WO2023033680A1

WO2023033680A1 - Substituted 2,3,4,5-tetrahydrobenzo[ f][1,4]oxazepines as modulators of trace amine-associated receptor 1 (taar1)

Info

Publication number: WO2023033680A1
Application number: PCT/RU2022/050271
Authority: WO
Inventors: Raul Radikovich GAINETDINOV; Andrey Sergeevich GERASIMOV; Aleksey Yurievich LUKIN; Mikhail Yurievich KRASAVIN
Original assignee: Limited Liability Company «Excellena Research And Development» (Llc «Excellena»)
Priority date: 2021-09-01
Filing date: 2022-09-01
Publication date: 2023-03-09
Also published as: WO2023033680A4

Abstract

7-Substituted 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines of general formula 1 and their pharmaceutically acceptable salts which are modulators of trace amine-associated receptor 1 (TAAR1) are disclosed. The method for producing the compounds of formula 1, pharmaceutical composition on their basis and use of said compounds and pharmaceutical composition for treating a disease, disorder or condition mediated by trace amine receptors TAAR1 such as mental disorders, cognitive disorders, metabolic disorders, neurological and neurodegenerative diseases are provided.

Description

SUBSTITUTED 2,3,4,5-TETRAHYDROBENZO[F][l,4]OXAZEPINES AS MODULATORS OF TRACE AMINE-ASSOCIATED RECEPTOR 1 (TAAR1) Field of the invention

The present invention relates to substituted 2,3,4,5-tetrahydrobenzo[/][l,4]oxazepines or pharmaceutically acceptable salts thereof exhibiting properties of a trace amine receptor (TAAR1) agonist, a method for production thereof, a pharmaceutical composition on their basis and a use thereof.

Background

The discovery in 2001 of a new class of monoaminergic receptors coupled to G-proteins (G protein-coupled receptors, GPCRs) - receptors associated with trace amines (Trace Amine- Associated receptors, TAARs, 9 genes identified in humans, TAAR1-TAAR9) - has opened an avenue for understanding the functional role of endogenous trace amines (Trace amines, TA) in mammalian physiology and pathology [Borowsky et al. 2001; Bunzow et al., 2001; Berry et al., 2017], Trace amines such as P-phenyl ethylamine (PEA), tyramine, tryptamine and octopamine are structurally similar to classical monoamines and play an important role in invertebrate physiology, but their functions in the body of mammals, where they are present in trace amounts, remain unknown. Determining the role of these amines and their receptors in mammalian physiology would explain many enigmas in pathology and pharmacology of monoaminergic synaptic transmission [Sotnikova et al., 2008], In general, TAs are present in the CNS and function in parallel with monoaminergic pathways. TAs are structurally related, co-localized and recovered with biogenic amines and neurotransmitters. TAs are thought to posses the neuromodulatory functions of classical neurotransmitters such as dopamine, serotonin and norepinephrine which levels are affected by all antidepressants and antipsychotics currently being used in clinical practice. Dysfunctions in TA physiology have long been associated with schizophrenia and mood disorders. Increased urine PEA levels, changes in tryptamine and tyramine metabolism, and changes in enzymes involved in the synthesis and catabolic pathways of these amines have been shown to be associated with schizophrenia. Four decades ago, PEA hypothesis was developed to explain causes underlining depression development which postulates that PEA deficiency is related to endogenous depression: pilot studies have shown that the use of this amine or its precursor reduces symptoms of depression. Altered levels of trace amines have also been found in patients suffering from attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, and some other brain diseases [Lindemann & Hoener, 2005], Therefore, it is believed that the identification of new ligands for TA receptors could lead to the development of therapeutics targeting this new neuromodulatory system.

TAAR1 is the most investigated receptor among TAARs which represents a new target for pharmacology of a wide range of mental, neurological and metabolic disorders, and substances acting on TAAR1 are already on the stage of clinical trials [Revel et al. 2011; Revel et al. 2012; Berry et al., 2017], TAAR1 is a proven target for endogenous TAs. The TAAR1 gene is expressed in brain structures associated with mental disorders, in particular in those key areas where modulation of dopamine (ventral tegmental region) and serotonin (brainstem raphe nucleus) occurs, as well as in the amygdala, hypothalamus, nucleus accumbens, entorhinal and frontal cortex and subiculum. Therefore, even if the TA function is not impaired, neuromodulatory effects on monoaminergic pathways could predictably lead to improved mental health. Several TAAR1 agonist molecules and the TAAR1 -knockout mouse strain (TAAR1-KO mice) have recently been developed [CA2856204; WO2016016292 Al; W02008052907A1; W02008046757A1], Their use in studies has shown that TAAR1 agonists should be effective in the treatment of mental and a number of other disorders such as schizophrenia, depression, ADHD, drug abuse, Parkinson’s disease, sleep disorders by acting either directly or indirectly on monoaminergic pathways [Revel et al. 2011; Revel et al. 2012], High TAAR1 expression levels were also found in the pancreas, stomach and intestines, and preclinical studies have shown the efficacy of TAAR1 agonists in metabolic disorders such as obesity and diabetes. TAAR1 expression was also shown in leukocytes suggesting the involvement of this receptor in immunological processes [Lam et al., 2015],

Searches for new TAAR1 receptor modulators and their use as agents for the treatment of mental disorders, cognitive disorders, metabolic disorders, neurological and neurodegenerative diseases are very relevant.

Summary of invention

The present inventors have surprisingly found that 7-substituted 2,3,4,5- tetrahydrobenzo[/][l,4]oxazepines exhibit properties of a trace amine receptor 1 (TAAR1) agonist and can be used to treat diseases mediated by trace amine receptors TAAR1. Therefore, the present invention relates to a number of 7-substituted 2,3,4,5- tetrahydrobenzo[/][l,4]oxazepines, a method for production thereof, a pharmaceutical composition on their basis and a use of said compounds.

According to one aspect, the present invention provides a compound of formula 1

or a pharmaceutically acceptable salt thereof, where R is selected from the group including:

Ci-Cio alkyl optionally substituted with 1-3 substituents selected from the group including: hydroxy group, aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and C3-C8 cycloalkyl, amino group wherein the amino group is optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkylcarbonyl group, Cs-Cs cycloalkylcarbonyl group and Ce-Cu aryl optionally substituted with 1-5 substituents selected from C1-C10 alkyl and halogen, and

C1-C10 alkoxy group wherein the alkoxy group is optionally substituted with C6-C14 aryl optionally substituted with 1-5 substituents selected from C1-C10 alkyl and halogen; aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including C1-C10 alkyl and C1-C10 alkyl Ce-Cu aryl wherein Ce-Cu aryl is optionally substituted with 1-5 substituents selected from C1-C10 alkyl and halogen, amino group optionally substituted with 1-2 substituents selected from the group including C1-C10 alkyl and C3-C8 cycloalkylcarbonyl group,

5- or 6-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen and sulfur, and

6-membered saturated heterocyclyl containing 2 heteroatoms selected from oxygen, sulfur and nitrogen wherein 1 heteroatom is nitrogen.

According to another aspect, the present invention provides a method for producing the compound of formula 1 comprising the following steps:

(a) contacting 5-bromosalicylic aldehyde with ethanolamine followed by reduction of the resulting compound to form the compound of formula 4

(b) attaching the protective tert-butoxycarbonyl group to the amino group of the compound of formula 4 to form a compound of formula 5

(c) cyclodehydrating the compound of formula 5 in the Mitsunobu reaction to form a compound of formula 6

(d) converting the compound of formula 6 to a compound of formula 1.

In another aspect, the present invention provides a pharmaceutical composition for treating a disease, disorder or condition mediated by trace amine receptors TAAR1 comprising a therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

According to another aspect, the present invention provides use of the compound of formula 1 or pharmaceutical composition described herein for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.

In another aspect, the present invention provides a compound described herein for use in treating a disease, disorder or condition mediated by trace amine receptors TAAR1.

In another aspect, the present invention provides use of compound described herein for producing a drug for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.

In another aspect, the present invention provides a method for treating disease, disorder or condition mediated by trace amine receptors TAAR1 in a subject comprising administration of a therapeutically effective amount of the compound of formula 1 or pharmaceutical composition described herein to the subject.

The present invention also relates to a method for activating the trace amine receptor TAAR1 by contacting said receptor with the compound of formula 1.

Detailed description of invention

Definitions of various terms used to describe the present invention are set forth below. These definitions apply to terms as used in this specification and claims, unless otherwise limited in specific cases, either individually or as part of a larger group. It should be noted that in the present specification and claims the singular forms include references to the plural, unless the context clearly dictates otherwise.

The term «alkyl» as used herein refers to straight or branched chain saturated hydrocarbon radicals containing 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms. Examples of Ci-Cio alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl and tertbutyl. The term «cycloalkyl» means a monovalent saturated carbocyclic group containing 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, which can be monocyclic or polycyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and etc.

The term «aryl» as used herein refers to a cyclic aromatic hydrocarbon without heteroatoms. Aryl groups include monocyclic, bicyclic and polycyclic ring systems and contain 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, even more preferably 6 to 10 carbon atoms in the ring moieties of the groups. Aryl groups include, but are not limited to, phenyl, diphenyl and naphthyl. Preferably, the term «aryl» means phenyl.

The term «alkylaryl» means alkyl substituted with aryl wherein the alkyl and aryl are as defined above.

The term «heteroaryl» as used herein refers to mono- or polycyclic aromatic radicals containing 5 or more ring members of which one or more is/are a heteroatom selected from N, O or S, and the remaining ring atoms are carbon atoms. In some embodiments of the invention, heteroaryl is 5- or 6-membered heteroaryl. In some embodiments of the invention, heteroaryl contain 1 or 2 heteroatoms selected from N, O or S. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl or quinoxalinyl.

The term «heterocyclyl» or «heterocyclic» means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system containing 3 or more atoms in the cycle of which one or more atom(s) is/are a heteroatom such as, but not limited to, N, O, S. In some embodiments, heterocyclyl is 5-10 membered heterocyclyl, preferably 5-6 membered heterocyclyl. In some embodiments, heterocyclic groups contain 1 or 2 heteroatoms selected from N, O, S. Heterocyclyl may have one or more substituents which may be the same or different. Nitrogen and sulfur atoms within heterocyclyl can be oxidized to N-oxide, S-oxide or S-di oxide. Examples of heterocyclyl s include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, l,4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, etc.

The term «hydroxy group» or «hydroxyl group» means -OH group.

The term «alkoxy» refers to -O-alkyl group or -O-cycloalkyl group wherein the alkyl and cycloalkyl are as defined above. Examples of -O-alkyl group include, but are not limited to: methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyl oxy. «Ci-Cio alkoxy» refers to -O-alkyl wherein the alkyl is Ci-Cio alkyl. Examples of -O-cycloalkyl groups include, but are not limited to: -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl and -O- cyclohexyl.

The term «halogen» refers to fluoride, bromide, chloride and iodide. The term «amino group» means -NH2 group.

The term «aminocarbonyl» or «aminocarbonyl group» means -C(=O)NH2 group.

The term «alkylcarbonyl» or «alkylcarbonyl group» means -C(=O)alkyl group wherein the alkyl is as defined above.

The term «cycloalkylcarbonyl» or «cycloalkylcarbonyl group» means -C(=O)cycloalkyl group wherein the cycloalkyl is as defined above.

In this specification, the term «optionally substituted» group refers to a substituted or unsubstituted group and means that said group may be substituted at one or more positions with 1, 2, 3, 4 or 5 substituents. The terms «optionally substituted» and «substituted or unsub stituted» may be used interchangeably. Examples of substituting groups (substituents) include, but are not limited to, alkyl, cycloalkyl, halogen, hydroxy group, alkoxy group, aryl, amino group, aminocarbonyl group, alkylcarbonyl group, cycloalkyl carbonyl group, heteroaryl, heterocyclyl.

Those skilled in the art will appreciate that compounds of the present invention may exhibit properties of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. Since the depicted structural formulas in the specification and claims may represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the present invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of compounds having one or more uses described herein, as well as mixtures of these different forms.

By «pharmaceutically acceptable» is meant a material that is not biologically or otherwise undesirable, for example, this material can be incorporated in a pharmaceutical composition administered to a subject without causing any undesirable biological effects or harmful interaction with any of other components of the composition containing the same. When the term «pharmaceutically acceptable» is used to refer to an excipient, it is understood that the excipient meets the required standards of toxicological and manufacturing tests.

The term «subject» refers to an animal, such as a mammal (including a human), that was or will be the subject of treatment, observation or experiment. «Subject» and «patient» may be used interchangeably unless indicated otherwise. The methods described in this specification can be used in the treatment of human and/or in veterinary. In some embodiments, the subject is a mammal. In some embodiments, the subject is human.

The terms «therapeutically effective amount» and «effective amount» are used interchangeably and refer to the amount of a compound that is sufficient to conduct the treatment, as defined below, when administered to a patient (e.g., human) in need of such treatment, in one or more doses. The therapeutically effective amount may vary depending on the disease to be treated, patient’s weight and/or age, disease severity or route of administration determined by the qualified physician prescribing a preparation or giving care.

The term «treatment» means administration of a compound described herein for the purpose of: (i) delaying disease onset, i.e. preventing the development or delaying clinical symptoms of a disease; (ii) inhibiting a disease, i.e. arresting the development of clinical symptoms; and/or (iii) alleviating a disease, i.e. causing regression of clinical symptoms or their severity.

The term «excipient» means pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, disintegrants, glidants, dispersants, preservatives, stabilizers, humectants, emulsifiers, suspending agents, thickeners, sweeteners, odorants, flavoring agents, antibacterial agents, lubricants, regulators of prolonged delivery, etc., the choice and ratio of which depend on the nature and method of prescription and dosage. Examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, as well as mixtures of these substances. The protection against the action of microorganisms can be provided using a variety of antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition can also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided by agents slowing down active ingredient absorption, e.g., aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohols and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers include lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of disintegrants and dispersants include starch, alginic acid and its salts, silicates. Examples of lubricants and glidants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.

The pharmaceutical composition of the present invention may be formulated as an oral dosage form such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions; sublingual and buccal dosage form; aerosols, implants; dosage form for topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, intraocular or rectal administration.

The most convenient route of administration is commonly oral using a normal daily dosage regimen which can be adjusted depending on disease severity and patient’s response.

In a tableting process, an active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compressed into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. Tablets may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like in addition to an active ingredient.

Liquid dosage forms suitable for oral administration are emulsions, syrups, elixirs and aqueous suspensions. They include solid dosage forms which are intended to be converted to liquid preparations immediately prior to use. Emulsions can be prepared in solutions, e.g., in aqueous solutions of propylene glycol, or may contain emulsifiers such as lecithin, sorbitol monooleate or acacia gum. Aqueous suspensions can be prepared by dispersing a finely grinded active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.

The term «pharmaceutically acceptable salt» means relatively non-toxic organic and inorganic salts of the compounds claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or specially prepared. In particular, base salts can be specially prepared from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts obtained in this manner are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (a detailed description of properties of such salts is provided in Berge S.M., et al., Pharmaceutical Salts, J. Pharm. Sci. 1977, 66: 1- 19).

The present invention relates to substituted 2,3,4,5-tetrahydrobenzo[/][l,4]oxazepines exhibiting properties of a trace amine receptor TAAR1 agonist, i.e. compounds of formula 1

or pharmaceutically acceptable salts thereof, where R is selected from the group including:

Ci-Cio alkyl optionally substituted with 1-3 substituents selected from the group including: hydroxy group, aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and Cs-Cs cycloalkyl, amino group wherein the amino group is optionally substituted with 1- 2 substituents selected from the group including Ci-Cio alkylcarbonyl group, Cs-Cs cycloalkylcarbonyl group and Ce-Cu aryl optionally substituted with 1- 5 substituents selected from C1-C10 alkyl and halogen, and

C1-C10 alkoxy group wherein the alkoxy group is optionally substituted with Ce-Cu aryl optionally substituted with 1-5 substituents selected from C1-C10 alkyl and halogen; aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including C1-C10 alkyl and C1-C10 alkyl Ce-Cu aryl wherein Ce-Cu aryl is optionally substituted with 1-5 substituents selected from C1-C10 alkyl and halogen, amino group optionally substituted with 1-2 substituents selected from the group including C1-C10 alkyl and C3-C8 cycloalkylcarbonyl group,

In one embodiment of the invention, R is 6-membered heteroaryl containing 1 nitrogen atom.

In another embodiment of the invention, R is aminocarbonyl group substituted with Ci- C10 alkyl Ce-Cu aryl wherein Ce-Cu aryl is optionally substituted with 1 substituent selected from C1-C10 alkyl and halogen.

In another embodiment of the invention, R is C1-C10 alkyl substituted with aminocarbonyl group.

In another embodiment of the invention, R is C1-C10 alkyl substituted with C1-C10 alkoxy group wherein the alkoxy group is substituted with Ce-Cu aryl optionally substituted with 1 substituent selected from C1-C10 alkyl and halogen.

In another embodiment of the invention, R is C1-C10 alkyl substituted with amino group wherein the amino group is substituted with 2 substituents selected from the group including Ci- C10 alkylcarbonyl group, C3-C8 cycloalkylcarbonyl group and Ce-Cu aryl optionally substituted with 1 substituent selected from C1-C10 alkyl and halogen.

In another embodiment of the invention, R is amino group substituted with 1-2 substituents selected from the group including C1-C10 alkyl and C3-C8 cycloalkylcarbonyl group.

In another embodiment of the invention, R is 6-membered saturated heterocyclyl containing 1 nitrogen atom and 1 heteroatom selected from oxygen and sulfur.

In another embodiment of the invention, R is C1-C10 alkyl substituted with hydroxy group.

The following compounds are preferred:

7-Pyridin-4-yl-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine dihydrochloride (1.1.1, TRX-0019)

7V-Benzyl-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine-7-carboxamide hydrochloride (1.2.1, TRX- 0021)

7V-(2-Fluorobenzyl)-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine-7-carboxamide hydrochloride

(1.2.2, TRX-0022)

HC1;

7-[(2-Chlorobenzyloxy)methyl]-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine hydrochloride (1.4.1,

TRX-0025)

7-[(3-Fluorobenzyloxy)methyl]-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine hydrochloride (1.4.2, TRX-0026)

7-[(4-Chlorobenzyloxy)methyl]-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine hydrochloride (1.4.3, TRX-0027)

2-Methyl-7V-(4-methylphenyl)-7V-[(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7-yl)methyl]- propanamide hydrochloride (1.5.1, TRX-0029)

7V-[(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)methyl]-7V-(4-fluorophenyl)acetamide hydrochloride (1.5.2, TRX-0030)

7V-[(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)methyl]-7V-phenylcyclopropanecarboxamide hydrochloride (1.5.3, TRX-0031)

7V,7V-Dimethyl-(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7-yl)amine dihydrochloride (1.6.1, TRX-0032)

7V-(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)cyclopropanecarboxamide hydrochloride

(1.6.2, TRX-0033)

; l-(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)ethanol hydrochloride (1.7.1, TRX-0035)

HC1;

(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)methanol hydrochloride (1.7.2, TRX-0036)

HC1.

In some embodiments, the compound of formula 1 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.1 mg to about 1000 mg, preferably about 1 mg to about 800 mg, more preferably about 10 mg to about 600 mg.

In some embodiments, the compound of formula 1 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg.

In some embodiments, the excipient may be selected from the group including pharmaceutically acceptable a carrier, a diluent, a filler and a solvent.

The amount of any individual excipient in the composition may vary depending on the role of excipient, requirements to the dosage of active agent components, and particular demands of the composition.

However, the excipient is typically present in the composition in an amount of about 1 wt.% to about 99 wt.%, preferably about 5 wt.% to about 98 wt.%, more preferably about 15 wt.% to about 95 wt.% of the total weight of the composition. In general, the amount of excipient present in the inventive composition is selected from the following: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 95% by weight.

The pharmaceutical composition of the present invention may be made as a dosage form selected from the group including tablets, powders, granules, pills, suspension, pellets, capsules, sachets and injectable solution.

In another aspect, the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt thereof or pharmaceutical composition described herein for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.

According to another aspect, the present invention provides the compound of formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.

In another aspect, the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt thereof or pharmaceutical composition described herein for producing a drug for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.

Typically, the therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof is about 0.1 mg/day to 1000 mg/day, preferably about 1 mg/day to about 800 mg/day, more preferably about 10 mg/day to about 600 mg/day administered either as a single dose or as multiple doses. In some embodiments, multiple doses include two, three or four doses per day. The dosage may be altered depending on patient’s age, body weight, susceptibility, symptom or compound efficacy.

In some embodiments, said disease, disorder or condition mediated by trace amine receptors TAAR1 is selected from the group including mental disorder, cognitive disorder, metabolic disorder, neurological and neurodegenerative disease.

In some embodiments, said disease, disorder or condition mediated by trace amine receptors TAAR1 is selected from the group including depression, anxiety, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-induced disorder, psychosis, schizophrenia, obsessive-compulsive disorder, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, high blood pressure, alcohol or drug abuse, nicotine addiction, eating disorder, diabetes, diabetes complications, obesity, dyslipidemia, disorders associated with energy consumption and expenditure, disorders associated with impaired body temperature homeostasis, sleep and circadian rhythm disorder, and cardiovascular disorder.

In another aspect, the present invention provides a method for activating the trace amine receptor TAAR1 by contacting said receptor with the compounds of formula 1.

In another aspect, the present invention provides the method for preparing the compound of formula 1 or a pharmaceutically acceptable salt thereof. Various synthetic approaches are used depending on the nature of substituent R, however, a common starting compound is 7- bromoxazepine 6 which is prepared according to the following scheme

Therefore, according to the present invention, the method for obtaining compound 1 includes the next steps:

(a) contacting 5-bromosalicylic aldehyde with ethanolamine followed by reduction of the resulting compound to form a compound of formula 4,

(b) attaching the protective tert-butoxycarbonyl group to the amino group of the compound of formula 4 to form a compound of formula 5,

(c) cyclodehydrating the compound of formula 5 in the Mitsunobu reaction to form a compound of formula 6, and

(d) converting the compound of formula 6 to a compound of formula 1

where values of R are as defined above for the compound of formula 1.

In one embodiment of the invention, in step (d), the compound of formula 6 is converted to the compound of formula 1 where R is heteroaryl, in particular to the heteroaryl -substituted benzoxazepine 1.1, according to the following scheme:

by introducing said heteroaryl using the Suzuki reaction and then removing the tertbutoxy carbonyl protective group.

In some embodiments of the invention, R in the compound of formula 1 is 5- or 6- membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen and sulfur. In a preferred embodiment of the invention, R in the compound of formula 1 is 6-membered heteroaryl containing 1 nitrogen atom.

In another embodiment of the invention, in step (d), the compound of formula 6 is converted to the compound of formula 1 where R is optionally substituted aminocarbonyl group, in particular to carboxamide 1.2, according to the following scheme:

by carbonylating the compound of formula 6 followed by reacting the resulting compound with amine and removing the tert-butoxy carbonyl protective group. In one embodiment of the invention, the reaction of the compound of formula 8 with amine is carried out in the presence of TV, TV ’-carbonyl diimidazole (CD I).

In some embodiments of the invention, said amine is the amine of general formula R.'R²NH where R¹ and R² are independently selected from the group including H, Ci-Cio alkyl and Ci-Cio alkyl Ce-Cu aryl wherein Ce-Cu aryl is optionally substituted with 1-5 substituents selected from C1-C10 alkyl and halogen.

In some embodiments of the invention, R in the compound of formula 1 is aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and Ci-Cio alkyl Ce-Cu aryl wherein Ce-Cu aryl is optionally substituted with 1-5 substituents selected from Ci-Cio alkyl and halogen.

In preferred embodiments of the invention, R in the compound of formula 1 is aminocarbonyl group substituted with Ci-Cio alkyl Ce-Cu aryl wherein Ce-Cu aryl is optionally substituted with 1 substituent selected from Ci-Cio alkyl and halogen.

In another embodiment of the invention, in step (d), the compound of formula 6 is converted to the compound of formula 1 where R is Ci-Cio alkyl substituted with optionally substituted aminocarbonyl group, in particular to benzoxazepinylpropanamide 1.3, according to the following scheme:

by formylating the compound of formula 6 followed by the Horner-Wodsworth-Emmons reaction to form the compound of formula 11, reducing a double bond in the resulting compound of formula 11 followed by hydrolysis of ester group to form the compound of formula 13, contacting the compound of formula 13 with amine, and removing the tert-butoxy carbonyl protective group.

In some embodiments of the invention, said amine is an amine of general formula R'R²NH where R¹ and R² are independently selected from the group including H, C1-C10 alkyl and C3-C8 cycloalkyl.

In some embodiments of the invention, R in the compound of formula 1 is C1-C10 alkyl substituted with aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including C1-C10 alkyl and C3-C8 cycloalkyl.

In a preferred embodiment of the invention, R in a compound of formula 1 is C1-C10 alkyl substituted with aminocarbonyl group.

In another embodiment of the invention, in step (d), the compound of formula 6 is converted to a compound of formula 1 where R is alkyl substituted with alkoxy group, in particular to the compound of formula 1.4, according to the following scheme:

by formylating the compound of formula 6 to form a compound of formula 10, reducing the carbonyl group of the resulting compound to form a compound of formula 15 followed by O- alkylation and removing the tert-butoxy carbonyl protective group.

In some embodiments of the invention, R in the compound of formula 1 is C1-C10 alkyl substituted with C1-C10 alkoxy group wherein the alkoxy group is optionally substituted with Ce- C14 aryl optionally substituted with 1-5 substituents selected from C1-C10 alkyl and halogen.

In preferred embodiments of the invention, R in the compound of formula 1 is C1-C10 alkyl substituted with C1-C10 alkoxy group wherein the alkoxy group is substituted with Ce-Cu aryl optionally substituted with 1 substituent selected from C1-C10 alkyl and halogen.

In one embodiment of the invention, in step (d), the compound of formula 6 is converted to a compound of formula 1 where R is alkyl substituted with amino group substituted with alkylcarbonyl or cycloalkyl carbonyl group, in particular to a compound of formula 1.5, according to the following scheme:

by formylating the compound of formula 6 to form the compound of formula 10, condensing the resulting compound with primary amine followed by N-acylation and removing the tertbutoxycarbonyl protective group.

In some embodiments, R in the compound of formula 1 is Ci-Cio alkyl substituted with amino group wherein the amino group is substituted with 1-2 substituents selected from the group including Ci-Cio alkylcarbonyl group, Cs-Cs cycloalkylcarbonyl group and Ce-Cu aryl optionally substituted with 1-5 substituents selected from Ci-Cio alkyl and halogen.

In preferred embodiments of the invention, R in the compound of formula 1 is Ci-Cio alkyl substituted with amino group wherein the amino group is substituted with Ci-Cio alkylcarbonyl group or C>,-Cx cycloalkylcarbonyl group and Ce-Cu aryl optionally substituted with 1 substituent selected from Ci-Cio alkyl and halogen.

In another embodiment of the invention, in step (d), the compound of formula 6 is converted to the compound of formula 1 where R is optionally substituted amino group, in particular to aminobenzoxazepine 1.6, according to the following scheme:

by aminating the compound of formula 6 and then removing the tert-butoxycarbonyl protective group.

In some embodiments of the invention, the step of compound 6 amination is carried out using the amine of general formula R'R²NH where R¹ and R² are independently selected from the group including Ci-Cio alkyl and Cx-Cx cycloalkylcarbonyl group, or R¹ and R² together with a nitrogen atom with which they are bound form 6-membered saturated heterocyclyl containing 2 heteroatoms selected from oxygen, sulfur and nitrogen wherein 1 heteroatom is nitrogen. In one embodiment of the invention, said amine is dimethylamine or cyclopropylcarbonylamine. In another embodiment of the invention, said amine is morpholine, thiomorpholine, piperazine.

In some embodiments of the invention, R in the compound of formula 1 is amino group optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and Cs-Cs cycloalkylcarbonyl group.

In some embodiments of the invention, R in the compound of formula 1 is 6-membered saturated heterocyclyl containing 2 heteroatoms selected from oxygen, sulfur and nitrogen wherein 1 heteroatom is nitrogen. In a preferred embodiment of the invention, R is 6-membered saturated heterocyclyl containing 1 nitrogen atom and 1 heteroatom selected from oxygen and sulfur.

In another embodiment of the invention, in step (d), the compound of formula 6 is converted to the compound of formula 1 where R is C1-C10 alkyl substituted with hydroxy group, in particular to the compound of formula 1.7, according to the following scheme:

by acylating the compound of formula 6, reducing the carbonyl group to form the compound 21 and then removing the tert-butoxy carbonyl protective group.

The present invention will now be described in various embodiments which are not intended to limit its scope. On the contrary, the present invention covers all alternatives, modifications and equivalents that may be included within the scope of the claims. Therefore, the following examples, which include particular embodiments, illustrate but do not limit the present invention.

Example 1. General procedure for obtaining the compounds of general formula 1.

The procedure for obtaining the compounds of general formula 1 is shown in the diagrams above.

Compound 4. Compound 2 solution (20.1 g, 0.1 mol) and amine 3 (9.2 g, 0.15 mol) in 300 ml of toluene were heated under boiling with the Dean-Stark trap for 1 hour. The reaction mixture was cooled to room temperature and added dropwise to NaBTU suspension (3.8 g, 0.1 mol) in 50 ml of ethanol, stirred for 1 hour and evaporated under vacuum. The residue was dissolved in water, and ammonia solution was added dropwise, the precipitate was filtered off, washed with water, dried and used in the next step without further purification. The yield was 14.7 g (60%).

Compound 5. BOC2O solution (21.8 g, 0.1 mol) in 50 ml dichloromethane (DCM) was added dropwise to amine 4 solution (24.6 g, 0.1 mol) in 300 ml of DCM and stirred overnight. The reaction mixture was washed with 5% aqueous HC1 solution. The organic layer was separated and evaporated under vacuum. The residue was recrystallized from alcohol. The yield was 24.2 g (70%).

Compound 6. PPI13 (26.2 g, 0.1 mol) and compound 5 (34.6 g, 0.1 mol) were dissolved in 300 ml of tetrahydrofuran (THF), and diisopropyl azodi carboxyl ate (DIAD) (21.8 g, 0.1 mol) was added dropwise. The reaction mixture was stirred overnight, poured into 500 ml of water and extracted with chloroform (3 times with 150 ml), the organic layers were separated, dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel by elution with the mixture of diethyl etherhexane 1 :1. The yield was 13.1 g (40%).

Compound 7. 0.01 mol of the corresponding boronic acid, 5 ml of aqueous K2CO3 solution (2.7 g, 0.02 mol) and Pd(PPh3)4 (0.005 mol) were added in argon flow to compound 6 solution (0.01 mol) in 25 ml of dioxane and stirred under boiling for 5 hours. The reaction mixture was cooled, poured into 200 ml of water, the precipitate was filtered off and recrystallized from alcohol.

Compound 1.1. 4M HC1 solution (5 ml) was added dropwise to compound 7 solution (0.005 mol) in 5 ml of dioxane, and the mixture was stirred overnight. The precipitate was filtered off and recrystallized from alcohol.

Compound 8. 60 ml (0.15 mol) of 2.5 M BuLi solution in hexane was added dropwise to compound 6 solution (32.8 g, 0.1 mol) in 250 ml of dry THF at -70°C. The reaction mixture was stirred for 1 hour and a flow of dry CO2 was passed through it. Cooling was stopped and stirring was conducted overnight. The reaction mixture was decomposed by careful dropwise addition of 5 ml of saturated aqueous NH4CI solution, poured into 300 ml of water and extracted with EtOAc. The aqueous layer was carefully acidified with 5% HC1 to pH 5. The precipitate was filtered off, washed with water, dried and used in the next step without further purification. The yield was 14.6 g (50%).

Compound 9. N,N’ -carbonyl diimidazole (CDI) (9.7 g, 0.06 mol) was added portionwise to compound 8 solution (14.7 g, 0.05 mol) in dry CHCh (250 ml) and the mixture was stirred for 1 hour. The corresponding amine (0.07 mol) was dissolved in 25 ml of CHCh and added dropwise to the reaction mixture. Stirring was conducted overnight, the reaction mass was washed with 5% HC1. The organic layer was separated, dried over anhydrous Na2SO4 and evaporated. The resulting residue was used in the next step without further purification. Compound 1.2. This compound was prepared similarly to the compound 1.1.

Compound 10. 60 ml (0.15 mol) of 2.5 M BuLi solution in hexane was added dropwise to compound 6 solution (32.8 g, 0.1 mol) in 250 ml of dry THF at -70°C. The reaction mixture was stirred for 1 hour and DMF (5 ml) was added dropwise. Cooling was stopped and stirring was conducted overnight. The reaction mixture was decomposed by careful dropwise addition of 5 ml of saturated aqueous NH4CI solution, poured into 300 ml of water and extracted with EtOAc. The organic layer was separated, dried over anhydrous TsfeSCU and evaporated. The resulting residue was purified by flash chromatography on silica gel by elution with the mixture of diethyl etherhexane 1 :1. The yield was 13.9 g (50%).

Compound 11. Triethylphosphonoacetate (26.8 g, 0.12 mol) was added dropwise to 60% NaH suspension (4.4 g, 0.11 mol) in 300 ml of dry THF. After 30 minutes, aldehyde 10 solution (26.9 g, 0.1 mol) was added dropwise to the resulting clear solution, and the reaction mass was stirred overnight, poured into 300 ml of water, and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4 and evaporated. The resulting residue was used in the next step without further purification. The yield was 24.3 g (75%).

Compound 12. Pd/C (3 g, 10 wt.%) was added to compound 11 solution (34.7 g, 0.1 mol) in 250 ml of EtOH in 500 ml autoclave and hydrogenated at an initial pressure of 50 atmospheres of hydrogen for 12 hours. The catalyst was filtered off, the reaction mass was evaporated. The resulting residue was used in the next step without further purification. The yield was 31.4 g (90%).

Compound 13. KOH solution (11 g, 0.2 mol) in 25 ml of water was added dropwise to compound 12 solution (31 g, 0.09 mol) in 300 ml of MeOH. The reaction mixture was stirred overnight and evaporated under vacuum. The residue was dissolved in 250 ml of water and extracted with EtOAc. The aqueous layer was carefully acidified with 5% HC1 to pH 5. The precipitate was filtered off, washed with water, dried and used in the next step without further purification. The yield was 23.1 g (80%).

Compound 14. This compound was prepared similarly to the compound 9.

Compound 1.3. This compound was prepared similarly to the compound 1.1.

Compound 15. Portions of NaBHj (4.2 g, 0.11 mol) were sprinkled to compound 10 solution (27.7 g, 0.1 mol) in 300 ml of ethanol and stirred for 1 hour, the reaction mixture was evaporated, water was added to the residue and extracted with ethyl acetate, the organic layers were separated, evaporated, the residue was dried and used in the next step without further purification. The yield was 90%.

Compound 16. Alcohol 15 solution (2.8 g, 0.01 mol) in 10 ml of DMF was added dropwise to 60% NaH suspension (0.6 g, 0.015 mol) in 30 ml of dry DMF, stirred for 1 hour, and the corresponding benzyl chloride (0.012 mol) was added dropwise. The reaction mass was stirred overnight, poured into 300 ml of water and extracted with EtOAc. The organic layer was separated, dried over anhydrous ISfeSCh and evaporated. The resulting residue was used in the next step without further purification.

Compound 1.4. This compound was prepared similarly to the compound 1.1.

Compound 17. Solutions of 0.1 mol of aldehyde 10 and 0.11 mol of the corresponding amine in 300 ml of toluene were heated with distillation of water for 1 hour. The reaction mass was cooled and added dropwise to a solution of 0.1 mol of sodium borohydride in 50 of ethanol. The mixture was stirred for 1 hour, the solvent was evaporated, ammonia solution was added to the residue, and the precipitate was filtered, dried and used in the next step without further purification.

Compound 18. 0.12 mol of the corresponding acid chloride was added dropwise to solutions of 0.1 mol of amine 17, 0.15 mol of triethylamine in 200 ml of DMF. Stirred for 2 hours and poured into water. The precipitate was filtered and recrystallized from alcohol.

Compound 1.5. This compound was prepared similarly to the compound 1.1.

Compound 19. 0.015 mol of the corresponding amine was added to the mixture of bromide 6 (3.28 g, 0.01 mol), Pd2(dba)3 (24 mg, 0.043 mmol), 2,2'-bis(diphenylphosphino)-l,l'- binaphthyl (BINAP) (53 mg, 0.086 mmol), CS2CO3 (3.25 g, 0.01 mol) in 50 ml of dioxane and heated in argon flow under boiling for 16 hours. The reaction mass was evaporated, the residue was purified by column chromatography on silica gel (eluent hexane:ethyl acetate 5: 1)

Compound 1.6. This compound was prepared similarly to the compound 1.1.

Compound 20. This compound was prepared similarly to the compound 10.

Compound 21. This compound was prepared similarly to the compound 15.

Compound 1.7. This compound was prepared similarly to the compound 1.1.

Example 2. Preparation of 7-pyridin-4-yl-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine dihydrochloride (1.1.1, TRX-0019). It was obtained as colorless crystals.

The yield was 828 mg (55%).

'H NMR (300 MHz, DMSO-d6) 8 10.15 (s, 1.9H), 9.05 - 8.84 (m, 2H), 8.47 - 8.19 (m, 3H), 8.11 - 7.97 (m, 1H), 7.32 - 7.17 (m, 1H), 4.53 - 4.41 (m, 2H), 4.36 - 4.22 (m, 2H), 3.56 - 3.39 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8 162.1, 153.8, 142.4, 131.7, 130.0, 129.3, 126.3, 123.1, 122.0, 68.4, 48.1, 47.7. MS m/z l. (M+H⁺).

Example 3. Preparation of 7-pyridin-3-yl-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine dihydrochloride (1.1.2, TRX-0020). It was obtained as colorless crystals.

The yield was 1 g (67%).

'H NMR (300 MHz, DMSO-d6) 8 10.04 (s, 1.8H), 9.21 - 9.14 (m, 1H), 8.86 - 8.80 (m, 1H), 8.78 - 8.69 (m, 1H), 8.11 - 7.99 (m, 2H), 7.91 - 7.83 (m, 1H), 7.27 - 7.19 (m, 1H), 4.43 - 4.38 (m, 2H), 4.34 - 4.24 (m, 2H), 3.53 - 3.38 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8 160.5,

141.4, 141.3, 140.4, 137.1, 130.6, 129.4, 129.1, 126.9, 126.2, 121.8, 68.4, 48.3, 47.9. MS m/z 227.2 (M+H⁺).

Example 4. Preparation of 7V-benzyl-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine-7- carboxamide hydrochloride (1.2.1, TRX-0021). It was obtained as colorless crystals.

The yield was 831 mg (52%).

'H NMR (300 MHz, DMSO-d6) 8 9.93 (s, 2H), 9.17 (t, J = 5.9 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.94 - 7.88 (m, 1H), 7.32 - 7.29 (m, 4H), 7.55 - 7.20 (m, 1H), 7.15 - 7.10 (m, 1H), 4.46 (d, J = 5.9 Hz, 2H), 4.35 - 4.31 (m, 2H), 4.29 - 4.25 (m, 2H), 3.46 - 3.39 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8 165.1, 161.6, 139.7, 131.3, 129.7, 129.4, 128.3, 127.2, 126.7, 124.9, 120.6,

66.4, 48.3, 48.1, 42.6. MS m/z 283.2 (M+H⁺).

Example 5. Preparation of 7V-(2-fluorobenzyl)-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine- 7-carboxamide hydrochloride (1.2.2, TRX-0022). It was obtained as colorless crystals.

The yield was 912 mg (54%).

'H NMR (300 MHz, DMSO-d6) 8 10.13 (s, 1.5H), 9.18 (t, J = 5.9 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.94 - 7.90 (m, 1H), 7.38 - 7.26 (m, 2H), 7.19 - 7.10 (m, 3H), 4.50 (d, J = 5.9 Hz, 2H), 4.35 - 4.32 (m, 2H), 4.29 - 4.26 (m, 2H), 3.48 - 3.43 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8

165.3, 161.6, 160.0 (d, J = 245.3 Hz), 131.4, 129.5, 129.4 (d, J = 5.5 Hz), 129.3, 129.4 (d, J = 8.0 Hz), 126.2 (d, J = 14.5 Hz), 124.9, 124.3 (d, J = 3.3 Hz), 120.6, 115.1 (d, J = 21.3 Hz), 68.4,

48.3, 48.0, 36.4. MS m/z 301.4 (M+H⁺).

Example 6. Preparation of 7V-(4-methylbenzyl)-2, 3,4,5- tetrahydrobenzo[/][l,4]oxazepine-7-carboxamide hydrochloride (1.2.3, TRX-0023). It was obtained as colorless crystals.

The yield was 800 mg (48%).

'H NMR (300 MHz, DMSO-d6) 8 10.01 (s, 1.5H), 9.11 (t, J = 5.9 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.93 - 7.87 (m, 1H), 7.21 - 7.17 (m, 2H), 7.14 - 7.08 (m, 3H), 4.41 (d, J = 5.9 Hz, 2H), 4.33 - 4.31 (m, 2H), 4.29 - 4.26 (m, 2H), 3.48 - 3.42 (m, 2H), 2.25 (s, 3H). ¹³C NMR (75 MHz, DMSO-d6) 8 165.0, 161.5, 136.7, 135.7, 131.3, 129.7, 129.3, 128.8, 127.2, 124.9, 120.6, 68.4,

48.3, 48.0, 42.3, 20.7. MS m/z 297.4 (M+H⁺).

Example 7. Preparation of 3-(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7-yl)propanamide hydrochloride (1.3.1, TRX-0024). It was obtained as colorless crystals.

The yield was 504 mg (42%). 'H NMR (300 MHz, DMSO-d6) 8 9.76 (s, 1.9H), 7.37 (s, 1H), 7.29 - 7.24 (m, 1H), 7.20 - 7.13 (m, 1H), 7.00 - 6.93 (m, 1H), 6.77 (s, 1H), 4.26 - 4.20 (m, 2H), 4.18 - 4.12 (m, 2H), 3.42 - 3.37 (m, 2H), 2.79 - 2.70 (m, 2H), 2.38 - 2.29 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8 173.3, 157.7, 137.1, 131.2, 130.0, 125.1, 120.6, 68.4, 48.7, 48.4, 36.5, 29.9. MS m/z 221.2 (M+H⁺).

Example 8. Preparation of 7-[(2-chlorobenzyloxy)methyl]-2, 3,4,5- tetrahydrobenzo[/][l,4]oxazepine hydrochloride (1.4.1, TRX-0025). It was obtained as colorless crystals.

The yield was 2.6 g (78%).

'H NMR (300 MHz, DMSO-d6) 8 9.84 (s, 2H), 7.57 - 7.52 (m, 1H), 7.47 - 7.42 (m, 2H), 7.38 - 7.30 (m, 3H), 7.08 - 7.03 (m, 1H), 4.60 (s, 2H), 4.55 (s, 2H), 4.29 - 4.25 (m, 2H), 4.22 -

4.17 (m, 2H), 3.44 - 3.33 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8 158.9, 135.7, 133.7, 132.1, 130.9, 129.6, 129.4, 129.3, 129.1, 127.2, 125.3, 120.7, 71.1, 68.8, 68.4, 48.6, 48.2. MS m/z 304.8 (M+H⁺).

Example 9. Preparation of 7-[(3-fluorobenzyloxy)methyl]-2,3,4,5- tetrahydrobenzo[/][l,4]oxazepine hydrochloride (1.4.2, TRX-0026). It was obtained as colorless crystals.

The yield was 2.3 g (72%).

'H NMR (300 MHz, DMSO-d6) 8 9.87 (s, 2H), 7.42 - 7.41 (m, 1H), 7.30 - 7.21 (m, 3H),

7.18 - 7.13 (m, 2H), 7.05 - 7.03 (m, 1H), 4.47 (s, 2H), 4.44 (s, 2H), 4.28 - 4.25 (m, 2H), 4.21 -

4.17 (m, 2H), 3.42 - 3.38 (m, 2H), 2.28 (s, 3H). ¹³C NMR (75 MHz, DMSO-d6) 8 162.2 (d, J = 243.4 Hz), 158.9, 141.4 (d, J = 7.1 Hz), 133.7, 130.9, 130.3 (d, J = 8.1 Hz), 129.6, 125.3, 123.3 (d, J = 2.8 Hz), 120.7, 114.2 (d, J = 20.8 Hz), 113.9 (d, J = 21.5 Hz), 70.8, 70.6, 68.4, 48.6, 48.2. MS m/z 288.2 (M+H⁺).

Example 10. Preparation of 7-[(4-chlorobenzyloxy)methyl]-2,3,4,5- tetrahydrobenzo[/][l,4]oxazepine hydrochloride (1.4.3, TRX-0027). It was obtained as colorless crystals.

The yield was 2.8 g (82%).

'H NMR (300 MHz, DMSO-d6) 8 9.91 (s, 1.8H), 7.43 - 7.35 (m, 5H), 7.32 - 7.26 (m, 1H), 7.06 - 7.01 (m, 1H), 4.50 (s, 2H), 4.46 (s, 2H), 4.29 - 4.25 (m, 2H), 4.22 - 4.17 (m, 2H), 3.44 - 3.38 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8 158.9, 137.4, 133.8, 132.0, 131.0, 129.6, 129.3, 128.3, 125.3, 120.7, 70.8, 70.6, 68.4, 48.6, 48.2. MS m/z 304.8 (M+H⁺).

Example 11. Preparation of 7-[(4-methylbenzyloxy)methyl]-2,3,4,5- tetrahydrobenzo[/][l,4]oxazepine hydrochloride (1.4.4, TRX-0028). It was obtained as colorless crystals.

The yield was 2.4 g (75%).

7.18 - 7.13 (m, 2H), 7.05 - 7.03 (m, 1H), 4.47 (s, 2H), 4.44 (s, 2H), 4.28 - 4.25 (m, 2H), 4.21 - 4.17 (m, 2H), 3.42 - 3.38 (m, 2H), 2.28 (s, 3H). ¹³C NMR (75 MHz, DMSO-d6) 8 158.8, 136.6,

135.2, 134.0, 130.9, 129.6, 128.9, 127.7, 125.2, 120.7, 71.3, 70.5, 68.4, 48.6, 48.2, 20.8. MS m/z 284.4 (M+H⁺).

Example 12. Preparation of 2-methyl-7V-(4-methylphenyl)-7V-[(2, 3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-yl)methyl]propanamide hydrochloride (1.5.1, TRX-0029). It was obtained as colorless crystals.

The yield was 1.7 g (45%).

'H NMR (300 MHz, DMSO-d6) 8 9.93 (s, 2H), 7.21 - 7.16 (m, 3H), 7.08 - 7.03 (m, 3H), 6.98 - 6.93 (m, 1H), 4.74 (s, 2H), 4.25 - 4.21 (m, 2H), 4.20 - 4.16 (m, 2H), 3.42 - 3.38 (m, 2H), 2.46 - 2.37 (m, 1H), 2.25 (s, 3H), 0.93 (d, J = 6.7 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6) 8

176.2, 158.5, 139.7, 137.3, 133.4, 130.8, 130.2, 129.6, 128.0, 125.3, 120.8, 68.4, 51.3, 48.7, 48.3, 30.4, 20.6, 19.6. MS m/z 339.6 (M+H⁺).

Example 13. Preparation of 7V-[(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7-yl)methyl]-7V- (4-fluorophenyl)acetamide hydrochloride (1.5.2, TRX-0030). It was obtained as colorless crystals.

The yield was 1.47 g (42%).

'H NMR (300 MHz, DMSO-d6) 8 9.93 (s, 2H), 7.32 - 7.10 (m, 6H), 7.05 - 6.98 (m, 1H), 4.43 (s, 2H), 4.29 - 4.23 (m, 2H), 4.20 - 4.16 (m, 2H), 3.43 - 3.37 (m, 2H), 2.11 - 2.09 (2s, 3H). ¹³C NMR (75 MHz, DMSO-d6) 170.28, 161.4 (d, J = 242.9 Hz), 158.7, 133.9 (d, J = 3.1 Hz), 133.27, 130.8, 129.8, 128.8, 125.8, 121.0, 115.7 (d, J = 21.5 Hz), 68.42, 50.1, 48.6, 48.2, 21.6. MS m/z 315.4 (M+H⁺).

Example 14. Preparation of 7V-[(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7-yl)methyl]-7V- phenylcyclopropanecarboxamide hydrochloride (1.5.3, TRX-0031). It was obtained as colorless crystals.

The yield was 1.36 g (38%).

'H NMR (300 MHz, DMSO-d6) 8 9.84 (s, 2H), 7.43 - 7.36 (m, 2H), 7.33 - 7.22 (m, 4H), 7.11 - 7.05 (m, 1H), 6.98 - 6.94 (m, 1H), 4.84 (s, 2H), 4.26 - 4.21 (m, 2H), 4.19 - 4.15 (m, 2H), 3.41 - 3.37 (m, 2H), 1.39 - 1.25 (m, 1H), 0.87 - 0.82 (m, 2H), 0.67 - 0.61 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8 172.5, 158.4, 142.2, 138.4, 133.4, 130.7, 129.6, 128.2, 127.5, 125.3, 120.7, 68.4, 51.3, 48.6, 48.2, 12.4, 8.3. MS m/z 323.4 (M+H⁺).

Example 15. Preparation of 7V,7V-dimethyl-(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7- yl)amine dihydrochloride (1.6.1, TRX-0032). It was obtained as colorless crystals.

The yield was 1.16 g (88%).

^XH NMR (300 MHz, DMSO-d6) 8 10.03 (s, 1.8H), 7.85 (s, 1H), 7.74 - 7.60 (m, 1H), 7.24 - 7.15 (m, 1H), 4.36 - 4.28 (m, 1H), 4.26 - 4.20 (m, 2H), 3.50 - 3.38 (m, 2H), 3.04 (s, 6H). ¹³C NMR (75 MHz, DMSO-d6) 8 158.4, 139.8, 126.7, 123.2, 122.1, 122.0, 68.5, 48.4, 47.9, 45.0. MS m/z 193.4 (M+H⁺).

Example 16. Preparation of A-(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7- yl)cyclopropanecarboxamide hydrochloride (1.6.2, TRX-0033). It was obtained as colorless crystals.

The yield was 1.17 g (76%).

^XH NMR (300 MHz, DMSO-d6) 8 10.55 (s, 1H), 9.74 (s, 1.9H), 7.66 - 7.64 (m, 1H), 7.52 - 7.46 (m, 1H), 6.96 - 6.91 (m, 1H), 4.18 - 4.14 (m, 2H), 4.12 - 4.08 (m, 2H), 3.39 - 3.32 (m, 2H), 1.88 - 1.80 (m, 1H), 0.74 - 0.67 (m, 4H). ¹³C NMR (75 MHz, DMSO-d6) 8 171.7, 154.8, 135.5, 125.4, 121.9, 121.0, 68.6, 48.8, 48.6, 14.4, 7.2. MS m/z 233.2 (M+H⁺).

Example 17. Preparation of 7-(morpholin-4-yl)-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine dihydrochloride (1.6.3, TRX-0034). It was obtained as colorless crystals.

The yield was 1.41 g (92%).

'H NMR (300 MHz, DMSO-d6) 8 10.01 (s, 2H), 7.67 - 7.65 (m, 1H), 7.52 - 7.47 (m, 1H), 7.13 - 7.09 (m, 1H), 4.29 - 4.26 (m, 2H), 4.22 - 4.18 (m, 2H), 3.97 - 3.91 (m, 4H), 3.43 - 3.40 (m, 2H), 3.37 - 3.32 (m, 4H). ¹³C NMR (75 MHz, DMSO-d6) 8 156.7, 141.7, 126.4, 122.1, 121.8, 120.8, 68.5, 64.5, 52.1, 48.5, 48.1. MS m/z 235.6 (M+H⁺).

Example 18. Preparation of l-(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7-yl)ethanol hydrochloride (1.7.1, TRX-0035). It was obtained as colorless crystals.

The yield was 1.1 g (67%).

'H NMR (300 MHz, DMSO-d6) 8 9.92 (s, 1.9H), 7.61 - 7.56 (m, 1H), 7.47 - 7.39 (m, 1H), 7.09 - 7.03 (m, 1H), 5.33 (q, J = 6.8 Hz, 1H), 4.69 (s, 0.9H), 4.31 - 4.24 (m, 2H), 4.24 - 4.19 (m, 2H), 3.44 - 3.38 (m, 2H), 1.77 (d, J = 6.8 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d6) 8 159.2, 138.1, 130.0, 128.8, 125.4, 120.9, 68.4, 58.3, 48.5, 48.0, 25.9. MS m/z 294.2 (M+H⁺).

Example 19. Preparation of (2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7-yl)methanol hydrochloride (1.7.2, TRX-0036). It was obtained as colorless crystals.

The yield was 955 mg (88%).

'H NMR (300 MHz, DMSO-d6) 8 9.85 (s, 1.9H), 7.37 - 7.31 (m, 1H), 7.29 - 7.22 (m, 1H), 7.04 - 6.97 (m, 1H), 4.43 (s, 2H), 4.27 - 4.22 (m, 2H), 4.20 - 4.15 (m, 2H), 3.43 - 3.36 (m, 2H). ¹³C NMR (75 MHz, DMSO-d6) 8 158.2, 138.2, 129.6, 128.4, 124.9, 120.4, 68.5, 62.1, 48.7, 48.4. MS m/z 180.6 (M+H⁺).

Example 20. Construction of expression plasmids, TAAR and stably transfected cell lines.

Materials and Methods.

We produced the pchTAARl expression vector containing the human TAAR1 receptor gene for conducting experiments. The expression vector pcEPAC was used to explore changes in cAMP concentrations in cells in response to the action of various chemical compounds. It provides constitutive expression of the Rluc-EPAC-YFP fused gene, the product of which is a biosensor for monitoring the activation of Gas-signaling pathway. It is based on cAMP- dependent factor EPAC1 (Exchange protein activated by cAMP 1) which changes its conformation in response to binding of cAMP molecule. Donor (Rluc) and acceptor (YFP) molecules are located in close proximity in an inactive form, however, when the biosensor binds to cAMP they move significantly away from each other (Barak et al., 2008). Consequently, a decrease in resonance energy transfer from the donor to the acceptor is observed. This is expressed mathematically as the ratio between acceptor luminescence intensity (535 nm) and donor luminescence intensity (480 nm) or the so-called BRET ratio (BRET ratio). Therefore, upon activation of Gas-signaling pathway, which occurs when the receptor under study is activated by a ligand, a decrease in the BRET ratio will be observed.

To perform BRET HEK293T cell culture (ATCC#CRL-3216) was grown in DMEM medium (Gibco) containing 4.5 g/L glucose until about 70-90% confluence was reached. Next, cells grown on 10 cm Petri dish were co-transfected with two expression vectors: pchTAARl (3-5 pg) and pcEPAC (3-5 pg) using Lipofectamine 2000 (Invitrogen) according to the standard protocol. The same amount of «empty» pcDNA3.1(+) vector was used as a negative control instead of the pchTAARl vector to assess non-specific interaction. After lipofection (conducted for 4 hours) the cells were removed from the dish, suspended in MEM medium without phenol red (Gibco) containing 2% of fetal bovine serum, and transferred to 96-well plate pretreated with 0.0001% poly-D-lysine solution at 100,000-150,000 cells per well. Cells were grown on plates for 24-48 hours. The culture medium was then carefully aspirated, and 70 pl of PBS buffer containing Ca²⁺ and Mg²⁺ ions, 10 pl of 2 mM IBMX solution (Sigma) and 10 pl of 50 pM coelenterazine h solution (Promega) were sequentially added to each well. The plate was incubated for 10 min at room temperature. Next, in order to determine the effective concentration (ECso) ligand solutions diluted from 0.1 nM to 10 pM were added and incubated for another 5 minutes at room temperature. A non-selective agonist of P2-adrenergic receptor, isoprotenerol (assessment of biosensor performance), at a concentration of 100 nM, as well as beta-phenyl ethylamine (a natural agonist of TAAR1 receptor) at concentrations 0.1 nM to 10 pM were used as positive controls. All compounds were tested in 3 replicates. Thereafter, the plate was placed in a reader, and values of luminescence intensity were read for 20 minutes with maxima at wavelengths of 535 and 480 nm. The BRET ratio was then calculated mathematically, dose-response curves were built, and the effective ligand concentration was determined. The results are shown in Table 1. Table 1. TAAR1 receptor activation by the compounds of the invention

Therefore, it can be concluded based on the data obtained that the compounds of formula 1 according to the present invention have agonistic activity on TAAR1 receptor and can be used to treat diseases mediated by trace amine receptors TAAR1 such as mental disorders, cognitive and neurodegenerative disorders, schizophrenia, depression, bipolar disorder, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, Parkinson’s disease, dementia (including Alzheimer’s disease), epilepsy, migraine, high blood pressure (hypertension), alcohol or drug abuse, nicotine addiction, obesity, diabetes, metabolic disorder, disorder associated with energy consumption and expenditure, disorder associated with impaired body temperature homeostasis, sleep and circadian rhythm disorder, and cardiovascular disorder.

References:

1. Borowsky, B., Adham, N., Jones, K. A., Raddatz, R., Artymyshyn, R., Ogozalek,

K. L., Gerald, C. (2001). Trace amines: Identification of a family of mammalian G protein- coupled receptors. Proc Natl Acad Sci U S A 98, 8966-8971. 2. Bunzow, J. R., Sonders, M. S., Arttamangkul, S., Harrison, L. M., Zhang, G., Quigley, D. I., Grandy, D. K. (2001). Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol 60, 1181-1188.

3. Sotnikova, T. D., Zorina, O. I., Ghisi, V., Caron, M. G., & Gainetdinov, R. R. (2008). Trace amine associated receptor 1 and movement control. Parkinsonism Relat Disord 14(Suppl. 2), S99-102.

4. Lindemann, L., & Hoener, M. C. (2005). A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol Sci 26, 274-281.

5. Revel, F. G., Moreau, J. L., Gainetdinov, R. R., Bradaia, A., Sotnikova, T. D., Mory, R., Hoener, M. C. (2011). TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A 108, 8485-8490.

6. Revel, F. G., Moreau, J. L., Gainetdinov, R. R., Ferragud, A., Velazquez- Sanchez, C., Sotnikova, T. D., Hoener, M. C. (2012). Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biol Psychiatry 72, 934-942.

7. Lam V. M., Espinoza S., Gerasimov A. S., Gainetdinov R. R., Salahpour A. (2015). In-vivo pharmacology of trace-amine associated receptor 1. Eur. J. Pharmacol. 763(Pt B), 136-142.

Claims

1. A compound of formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease, disorder or condition mediated by trace amine receptors TAAR1, wherein the compound of formula 1 is:

where R is selected from the group consisting of:

Ci-Cio alkyl optionally substituted with 1-3 substituents selected from the group including: hydroxy group; aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and Cs-Cs cycloalkyl, amino group wherein the amino group is optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkylcarbonyl group, C3- Cx cycloalkylcarbonyl group and Ce-Cu aryl optionally substituted with 1-5 substituents selected from C1-C10 alkyl and halogen, and

2. The compound of claim 1, wherein R is 6-membered heteroaryl containing 1 nitrogen atom.

3. The compound of claim 1, wherein R is aminocarbonyl group substituted with Ci- C10 alkyl Ce-Cu aryl wherein Ce-Cu aryl is optionally substituted with 1 substituent selected from C1-C10 alkyl and halogen.

4. The compound of claim 1, wherein R is C1-C10 alkyl substituted with aminocarbonyl group.

5. The compound of claim 1, wherein R is Ci-Cio alkyl substituted with Ci-Cio alkoxy group wherein the alkoxy group is substituted with Ce-Cu aryl optionally substituted with 1 substituent selected from Ci-Cio alkyl and halogen.

6. The compound of claim 1 wherein R is Ci-Cio alkyl substituted with amino group wherein the amino group is substituted with Ci-Cio alkylcarbonyl group or Cx-Cx cycloalkylcarbonyl group and Ce-Cu aryl optionally substituted with 1 substituent selected from Ci-Cio alkyl and halogen.

7. The compound of claim 1, wherein R is amino group substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and Cx-Cx cycloalkylcarbonyl group.

8. The compound of claim 1, wherein R is 6-membered saturated heterocyclyl containing 1 nitrogen atom and 1 heteroatom selected from oxygen and sulfur.

9. The compound of claim 1, wherein R is Ci-Cio alkyl substituted with hydroxy group.

10. The compound of claim 1, wherein the compound of formula 1 is selected from the group including:

7-Pyridin-4-yl-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine dihydrochloride;

7-Pyridin-3-yl-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine dihydrochloride;

7V-Benzyl-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine-7-carboxamide hydrochloride;

7V-(2-Fluorobenzyl)-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine-7-carboxamide hydrochloride;

7V-(4-Methylbenzyl)-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine-7-carboxamide hydrochloride;

3-(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)propanamide hydrochloride;

7-[(2-Chlorobenzyloxy)methyl]-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine hydrochloride; 7-[(3-Fluorobenzyloxy)methyl]-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine hydrochloride;

7-[(4-Chlorobenzyloxy)methyl]-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine hydrochloride; 7-[(4-Methylbenzyloxy)methyl]-2,3,4,5-tetrahydrobenzo[/][l,4]oxazepine hydrochloride;

2-Methyl-7V-(4-methylphenyl)-7V-[(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7- yl )m ethyl ] propanami de hydrochi ori de;

7V-[(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)methyl]-7V-(4-fluorophenyl)acetamide hydrochloride;

7V-[(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)methyl]-7V- phenyl cy cl opropanecarb oxami de hydrochi ori de;

7V,7V-Dimethyl-(2,3,4,5-tetrahydrobenzo[/][l,4]oxazepin-7-yl)amine dihydrochloride; A-(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)cyclopropanecarboxamide hydrochloride;

7-(Morpholin-4-yl)-2, 3 ,4,5 -tetrahydrob enzof/] [ 1 ,4] oxazepine dihydrochlori de; l-(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)ethanol hydrochloride;

(2,3,4,5-Tetrahydrobenzo[/][l,4]oxazepin-7-yl)methanol hydrochloride.

11. The compound of claim 1, wherein the disease, disorder or condition is selected from the group including a mental disorder, a cognitive disorder, a metabolic disorder, a neurological disease and a neurodegenerative disease.

12. The compound of claim 1, wherein the disease, disorder or condition is selected from depression, anxieties, bipolar disorders, attention deficit hyperactivity disorder (ADHD), stress-induced disorders, psychoses, schizophrenia, obsessive-compulsive disorder, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, high blood pressure (hypertension), alcohol or drug abuse, nicotine addiction, eating disorders, diabetes, diabetes complications, obesity, dyslipidemia, disorders associated with energy consumption and expenditure, disorders associated with impaired body temperature homeostasis, sleep and circadian rhythm disorders, and cardiovascular disorders.

13. A pharmaceutical composition for use in the treatment of a disease, disorder or condition mediated by trace amine receptors TAAR1 comprising a therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the compound of formula 1 is: a- ) where R is selected from the group consisting of:

Ci-Cio alkyl optionally substituted with 1-3 substituents selected from the group including: hydroxy group, aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and Cs-Cs cycloalkyl, amino group wherein the amino group is optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkylcarbonyl group, Cs-Cs cycloalkylcarbonyl group and Ce-Cu aryl optionally substituted with 1-5 substituents selected from Ci-Cio alkyl and halogen, and

Ci-Cio alkoxy group wherein the alkoxy group is optionally substituted with Ce- Ci4 aryl optionally substituted with 1-5 substituents selected from Ci-Cio alkyl and halogen; aminocarbonyl group optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and Ci-Cio alkyl Ce-Cu aryl wherein Ce-Cu aryl is optionally substituted with 1-5 substituents selected from Ci-Cio alkyl and halogen. amino group optionally substituted with 1-2 substituents selected from the group including Ci-Cio alkyl and Cs-Cs cycloalkylcarbonyl group,

14. The pharmaceutical composition of claim 13, wherein the excipient is selected from the group including a pharmaceutically acceptable carrier, diluent, filler and solvent.

15. The pharmaceutical composition of any one of claims 13-14, wherein the pharmaceutical composition is present as a dosage form selected from the group including tablet, powder, granule, pill, suspension, pellet, capsule, sachet and injectable solution.

16. The pharmaceutical composition of any one of claims 13-15, wherein the disease, disorder or condition is selected from the group including mental disorder, cognitive disorder, metabolic disorder, neurological disease and neurodegenerative disease.

17. The pharmaceutical composition of any one of claims 13-16, wherein the disease, disorder or condition is selected from depression, anxieties, bipolar disorders, attention deficit hyperactivity disorder (ADHD), stress-induced disorders, psychoses, schizophrenia, obsessive- compulsive disorder, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, high blood pressure (hypertension), alcohol or drug abuse, nicotine addiction, eating disorders, diabetes, diabetes complications, obesity, dyslipidemia, disorders associated with energy consumption and expenditure, disorders associated with impaired body temperature homeostasis, sleep and circadian rhythm disorders, and cardiovascular disorders.