phenol (Z b = O) or aniline (Z b = NR 4) Acylation is carried out in a similar manner as described above for the preparation of Io (Scheme 10), and then in the presence of an alcohol (such as isopropyl alcohol), benzaldehyde Iv is reduced with a reagent (such as sodium borohydride) in a solvent (such as dichloromethane).

[0251] Scheme 12

[0252]

[0253] The phosphonate prodrug of formula Iaa can be prepared by coupling the desired amine II with benzyl alcohol Iz, as presented in Scheme 13 below, and following a similar assembly sequence as described previously in Scheme 11. The protected phosphate ester Iy can be obtained by reacting the commercially available phenol Iq-1 with a protected phosphate ester reagent (such as di-tert-butyl chlorophosphate or dibenzyl chlorophosphate) in the presence of a base (such as triethylamine, i-Pr 2 NEt or DBU), in a solvent (such as THF or dichloromethane), in the presence of a catalyst (such as DMAP). Benzyl alcohol Iz is obtained by treating benzaldehyde Iy with a reagent (such as sodium borohydride) in a solvent (such as dichloromethane) in the presence of an alcohol (such as isopropyl alcohol). The formation of the carbamate linkage can be carried out by reacting benzyl alcohol with a reagent (such as carbonyldiimidazole), and then adding amine II. The phosphate ester can be deprotected under acidic conditions (Pg = tert-butyl) using a reagent (such as TFA or HCl aq. ) in a solvent (such as dichloromethane or THF) to obtain Iaa. Unless R 6 is incompatible with the reduction conditions, such as R 6 = NO 2 、CN or Br, the deprotection can also be carried out under hydrogenolysis conditions (Pg = benzyl) using Pd / C as a catalyst in a solvent (such as methanol) under an H 2 atmosphere.

[0254] Scheme 13

[0255]

[0256] The phosphonate prodrug of formula Idd can be prepared by coupling the desired amine II with benzyl alcohol Icc, as presented in Scheme 14 below, and following a similar assembly sequence as described previously in Scheme 11. The protected phosphate ester Ibb can be obtained by reacting in the presence of a base (such as triethylamine, i-Pr 2In the case of NEt or DBU), in a solvent (such as THF or dichloromethane), in the presence of a catalyst (such as DMAP), a commercially available phenol Iu-1 is reacted with a protected phosphate reagent (such as di-tert-butyl chlorophosphate or dibenzyl chlorophosphate) to obtain. In a solvent (such as dichloromethane), in the presence of an alcohol (such as isopropanol), benzaldehyde Ibb is treated with a reagent (such as sodium borohydride) to obtain benzyl alcohol Icc. The formation of the carbamate linkage can be carried out by reacting the benzyl alcohol with a reagent (such as carbonyldiimidazole), and then adding amine II. It can be carried out under acidic conditions (Pg = tert-butyl), using a reagent (such as TFA or HCl aq. ), in a solvent (such as dichloromethane or THF) to deprotect the phosphate to obtain Iaa. Unless R 6 is incompatible with the reduction conditions, such as R 6 =NO 2 , CN or Br, otherwise the deprotection can also be carried out under reduction conditions (Pg = benzyl), using Pd / C as a catalyst, in a solvent (such as methanol) under an H 2 atmosphere.

[0257] Scheme 14

[0258]

[0259] The amide prodrug of formula Ihh can be prepared by coupling the required amine II with carboxylic acid Igg, as presented in Scheme 15 below. This carboxylic acid can be generated in a 3-step sequence, starting from phenol Iee, which can be prepared according to the synthesis reported by Nicolaou M.G. et al. (J. Org. Chem, 1996, 61, 8636). The 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), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (HBTU) and azabenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (HATU) or other similar reagents well-known to those skilled in the art. Alternatively, it can also be carried out in the presence of a base (such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO 3 , K 2 CO 3 or 2,6-lutidine), in a suitable solvent (such as dichloromethane, THF, DMF, acetonitrile or toluene), reacting phenol Iee with an acyl chloride (Z = Cl) or an acid anhydride (Z = -OC(O)R 3Or - OC(O)tert - butyl) reaction. It can be carried out under weakly acidic conditions (Pg = TBS) using a reagent (such as PPTS) in a solvent (such as methanol) (Crouch, R. D. Tetrahedron, 2013, 69, 2383), or under reducing conditions (Pg = benzyl) using Pd / C as a catalyst in a solvent (such as methanol) in an H 2 The deprotection of Iff can be carried out under an H atmosphere. The corresponding primary alcohol can be oxidized using a reagent (such as Jones reagent) in a solvent (such as acetone) to obtain carboxylic acid Igg, which can then be coupled with amine II in the presence of a coupling reagent as described above.

[0260] Scheme 15

[0261]

[0262] The phosphonate prodrug of formula Ijj can be prepared by coupling the required amine II with carboxylic acid Iii, as presented in Scheme 16 below. This carboxylic acid can be obtained according to the synthesis reported by Nicolaou M. G. et al. (J. Org. Chem, 1996, 61, 8636). The formation of the amide bond can be carried out by the reaction of the required amine II with 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), benzotriazol - 1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (HBTU), and O - (7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other similar reagents well known to those skilled in the art. The phosphonate prodrug Ijj can be obtained by deprotecting the corresponding dibenzyl phosphate under reducing conditions using Pd / C as a catalyst in a solvent (such as methanol) in an H 2 atmosphere.

[0263] Scheme 16

[0264]

[0265] The amide prodrug of formula Inn can be prepared by coupling the desired amine II with a carboxylic acid Imm, as presented in Scheme 17 below. This carboxylic acid can be generated in a 4-step sequence, starting from phenol Ikk, which can be prepared according to the synthesis reported by Liao Y. and Wang B. (Bioorg. Med. Chem. Lett., 1999, 9, 1795). The acylation of Ikk 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) and azabenzotriazole tetramethyluranium hexafluorophosphate (HATU) or other similar reagents well known to those skilled in the art. Alternatively, the reaction mixture may be prepared in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO 3 , K 2 CO 3 or 2,6-lutidine), phenol Ikk is reacted with an acyl chloride (Z=Cl) or an anhydride (Z=-OC(O)R in a suitable solvent such as dichloromethane, THF, DMF, acetonitrile or toluene. 3 or -OC(O) tert-butyl). The reaction can be carried out under weakly acidic conditions (Pg = TBS) using a reagent such as AcOH in a solvent mixture such as THF / H 2 The corresponding primary alcohol can be oxidized to the carboxylic acid Imm in a two-step sequence, where first a reagent such as MnO 2 ), the alcohol is oxidized to an aldehyde in a solvent such as dichloromethane, and then a Kraus-type reaction is performed using reagents well known to those skilled in the art. Finally, the carboxylic acid Imm can be coupled with an amine II in the presence of a coupling reagent as described above to give the prodrug Inn.

[0266] Solution 17

[0267]

[0268] Examples of compounds of formula (I) according to the present invention include any one of compounds 1 to 402 in Tables 1, 2 and 3 below and compounds 403 to 511 in Table 4 (and pharmaceutically acceptable salts of any of these compounds):

[0269] Table 1

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] Table 2

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285] Table 3

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292] Table 4

[0293]

[0294]

[0295]

[0296]

[0297]

[0298] Compound 1: (2S)-2,6-diamino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylhexanamide

[0299]

[0300] 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. 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 to a solution of methyl ketone hydrochloride (1.03 g) in 100 mL of CH 2 Cl 2 . The reactants were stirred overnight at room temperature and then 100 mL of CH 2 Cl 2 was added. The resulting solution was washed with 200 mL of 1 M HCl, 200 mL of saturated aqueous NaHCO 3 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 hexane. The pure fractions were then combined and concentrated to give the desired Boc-protected intermediate as an off-white solid.

[0301] Step 2: (2S)-2,6-diamino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylhexanamide. Trifluoroacetic acid (10 mL) was added 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 CH 2 Cl 2 (10 mL). The reactants were stirred at room temperature for 4 hours, diluted with 10 mL of CH 2 Cl 2 and adjusted to pH 1 with 20 mL of 1 M HCl. The layers were separated and 20% NaOH aq. was added to the aqueous layer to give pH > 10. This resulting basic aqueous layer was extracted twice with 20 mL of CH 2 Cl 2 . The combined organic layers were concentrated under reduced pressure to give Compound 1 as a solid.

[0302] Compound 2: 2-Amino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylethanamide.

[0303]

[0304] 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. At room temperature, diisopropylethylamine (1.8 mL), Boc-glycine (0.47 g), EDC (0.5 mL), DMAP (0.1 g), and HOBT (0.42 g) were added to a solution of methyl ketone hydrochloride (0.5 g) in 50 mL of CH 2 Cl 2 . The reaction mixture was stirred overnight at room temperature and then 50 mL of CH 2 Cl 2 was added. The resulting solution was washed with 100 mL of 1 M HCl, 100 mL of saturated aqueous NaHCO 3 and 100 mL of saturated aqueous NaCl. 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.

[0305] Step 2: 2-Amino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylethanamide. 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 CH 2 Cl 2 (10 mL) was added 10 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 h, diluted with 30 mL of CH 2 Cl 2 and adjusted to pH 1 with 20 mL of 1 M HCl. The layers were separated and 20% NaOH aq. was added to the aqueous layer to give pH > 10. The resulting basic aqueous layer was extracted twice with 20 mL of CH 2 Cl 2 . The combined organic layers were concentrated under reduced pressure to give Compound 2 as a solid.

[0306] Compound 25: N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylethanamide.

[0307]

[0308] Compound 25 was prepared by the following procedure: Diisopropylethylamine (0.9 mL) was added to a solution of methyl ketone hydrochloride (0.5 g) in 50 mL of CH 2 Cl 2 . The solution was stirred at room temperature for 15 minutes, cooled to 0 °C and acetyl chloride (0.3 mL) was added. After 30 minutes at 0 °C, the reaction mixture was warmed to room temperature and stirred overnight. The volatiles were then removed under reduced pressure to give a yellow solid, which was dissolved in 150 mL of CH 2 Cl 2 . The resulting solution was washed twice with 100 mL of saturated aqueous NaHCO 3 and 100 mL of saturated aqueous NaCl. The organic layer was concentrated under reduced pressure to give Compound 25 as a solid.

[0309] Compound 45: N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-2,2,2-trifluoro-N-methylethanamide.

[0310]

[0311] Compound 45 was prepared by the following procedure: Under nitrogen, methyl ketone hydrochloride (500 mg, 2.05 mmol, 1.0 equiv) and DCM (4 mL, 8 vol) with DIPEA (1.09 mL, 6.25 mmol, 3 equiv) were added to a 25 mL round bottom flask. After stirring for 10 min, a light brown solution was formed. The solution was cooled to 0 °C and trifluoroacetic anhydride (483 mg, 2.3 mmol, 1.12 equiv) in DCM (1 mL, 2 vol) was added dropwise, with evolution of gas and a small exotherm from 4 °C to 10 °C being observed. After stirring at 0 °C to 10 °C for 30 min, HPLC monitoring indicated 66% product and 33% starting material. Additional DIPEA (0.44 mL, 1.23 mmol equiv) and trifluoroacetic anhydride (237 mg, 0.55 equiv) were added and the reaction mixture was stirred at ambient temperature overnight. HPLC analysis the next day showed 95% product and undetectable starting material. The reaction mixture was washed with water (5 mL x 2), dried (MgSO 4 ) and the DCM layer was concentrated to give an orange solid. The solid was purified by column chromatography (10 g silica gel, 100% DCM) to give 372 mg of Compound 45 as a solid.

[0312] Compound 50: 1-(((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamoyl)oxy)ethyl 2-methylpropanoate.

[0313]

[0314] Compound 50 was prepared by the following procedure: To a suspension of methyl ketone hydrochloride (1.35 g) at 0 °C in CH 2 Cl 2 (10 mL) was added triethylamine (1.19 g, in 2 mL CH 2 Cl 2 . The resulting beige solution was stirred at 0 °C for 10 minutes and then 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl isobutyrate (2.0 g, in 4 mL CH 2 Cl 2 ) was added dropwise over 5 minutes. The reaction mixture was stirred between -5 and 5 °C for 1 h and then warmed to RT (15 - 20 °C) and stirred over the weekend (about 66 h) to afford an orange solution. Then, below 25 °C, 1 M aqueous acetic acid (7 mL) was added dropwise over 5 minutes and stirred for 5 minutes. The phases were separated and the organic layer was washed with 1 M K 2 CO 3 aqueous solution (3 x 7 mL) and then with 20% brine (7 mL). The material was concentrated in vacuo at 30 °C and then redissolved in ethyl acetate (10 mL). The organic matter was washed with 1 M K 2 CO 3 aqueous solution (2 x 7 mL), then with 20% brine (7 mL), and then concentrated in vacuo at 40 °C. The crude material was purified by silica gel column chromatography and eluted with 1 - 10% ethyl acetate in heptane. The clear fractions were concentrated in vacuo at 40 °C and then stripped from TBME (3 x 20 mL) to give Compound 50.

[0315] Compound 71: Methyl (1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamate.

[0316]

[0317] Compound 71 was prepared by the following procedure: Under nitrogen, methyl ketone hydrochloride (500 mg, 2.05 mmol, 1.0 equiv) and DCM (4 mL, 8 vol) with DIPEA (1.09, 6.25 mmol, 3 equiv) were added to a 25 mL round-bottom flask. The reactants were cooled to 0 °C, and methyl chloroformate (257 mg, 2.7 mmol, 1.3 equiv) in DCM (1 mL, 2 vol) was added dropwise over 5 minutes to form a pale brown solution, and an exotherm from 6 °C to 12 °C was observed. HPLC analysis showed 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. The oil was purified by column chromatography (10 g silica gel, 100% DCM) to give 197 mg of Compound 71 as a clear oil.

[0318] Compound 77: Pentyl (1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamate.

[0319]

[0320] Compound 77 was prepared by the following procedure: Diisopropylethylamine (0.9 mL) and triethylamine (0.46 mL) were added to a solution of methyl ketone hydrochloride (0.5 g) in 50 mL of CH 2 Cl 2 The solution was stirred at room temperature for 15 minutes, cooled to 0 °C and pentyl chloroformate (0.5 mL) was added dropwise. The reactants were warmed to room temperature and stirred for 90 minutes. Volatiles were removed under reduced pressure to give an off-white solid, which was then dissolved in 100 mL of CH 2 Cl 2 The resulting solution was washed twice with 100 mL of saturated aqueous NaHCO 3 and 100 mL of saturated aqueous NaCl. The organic layer was concentrated under reduced pressure to give Compound 77 as a solid.

[0321] Example 2

[0322] Evaluate the effect of the prodrug on the pharmacokinetic properties of methyl ketone

[0323] The pharmacokinetic properties of methyl ketone were determined in male Sprague Dawley rats after single intravenous (IV), intraperitoneal (IP), or oral gavage (PO) administration using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method that had been established and validated in rats for methyl ketone. Rats (n = 3 per group) received a single dose of methyl ketone: 5 mg / kg IV, 15 mg / kg IP, or 15 mg / kg PO. Plasma was sampled at time points between 0.083 - 24 hours to determine methyl ketone levels, and key parameters (e.g., C max 、T max 、T 1 / 2 and AUC) were determined based on the data analysis. The results are shown in Table 5.

[0324] Table 5. Selected pharmacokinetic parameters of methyl ketone after single IV, PO, and IP administration to male Sprague-Dawley rats

[0325]

[0326] To investigate whether the prodrug prolongs the half-life or alters other fundamental pharmacokinetic properties of methyl ketone (e.g., C max or T max ), rats were treated with each prodrug IV, IP, or PO. For each compound, three groups of rats were treated as follows: For Group 1, a single dose of methyl ketone was administered to 3 male Sprague-Dawley rats by an IV bolus at 5 mg / kg. For Group 2, a single dose of methyl ketone was administered to 3 male Sprague-Dawley rats by oral gavage at 15 mg / kg. For Group 3, a single dose of methyl ketone was administered to 3 male Sprague-Dawley rats by IP at 15 mg / kg. For all groups, blood samples were collected from each animal at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing to determine plasma concentrations. Plasma concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC-MS / MS). A bioanalytical method had been established and validated, yielding a lower limit of quantification (LLOQ) of 1 ng / mL and an upper limit of quantification (ULOQ) of 3000 ng / mL for methyl ketone. Phoenix WinNonlin (version 8.3) was used to analyze plasma concentration-time data to characterize the PK properties of the analyte. A non-compartmental analysis model and the linear / log trapezoidal method were applied to the calculation of PK parameters.

[0327] Behavioral pharmacology studies to explore the efficacy of the prodrug

[0328] Antidepressant efficacy in the forced swim test (FST)

[0329] The forced swim test (FST) is a classical model for evaluating the antidepressant-like activity of compounds and has been used for over 40 years (Porsolt et al. (1977) Nature 266:730-732; Detke et al. (1995) Psychopharmacology 121:66-72). All classes of antidepressants, including selective serotonin reuptake inhibitors, noradrenergic reuptake inhibitors, tricyclic antidepressants, and more recent rapid-acting antidepressants such as ketamine, psilocybin, or MDMA, have all been shown to reduce immobility in the FST. Methyl ketone has a robust, dose-dependent antidepressant-like effect in the rat forced swim test (FST). Compared to vehicle-treated control groups, a single dose of 5 mg / kg methyl ketone reduced immobility by approximately 50%, while a 15 mg / kg dose reduced immobility by nearly 100%. The accompanying changes in climbing and / or swimming behavior reflect the noradrenergic and serotonergic activities of methyl ketone, respectively.

[0330] All FST studies were conducted and scored by experimenters blinded to the treatment groups and according to a standard protocol. Briefly, rats were placed in a round plexiglass container filled with water. For each animal, the water temperature was maintained at 22-25 °C and varied. Day 1 (training) consisted of a 15-min adaptation trial, and Day 2 (testing, 24 h later) consisted of a 5-min test. Using a time-sampling procedure, animals were observed every 5 s during the test session (60 times or 5 min) and scored for immobility (defined as failure to struggle), swimming (defined as circular motion around the circumference of the tank), or climbing (defined as upward escape behavior). Data were expressed as a percentage of the test session (e.g., the number of immobility counts divided by 60). After typical statistical analyses (e.g., unpaired t-tests or ANOVA), p values less than 0.05 indicated statistical significance.

[0331] To determine that the prodrug has an antidepressant-like effect and compare it to methyl ketone, rats were treated with each compound 30 min prior to testing. Additional testing was performed 24, 72, 168 h, or longer after dosing.

[0332] Effect on fear extinction in a post-traumatic stress disorder (PTSD) model

[0333] Methyl ketone (30 mg / kg, IP) significantly improved fear extinction recall in a PTSD mouse model ( Figure 1)。A fear extinction memory deficit is characteristic of PTSD in patients (Wicking et al. (2016) Neurobiology of Learning and Memory 136:116). SSRI antidepressants, similar to two drugs already approved for treating PTSD (i.e., paroxetine and sertraline), prevent fear memory generalization and enhance extinction (Pedraza et al. (2019) Transl Psychiatry 9:53). Enhanced fear extinction may also underlie the beneficial effects of MDMA as a treatment for PTSD (Feduccia and Mithoefer (2018) Progress in Neuro-Psychopharmacology & Biological Psychiatry 84(Part A), 221-228).

[0334] Effective PTSD treatment facilitates the dissociation between traumatic memories and the patient's fear response, such that the cues of traumatic memories less readily trigger fear responses. This is modeled using a 3-day mouse fear extinction paradigm. On Day 1 (conditioned fear), mice are trained to acquire a "traumatic memory" by associating a conditioned stimulus (CS, tone) with an unconditioned stimulus (US, foot shock). On Day 2 (extinction training), they are trained to forget the traumatic memory association by presenting the CS 6 times (without the US) in a novel environment. On Day 3 (extinction recall), the mice are "questioned" as to whether the tone (CS) still elicits a fear response, as measured by the time spent freezing upon hearing the tone. The shorter the freezing time, the better the memory extinction. Drugs that improve extinction recall reduce the freezing time on Day 3 and thus show potential as a treatment for PTSD.

[0335] Work using MDMA has shown that, following conditioned fear, administration of MDMA (7.5 mg / kg) 30 minutes before extinction training enhances extinction recall, measured as a 35% reduction in freezing compared to a saline-injected control group (Young et al. (2015) Transl Psychiatry 5:e634). Using a similar experimental design, recent results have shown that, compared to a saline control ( Figure 1 B), methone (30 mg / kg) significantly enhances fear extinction recall ( Figure 1 ), approaching 60%. Using these methods, prodrugs are administered to mice and their efficacy is tested in a fear extinction model to evaluate their efficacy in treating PTSD and other memory disorders.

[0336] Anxiolytic effects in other behavioral anxiety models

[0337] The anti - anxiety effects of methyl ketones and their prodrugs in mice or rats were evaluated using additional behavioral tests including thigmotaxis in the elevated plus - maze (EPM) and open - field test (OFT). Methyl ketones (5, 10, 20 mg / kg, SC) have been shown to reduce thigmotaxis (time spent close to the periphery of the open field) in rats ( et al. (2017) Front Psychiatry 8:232), consistent with an anti - anxiety effect. These models are described in more detail below. Prodrugs were screened in these behaviors to determine the anti - anxiety efficacy of each compound.

[0338] Methyl ketones can reduce the time spent in the center relative to the periphery in the OFT, which is consistent with an anxiolytic - like response. Methyl ketones are also a stimulant, which increases locomotor activity in this test. The effects of drug precursor compounds on both parameters were screened. Briefly, rodents were evaluated in a 30 - minute OFT using an automated activity monitoring system. Rodents were acclimated to the room 30 minutes before the start of the test. The following parameters were captured: horizontal travel distance, total movement time, and number of movements. Vertical activity (time and count), time data for the center and periphery, and total time were reported in 5 - minute bins.

[0339] The EPM is a classic anxiety model that also exploits the rodents' dislike of open spaces. The effects of prodrug compounds and methyl ketones were tested in this model. Briefly, rodents were acclimated to the holding room for at least 30 minutes before the experiment. The test was conducted 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 small ledge, while the closed arms are bordered by 15 - cm walls. At the start of the task, the rodent was placed in the center of the elevated plus - maze, facing an open arm, and video - tracked while exploring the maze for 5 minutes. The time spent in the open and closed arms was measured and analyzed. A longer time in the open arms compared to the closed arms is consistent with an anti - anxiety effect.

[0340] Example 3

[0341] Evaluate the effects of prodrugs on the pharmacokinetic properties of methyl ketones

[0342] Methy ketone is in clinical development for PTSD, supported by robust data from animals and humans demonstrating its safety and potential for clinical benefit. However, the generation of methy ketone prodrugs has distinct advantages that address the short half-life of methy ketone and the dose-dependent increases in heart rate and blood pressure. The current clinical treatment protocol for methy ketone employs a supervised, split-dose regimen (i.e., two sub-effective doses administered approximately 1 hour apart), frequent monitoring of blood pressure and heart rate for 6 - 8 hours post-dose, and exclusion of patients with a history of cardiovascular conditions. Improving the PK properties of methy ketone using prodrugs (e.g., lower C max and longer half-life) could reduce or eliminate the need for frequent blood pressure and heart rate monitoring and potentially expand the eligibility criteria to allow more patients to benefit clinically from methy ketone.

[0343] Methy ketone prodrug analogs have been synthesized. The synthesis of compound 50 is illustrated below (Scheme 18). This acyloxyalkoxycarbonyl prodrug was efficiently prepared via a one-step process by direct N-acylation of methy ketone with 1-(4-nitrophenoxycarbonyloxy)ethyl 2-methylpropionate. The rate of prodrug bioactivation from esterase hydrolysis can be modulated by varying the nature of the ester residue. Thus, an alternative method was also proposed according to US2010 / 0160666, which is incorporated herein by reference. This strategy enables the rapid assembly of a series of different ester analogs from a common intermediate.

[0344]

[0345] Design, synthesis, and characterization of methy ketone prodrugs:

[0346] Methy ketone has been developed for the treatment of PTSD based on its rapid, robust, and long-lasting beneficial effects in animals and humans. Overall, methy ketone is well tolerated. However, certain aspects of the pharmacological profile of methy ketone still warrant improvement. Developing an alternative therapeutic agent that exhibits the same overall safety and impressive beneficial effects as methy ketone but has a longer duration of action (extended therapeutic window) and lower C max (minimizing cardiovascular effects) would be a significant advantage over the parent methy ketone and potentially have an even greater impact on PTSD and other patient populations.

[0347] The methyl ketone can be covalently conjugated with different precursor moieties through direct derivatization of its amino group. Prodrug bioactivation was first determined by studying the chemical, hepatic, and whole blood in vitro stability in rat and human matrices. Based on the rate of its in vitro cleavage to release the methyl ketone active agent, the prodrug was selected and further characterized via rat PK for in vivo validation of the bioactivation process. Then, a complete DMPK profile was generated in 4 model species (mouse, rat, dog, NHP) and humans. Finally, the collected data were used for human PK prediction.

[0348] Prodrug synthesis: Methyl ketone prodrugs were synthesized by direct functionalization of the amino group of the methyl ketone as shown in Scheme 19. This method provided seven different classes of prodrugs as defined by the newly generated functional groups: amide (I), peptide (II), carbamate (III), acyloxyalkoxycarbonyl (IV), phosphoramide (V), acyloxymethyl (VI), and phosphonyloxymethyl (VII).

[0349] Although the enzymatic biotransformation of each of these functional groups has been clinically verified, it involves a primary amine or a less hindered N-substituted system compared to the secondary amine of the methyl ketone. It is known that steric hindrance significantly affects the rate of peptide bond hydrolysis. For some methyl ketone prodrugs (such as classes I, II, or III), this may inhibit the bioactivation process. Therefore, prodrugs with a more "distant" activation site, such as acyloxyalkoxycarbonyl IV, which is less dependent on the structural features of the parent molecule, were also investigated.

[0350]

[0351] Bioactivation potential of prodrug candidates: After synthesizing the prodrugs, their bioactivation potential to release the methyl ketone was evaluated under in vitro conditions. Since the prodrugs were designed to be enzymatically activated by esterases and amidases / peptidases present in the blood and / or liver, each prodrug was incubated in human and rat whole blood as well as hepatocytes. In these assays, the percentage of the released parent methyl ketone and the percentage of the remaining prodrug were measured at different time points over a 2-hour period. Chemical stability assessment of each prodrug was also performed under different pH conditions to ensure that the released methyl ketone was the result of enzymatic hydrolysis. Then, the prodrugs showing in vitro bioactivation were administered (IV / PO) to rats, and blood samples were collected to evaluate the pharmacokinetic characteristics of each prodrug.

[0352] For example, the metabolic stability of prodrug candidates to release the methyl ketone can be evaluated in vitro according to the following protocol: Cryopreserved human and rat hepatocytes were thawed in recovery medium and diluted in plating medium to a viable cell density of 1×10 6 cells per milliliter. Viability was determined by trypan blue exclusion. 350 μL of the cell suspension was added to individual multi-well tubes and incubated at 37 °C, 5% CO2 Pre-incubate for 10 minutes. After pre-incubation, 350 μL of the prodrug and reference compounds (testosterone and ethoxycoumarin) were added repeatedly at a final concentration of 1 μM to initiate the reaction. A 100 μL aliquot from the mixture was transferred to a 96-well plate for incubation. At selected time points (0, 10, 30, 60, 90, 120 minutes), the incubation was quenched with 200 μL of ice-cold acetonitrile (ACN) containing internal standards (1 μM glyburide and labetalol). Pre-quenched methyl ketone samples were prepared to calculate the percentage of appearance of the active drug at different time points of 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) were analyzed by LC-MS / MS to measure the concentration of the released methyl ketone and the concentration of the remaining corresponding prodrug. The target was a set standard of 100% recovery, where the sum of the percentage of the remaining prodrug and the percentage of the released methyl ketone should be 100%, with an experimental error tolerance of ±20%.

[0353] When compound 50 was incubated with human hepatocytes under the conditions described above, at t = 60 minutes, approximately 100% of the prodrug had been converted to methyl ketone, with a total recovery of approximately 100%. As a negative control, when compound 50 was incubated for up to 2 hours in the absence of hepatocytes in pH 6.8 phosphate buffer at 37 °C, no parent methyl ketone was released.

[0354] DMPK profiling: Then, based on the rat PK data, prodrugs were selected for a more extensive evaluation of their DMPK characteristics. To perform human PK predictions, datasets for 4 species (mouse, rat, dog, and NHP) and humans (only in vitro assays) were collected, including PK parameters, whole blood stability, hepatocyte metabolic characteristics, microsomal clearance, and plasma protein binding. Comparison of the human in vitro metabolic profile and the preclinical species DMPK datasets enabled human PK predictions.

[0355] Metabolic resistance to prodrug bioactivation: As mentioned above, the steric hindrance of the α-substituted secondary amine of the methyl ketone may slow down the hydrolysis rate of the amide-type prodrug, so that little parent is released from the system. Alternative prodrugs were designed to rely on a dual activation process, such as acyloxyalkoxycarbonyl (IV), acyloxymethyl (VI), or phosphonyloxymethyl (VII). In this case, although the first step of prodrug activation is still an enzymatic hydrolysis process, it does not involve the amino group of the methyl ketone. The distal functional group is cleaved off, followed by a chemical self-degradation that is completely independent of the methyl ketone to amine structural characteristics.

[0356] Differences between predicted human PK and preclinical POC species (rats, mice): Due to significant differences in the hydrolytic activities of esterases and / or amidases between different species, prodrugs suitable for predicted human PK may be identified, but due to PK differences, such prodrugs cannot be used in preclinical models to evaluate the duration of action. Therefore, we may have to advance so-called POC molecules with PK characteristics suitable for the purpose. Candidates will mean lead candidates and backup candidates.

[0357] Demonstrate the efficacy and improved cardiovascular safety of the prodrug in preclinical models:

[0358] Given that a longer half-life generally implies an extended duration of action, it is necessary to evaluate the overall impact of this new PK profile on the therapeutic index of the methyl ketone. Similar to the parent compound, the efficacy of the prodrug was tested in vivo in rats in the forced swim test to evaluate antidepressant-like activity and was tested in fear extinction (PTSD model) to determine the therapeutic dose range. To evaluate the cardiovascular effects, the heart rate and blood pressure of rats at an effective dose, established in the behavioral tests and compared to the parent methyl ketone, were monitored using the tail cuff method.

[0359] The parent methyl ketone showed antidepressant-like activity in the forced swim test in rats (Warner-Schmidt et al., 2023) and enhanced fear extinction, which is consistent with the beneficial effects in the mouse PTSD model (Yu et al., 2022). These three tests were used to evaluate the activity of the prodrug compared to the vehicle or methyl ketone-treated control groups. For all studies, Graphpad Prism 9 software was used, and groups were compared using ANOVA and appropriate post hoc tests. Statistical significance was set at p < 0.05. Outliers were defined as individual values more than 2 standard deviations from the mean and were removed from the analysis.

[0360] Forced swim test: To test the antidepressant-like effects of the methyl ketone prodrug compared to the parent methyl ketone, male Sprague Dawley (SD) rats weighing 180 - 200 g at arrival were subjected to the FST. Briefly, rats (N = 6 - 8 per group) were given a 15-min swim training 24 h before the 5-min FST test session. The prodrug (at 5 doses selected based on PK characteristics), parent methyl ketone (10 mg / kg), or vehicle control was administered 30 min before the test. The immobility state during the 5-min test session was scored. A decrease in immobility state reflects an antidepressant-like response. The predicted effective dose of the prodrug was determined based on the difference in immobility time between treated animals and the control group.

[0361] Fear extinction: Conditional fear is a PTSD model in which traumatic memories are formed after a single presentation (e.g., the association between a tone and a painful foot shock). Drugs that are predicted to facilitate the extinction of conditional fear (i.e., forgetting the traumatic memory) would have therapeutic benefits in PTSD. A single dose of methyone (30 mg / kg) has been shown to enhance fear extinction in mice. To test whether the prodrug maintains this beneficial effect of methyone, male C57BL / 6 mice (N = 10 - 12 per group) were tested in a conditional fear experiment. Briefly, mice were exposed to cued conditioning (one CS-US presentation in context A) on day 1, fear extinction training (six CS presentations in context B) on day 2, and extinction testing (six CS presentations in context B) on day 3. The prodrug (five doses selected based on PK profiles), the parent methyone (10 mg / kg), or vehicle control was administered 30 min before extinction training. Freezing behavior was scored as an index of the mice's memory of the CS-US association. Methyone significantly reduced freezing behavior on day 3, indicating facilitation of extinction recall. The effect of the prodrug on the time spent freezing in response to CS presentation on day 3 was compared to the vehicle or methyone-treated control groups.

[0362] Low heart rate and blood pressure assessment: Male Sprague-Dawley rats were orally administered once with the prodrug (3 - 5 doses determined by the results of the FST), the methyone positive control, or the vehicle negative control. The blood pressure parameters of the animals were evaluated using a Visitech BP-2000 tail-cuff device. The following parameters were obtained or calculated: (1) systolic blood pressure (SP, primary); (2) diastolic blood pressure (DP, primary); (3) mean pressure = (SP + DP) / 2; (4) mean arterial pressure (MAP) = DP + (SP - DP) / 3 (approximate); (5) pulse pressure = SP - DP; and (6) heart rate (HR); derived from the peak pulse pressure.

[0363] In the week prior to the day of testing the test article (prodrug) and the positive control (methyone) reagent for blood pressure effects, animals were trained in the tail-cuff device in five sessions over 5 days. In the tests after administration of the vehicle or test agent, blood pressure was evaluated at nine time points (-60, 15, 30, 45, 60, 75, 90, 105, 120 min) relative to dosing. Using GraphPad Prism, with an α threshold of 0.05, differences between the vehicle control, methyone, and each treatment group were determined by one-way ANOVA with Dunnett's multiple comparison test. The difference between the prodrug and the methyone group was particularly relevant for demonstrating improvement in the cardiovascular effects of the prodrug.

[0364] Conduct IND-supportive preclinical studies for administration to patients in the clinic:

[0365] The methyl ketone prodrug was scaled up, purified, and formulated into GMP batches, and the non-clinical toxicology program was initiated in two species (rats and dogs). A 7-day dose range finding study was conducted, followed by a 28-day GLP toxicology study to evaluate clinical signs and histopathology at three dose levels in both species. Bioanalytical testing was performed in these animals to determine the PK profiles in both species. The mutagenic potential and genotoxicity were evaluated by Ames study and chromosomal aberration (in vitro micronucleus) testing. Cardiac safety was demonstrated in a cardiovascular safety study in dogs and was supported by hERG assay (surrogate). Additional in vivo safety pharmacology included in vivo micronucleus study and respiratory and CNS studies in rats. These studies followed ICH and FDA guidance and were matched to those conducted for the parent methyl ketone.

[0366] Formulation of R&D and GMP batches: After identifying the prodrug candidate, Pisgah Laboratories initiated R&D formulation optimization. Identity and structure confirmation were performed using HPLC, FTIR, proton ( 1 H) nuclear magnetic resonance (NMR), carbon-13 ( 13 C) NMR, and liquid chromatography-mass spectrometry (LC-MS). The synthetic route that consistently yielded the prodrug with ≥95% purity at a ≥85% yield was selected for scale-up batches. Initial scale-up was completed under R&D conditions (e.g., 50 g scale based on methyl ketone). The results of synthetic optimization and initial scale-up batches were used to identify potential impurities and form the basis for stability measurements. After successful synthesis of the prodrug during the R&D process, the material was scaled up to a larger scale (e.g., 500 g based on methyl ketone) under CGMP conditions. The material produced under CGMP conditions was used for IND-enabling studies.

[0367] IND-enabling studies: For all in vivo studies, Sprague Dawley rats or beagle dogs were used, which was consistent with the previous IND-enabling studies conducted with the parent methyl ketone. All studies were conducted under GLP conditions, except for the initial dose range finding studies in rats and dogs.

[0368] Model Selection and Rationale: Rats were selected as they are a commonly used species in non-clinical studies, i.e., a rodent species accepted by regulatory agencies for non-clinical toxicity assessment. Rodents exhibit reproducible growth rates under laboratory conditions, have few exotic diseases, and a low level of spontaneous abnormalities. The total number of animals was the minimum required to correctly characterize the responses related to the administration of methyl ketone hydrochloride and thus met the experimental objectives. There is no fully validated alternative test system to replace the use of live animals in this study. Every effort has been made to obtain the maximum amount of information while minimizing the number of animals required for this study. Beagles were selected as they are a commonly used non-rodent model for evaluating the toxicity of various test articles and have an extensive historical database. The total number of animals to be used in these studies was considered the minimum required to correctly characterize the effects of the test article and was designed such that no unnecessary number of animals was required to achieve its purpose.

[0369] Toxicology Studies:

[0370] Dose Range Finding (DRF) Studies in Rats and Dogs: On Day 1, four groups of primary study animals (N = 5 per sex per group) and corresponding satellite TK study animals (N = 6 per sex per group) were dosed once by oral gavage and again on Day 8 to determine the tolerance of four different doses of the prodrug selected based on the results of pharmacokinetic analysis and the above efficacy and cardiovascular study results. The same study design applied to the DRF study in beagles (N = 2 per sex per group for the primary study and another N = 2 per sex per group for TK analysis). All animals were evaluated for their life procedures (mortality / cage-side observations, clinical cage-side observations, body weight, food consumption, and ophthalmic examinations), clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), bioanalysis and toxicokinetic evaluations, and terminal necropsy (gross pathology) according to standard procedures, statistical analysis, and in accordance with FDA guidance. The results provided information for dose selection for all in vivo IND-supportive studies.

[0371] 28-Day Toxicology Studies in Rats and Dogs: The objective was to determine the potential toxicity of the prodrug when administered once weekly for four weeks. In accordance with the standard protocol, as in the studies using the parent methyl ketone, the prodrug was studied for four weeks in rats and dogs by oral gavage, with a 14-day recovery period. There were four groups (3 dose levels + vehicle) of male and female rats (for the main study, N = 10 per sex per group; for the recovery study, N = 5 per sex per group) and corresponding satellite animal cohorts for TK analysis (N = 3 per sex per group for the vehicle group; N = 9 per sex per group for the treated groups). The prodrug was administered by oral gavage on Days 1, 8, 15, and 22, consistent with the studies of the parent methyl ketone. The same experimental design applied to the 28-day study in beagle dogs (for the main study, N = 4 per sex per group; for the recovery study, N = 2 per sex per group). All procedures were conducted under GLP conditions. All animals (main study and recovery) were evaluated for lifetime procedures (mortality / cage-side observations, clinical cage-side observations, detailed clinical observations, body weight, food consumption, and ophthalmic examinations), clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), bioanalytical and toxicokinetic evaluations, and terminal necropsy (tissue collection, organ weights, histopathology, and microscopic evaluations) according to standard procedures, statistical analysis, and in accordance with FDA guidance.

[0372] Ames Study (Bacterial Reverse Mutation): The objective of this study was to evaluate the mutagenic potential of the prodrug in inducing 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. The prodrug, appropriate positive controls (ICR, 2NF, SA, NQNO, and 2AA), and negative control (vehicle) were run in triplicate with and without the metabolic activation mixture S9. Standard test article concentrations were 1.0, 5.0, 10, 50, 500, 1000, and 5000 μg / plate in the absence of toxicity or solubility limitations. After a two-day incubation period, each plate was evaluated for precipitation of the test article and thinning of the background lawn. The number of reverse mutation colonies was counted and recorded. If the test article induced an increase in the mean revertants per concentration with increasing test article concentration, and this increase was at least 2-3 times the background frequency of the vehicle control, the test article was considered positive for mutagenicity.

[0373] Rat micronucleus study: The aim was to determine the potential genotoxicity of the prodrug when administered to rats by oral gavage for two consecutive days. The dose range finding (DRF) phase determined the tolerance and provided dose levels for the definitive study. For the DRF, the tolerance of three groups of rats (N = 3 per group) treated with three doses of the prodrug was evaluated. For the main study, five groups of rats (N = 5 per group) were treated once daily by oral gavage with the vehicle or 4 doses of the prodrug (based on the micronucleus DRF results) for 2 days. Detailed cage-side and clinical observations were made before dosing, after dosing, and daily until termination, 48 h after dosing. Micronucleus evaluation was performed by flow cytometry using peripheral blood and a standard protocol. Criteria for a positive response: (1) compared to the concurrent negative control, at least one treatment group showed a statistically significant increase in the percentage of reticulocytes with micronuclei (MN-RET) (p ≤ 0.05); and (2) this increase was dose-related (p ≤ 0.05); and (3) any increase exceeded the 95% control interval of historical negative control data. Criteria for a negative response: (1) compared to the concurrent negative control, no treatment group showed a statistically significant increase in %MN-RET; and (2) the increase in %MN-RET was not dose-related; and (3) all results were within the 95% control interval of historical negative control data; and (4) bone marrow exposure to the test item had been demonstrated.

[0374] Chromosome aberration (in vitro micronucleus) test: This test evaluates the ability of the test article to disrupt chromosomes to interfere with normal cell mitosis. The aim of this study was to evaluate the potential of the prodrug to induce micronuclei in TK6 cells in the presence and absence of an exogenous metabolic activation system using short-term and long-term treatments. The prodrug, vehicle control, or appropriate positive controls (cyclophosphamide monohydrate, mitomycin C, vinblastine sulfate) were evaluated using standard procedures. The target concentrations for the DRF study were 0.977, 1.95, 3.91, 7.81, 15.6, 31.3, 62.5, 125, 250, 500 μg / mL. Cytotoxicity, pH changes, and signs of precipitation of all cultures were visually evaluated at the time of dosing, washing, and harvesting. For the definitive study, single cultures were treated with the vehicle, positive control, and the 6 highest test article concentrations determined in the DRF. Criteria for a positive response were: (1) compared to the concurrent negative control, at least one test concentration showed a statistically significant increase; (2) the increase was dose-related; and (3) any result exceeded the 95% control limit of the historical negative control distribution.

[0375] hERG assay: The aim of this study was to examine the effect of the prodrug on hERG (human ether-à-go-go related gene) channel current (I KrSubstitute, in vitro effects on rapidly activating, delayed rectifier cardiac potassium current). hERG gives rise to the rapidly delayed rectifier current (I Kr ) in the human ventricle. This channel was chosen for evaluation because inhibition of I Kr is the most common cause of drug-induced prolongation of the cardiac action potential. An increase in action potential duration leads to QT interval prolongation and is associated with dangerous ventricular arrhythmias, torsades de pointes (TdP). In this assay, the hERG potassium channel was expressed in a human embryonic kidney (HEK-293) cell line lacking endogenous I Kr . The concentration-response relationship of the prodrug's effect on hERG potassium channel current was evaluated at near-physiological temperature (35 to 37 °C). Using one-way ANOVA followed by Dunnett's multiple comparison, the percentage of inhibition at each concentration in the test groups was compared to the vehicle control group, and significant inhibition was defined as p < 0.05 level.

[0376] Core battery of safety pharmacology studies:

[0377] Dog cardiovascular (CV) study: The aim was to evaluate the potential CV effects of the prodrug in conscious, freely moving beagle dogs when administered once via oral gavage at each dose level using a Latin square design. Four groups (N = 4 male dogs per group) received three different doses of the prodrug or vehicle control. Hemodynamic endpoints, body temperature, and electrocardiogram (ECG) were continuously monitored via an implanted telemetry device for at least 2 hours before dosing and at least 24 hours after dosing. Interpretation of the results was based on safety thresholds according to FDA guidelines.

[0378] Rat respiration study: The aim of this study was to evaluate the potential acute respiratory effects of the prodrug in rats. Four groups of male rats (N = 8 per group) were being studied. Parameters to be evaluated included respiratory rate, tidal volume, and minute volume. Animals were placed in a respiration monitoring chamber for at least 2.5 hours before dosing to allow for environmental acclimation and collection of pre-dose data. After at least 2.5 hours in the chamber, the animals were temporarily removed from the chamber for dosing with the prodrug (3 dose levels) or vehicle. Immediately after dosing, the animals were returned to the chamber and respiration monitoring continued for at least a 6-hour period. Data were collected continuously during the study, recorded at 1-minute intervals, and reported at 15-minute intervals. Repeated measures analysis of covariance was used to evaluate the treatment effect over time.

[0379] Rat CNS Study: The purpose of this study was to evaluate the potential acute neurobehavioral effects of the prodrug. Four groups of male Sprague Dawley rats (N = 8 per group) were treated with one of three doses of the prodrug vehicle or the vehicle. Neurobehavioral evaluations (activity, autonomic, excitatory, neuromuscular, physiological, and sensorimotor) were performed before dosing (Day -1) and at approximately 1.5, 6, and 24 h after dosing. Each animal was observed for 2 minutes in an opaque open - top observation chamber.

[0380] Those skilled in the art will appreciate that changes can be made to the above - described embodiments without departing from the broad inventive concept of the invention. It is, therefore, to be understood that the invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the invention as defined by the appended claims.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is -C(O)- or -CH 2 -; X is independently selected from the group consisting of: (a) an amino acid or a 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 ; (i) (j) (k) and (l) wherein: n is 3 or 4; R 1 and R 2 each independently is -C 1-6 alkyl or -C 3-6 cycloalkyl; R 3 selected from the group consisting of: -C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, R 4 、R 7 、R 8 、R 9 and R 10 each independently is H, -C 1-6 alkyl or C 3-6 cycloalkyl; R 5 selected from the group consisting of: -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids, and peptides; Z a and Z b each independently is O or NR 4 ; Z c Selected from: OC(O)R 3 or OP(O)(OR 4 ) 2 ; R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ; R 11 and R 12 each independently is H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl; Wherein when Y is -CH 2 -, X is not an amino acid, a peptide or a -P(O)(OH) 2 group.

2. The compound according to claim 1, wherein R 1 and R 2 are each independently methyl or ethyl.

3. The compound according to claim 1, wherein R 4 is H or methyl.

4. The compound according to claim 1, wherein Y is -C(O)- and X is an amino acid.

5. The compound according to claim 1, wherein X is 6. A compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein n is 3 or 4; X is independently selected from the group consisting of: (a) an amino acid or a 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 ; (i) (j) (k) and (l) wherein R 1 and R 2 each independently is -C 1-6 alkyl or -C 3-6 cycloalkyl; R 3 selected from the group consisting of: -C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, R 4 、R 7 、R 8 、R 9 and R 10 each independently is H, -C 1-6 alkyl or C 3-6 cycloalkyl; R 5 selected from the group consisting of: -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids and peptides; Z a and Z b each independently is O or NR 4 ; Z c Selected from: OC(O)R 3 or OP(O)(OR 4 ) 2 ; R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ; R 11 and R 12 each independently is H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

7. The compound according to claim 6, wherein R 1 and R 2 are each independently methyl or ethyl.

8. The compound according to claim 6, wherein R 4 is H or methyl.

9. The compound according to claim 6, wherein X is an amino acid.

10. The compound according to claim 6, wherein X is 11. The compound according to claim 6, wherein the compound is selected from the group consisting of Compounds 1 - 402 of Tables 1, 2, and 3.

12. A compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: X is independently selected from the group consisting of: (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 , (g) (h) (i) and (j) wherein: n is 3 or 4; R 1 and R 2 each independently is -C 1-6 alkyl or -C 3-6 cycloalkyl; R 3 selected from the group consisting of: -C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, R 4 、R 7 、R 8 、R 9 and R 10 each independently is H, -C 1-6 alkyl or C 3-6 cycloalkyl; R 5 selected from the group consisting of: -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids and peptides; Z a and Z b each independently is O or NR 4 ; Z c Selected from: OC(O)R 3 or OP(O)(OR 4 ) 2 ; R 6 selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ; R 11 and R 12 each independently is H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

13. The compound according to claim 12, wherein R 1 and R 2 are each independently methyl or ethyl.

14. The compound according to claim 12, wherein R 4 is H or methyl.

15. The compound according to claim 12, wherein X is 16. A compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein: X is independently selected from the group consisting of: (a) an amino acid or a 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 ; (i) (j) (k) and (l) wherein: n is 3 or 4; R 3 selected from the group consisting of: -C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, R 4 、R 7 、R 8 、R 9 and R 10 each independently is H, -C 1-6 alkyl or C 3-6 cycloalkyl; R 5 selected from the group consisting of: -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 each independently is O or NR 4 ; Z c Selected from: OC(O)R 3 or OP(O)(OR 4 ) 2 ; R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ; R 11 and R 12 each independently is H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

17. The compound according to claim 16, wherein R 4 is H or methyl.

18. The compound according to claim 16, wherein X is an amino acid.

19. A compound of formula (50): or a pharmaceutically acceptable salt thereof.

20. A compound of formula (VI): or a pharmaceutically acceptable salt thereof, wherein: X is independently selected from the group consisting of: (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 , (g) (h) (i) and (j) wherein: n is 3 or 4; R 3 selected from the group consisting of: -C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl, R 4 、R 7 、R 8 、R 9 and R 10 are each independently H, -C 1-6 alkyl or C 3-6 cycloalkyl; R 5 selected from the group consisting of: -C(O)R 3 、-C(O)OR 3 、-P(O)OR 11 (OR 12 )、amino acids and peptides; Z a and Z b each independently is O or NR 4 ; Z c Selected from: OC(O)R 3 or OP(O)(OR 4 ) 2 ; R 6 selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF 3 ; R 11 and R 12 each independently is H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

21. The compound according to claim 20, wherein R 4 is H or methyl.

22. The compound according to claim 20, wherein X is 23. The compound according to claim 20, wherein the compound is selected from the group consisting of Compounds 403 - 511 of Table 4.

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

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

26. The method according to 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, conditions associated with cancer, hypomotility, burnout, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorder, nausea or vomiting.

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

28. The method according to claim 25, wherein the treatment is for anxiety disorder.

29. The method according to claim 25, wherein the treatment is for depression.

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