WO2023033681A1

WO2023033681A1 - Substituted 2-(5-aryl-4 h-1,2,4-triazol-3-yl)ethanamines as modulators of trace amine-associated receptor 1 (taar1)

Info

Publication number: WO2023033681A1
Application number: PCT/RU2022/050272
Authority: WO
Inventors: Raul Radikovich GAINETDINOV; Andrey Sergeevich GERASIMOV; Aleksey Yurievich LUKIN; Anna Gennadievna BAHOLDINA; 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: WO2023033681A4

Abstract

Disclosed are substituted 2-(5-aryl-4H-1,2,4-triazol-3-yl)ethanamines of general formula 1 and their pharmaceutically acceptable salts which are modulators of trace amine-associated receptor 1 (TAAR1). 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-(5-ARYL-4H-1,2,4-TRIAZOL-3-YL)ETHANAMINES AS MODULATORS OF TRACE AMINE-ASSOCIATED RECEPTOR 1 (TAAR1) Field of invention The present invention relates to substituted 2-(5-aryl-4H-1,2,4-triazol-3-yl)ethanamines 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 β-phenylethylamine (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; WO2016016292A1; WO2008052907A1; WO2008046757A1]. 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 substituted 2-(5-aryl-4H-1,2,4- triazol-3-yl)ethanamines 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 substituted 2-(5-aryl-4H-1,2,4-triazol-3-yl)ethanamines, 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,

1 or a pharmaceutically acceptable salt thereof, where R is: С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group consisting of: С₁-С₁₀ alkyl optionally substituted with 1-3 halogen atoms, С₁-С₁₀ alkoxy optionally substituted with 1-3 halogen atoms or С₆-С₁₄ aryl optionally substituted with a halogen atom, С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group including halogen and С₁-С₁₀ alkoxy optionally substituted with 1-3 halogen atoms, halogen, amino group of formula -N(R¹)₂ where each R¹ is independently hydrogen or С₁-С₁₀ alkyl, nitro group, and C₆-C₁₄ aryloxy optionally substituted with С₁-С₁₀ alkyl; or 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen or sulfur. According to another aspect, the present invention provides a method for producing the compound of formula 1 comprising the following steps: (a) obtaining the compound of formula 5

by a method selected from: contacting the compound of formula 4

with hydrazine hydrate; or heating the compound of formula 11:

or the compound of formula 15:

to the melting temperature of said compounds; (b) removing the tert-butoxycarbonyl protecting group, to produce the compound of formula 1 where values of R are as defined above. In another aspect, the present invention provides a pharmaceutical composition for the treatment of 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 the use of a 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 the method for treating a 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 С₁-С₁₀ alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl and tert- butyl. 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 rings moieties of the groups. Aryl groups include, but are not limited to, phenyl and naphthyl. Preferably, the term «aryl» means phenyl. 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 S, O or N, and the remaining ring atoms are carbon atoms. In some embodiments of the invention, the heteroaryl is 5-membered heteroaryl. In some embodiments of the invention, the heteroaryl contains 1 heteroatom selected from S, O or N. Heteroaryl includes, but is not limited to, thiophene, furan, or pyrrole. The term «alkoxy» refers to -O-alkyl group where alkyl is as defined above. Examples of -O-alkyl group include, but are not limited to: methoxy, ethoxy, n-propyloxy, isopropyloxy, n- butyloxy, isobutyloxy, tert-butyloxy. «С₁-С₁₀ alkoxy» refers to -O-alkyl where alkyl is С₁-С₁₀ alkyl. The term «aryloxy» refers to -O-aryl group where aryl is as defined above. Examples of - O-aryl group include, but are not limited to: phenyloxy, naphthyloxy. «С₆-С₁₄ aryloxy» refers to -O-aryl where aryl is С₆-С₁₄ aryl. The term «halogen» refers to fluoride, bromide, chloride, and iodide. The term «nitro group» refers to –NO₂ group. The term «amino group» refers to the group of formula -NR1 2 where each R1, independently of each other, is hydrogen, alkyl or cycloalkyl, e.g., -NH₂, methylamino, dimethylamino, diethylamino, cyclohexylamino, tert-butylamino or ethylamino. 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 unsubstituted» may be used interchangeably. Examples of substituting groups (substituents) include, but are not limited to, alkyl, cycloalkyl, halogen, alkoxy group, aryl, nitro group, amino group. 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 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., 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-(5-aryl-4H-1,2,4-triazol-3-yl)ethanamines exhibiting properties of a trace amine receptor TAAR1 agonist, i.e. compounds of general formula 1:

or pharmaceutically acceptable salts thereof, where R is: С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group consisting of: С₁-С₁₀ alkyl optionally substituted with 1-3 halogen atoms, С₁-С₁₀ alkoxy optionally substituted with 1-3 halogen atoms or С₆-С₁₄ aryl optionally substituted with a halogen atom, С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group including halogen and С₁-С₁₀ alkoxy optionally substituted with 1-3 halogen atoms, halogen, amino group of formula -N(R¹)₂ where each R¹ is independently hydrogen or С₁-С₁₀ alkyl, nitro group, and C₆-C₁₄ aryloxy optionally substituted with С₁-С₁₀ alkyl; or 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen or sulfur. In one embodiment of the invention, R is С₆-С₁₄ aryl, preferably С₆-С₁₀ aryl, more preferably phenyl. In another embodiment of the invention, R is С₆-С₁₄ aryl substituted with 1-2 substituents selected from optionally substituted С₁-С₁₀ alkoxy. In a preferred embodiment of the invention, unsubstituted С₁-С₁₀ alkoxy is methoxy, ethoxy, propoxy or butoxy. In another embodiment of the invention, substituted С₁-С₁₀ alkoxy is trifluoromethoxy. In another embodiment of the invention, substituted С₁-С₁₀ alkoxy is methoxy substituted with С₆-С₁₄ aryl optionally substituted with a halogen atom. In another embodiment of the invention, R is ^С6^-С14 aryl substituted with 1-2 substituents selected from optionally substituted ^C6^-C14 aryloxy. In a preferred embodiment of the invention, ^С6^-С14 aryloxy is phenyloxy optionally substituted with С₁-С₁₀ alkyl, preferably С₁-С₄ alkyl. In another embodiment of the invention, R is С₆-С₁₄ aryl substituted with 1-2 substituents selected from optionally substituted С₆-С₁₄ aryl. In a preferred embodiment of the invention, R is phenyl substituted with phenyl optionally substituted with 1-2 substituents selected from halogen or optionally substituted С₁-С₁₀ alkoxy. In a preferred embodiment of the invention, unsubstituted С₁-С₁₀ alkoxy is methoxy, ethoxy, propoxy or butoxy. In another preferred embodiment of the invention, substituted ^С1^-С10 alkoxy is trifluoromethoxy. In another embodiment of the invention, R is С₆-С₁₄ aryl substituted with 1-2 substituents selected from optionally substituted С₁-С₁₀ alkyl, preferably С₁-С₄ alkyl. In a preferred embodiment of the invention, С₁-С₁₀ alkyl is methyl, ethyl, propyl, butyl. In another embodiment on the invention, substituted С₁-С₁₀ alkyl is trifluoromethyl. In another embodiment of the invention, R is С₆-С₁₄ aryl substituted with 1-2 substituents selected from fluoride, chloride or bromide. In another embodiment of the invention, R is С₆-С₁₄ aryl substituted with an amino group. In a preferred embodiment of the invention, the amino group is selected from methylamino, dimethylamino or diethylamino. In another embodiment of the invention, R is С₆-С₁₄ aryl substituted with a nitro group. In another embodiment of the invention, R is 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen or sulfur. In a preferred embodiment of the invention, the heteroaryl is thiophene. In a preferred embodiment, the pharmaceutically acceptable salt is hydrochloride of the compound of formula 1. The following compounds are preferred: 5-(3-methoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.1, TRX-0037); 5-(3-trifluoromethylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.2, TRX-0038); 5-(4-trifluoromethoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.3, TRX-0039); 5-(2-thiophene)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.4, TRX-0040); 5-(4-(benzyloxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.5, TRX-0041); 5-(3-bromophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.6, TRX-0042); 5-(3,5-dichlorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.7, TRX-0043); 5-(phenyl-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.8, TRX-0044); 5-(2-methylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.9, TRX-0045); 5-(4-ethoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.10, TRX-0046); 5-(4-chlorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.11, TRX-0047); 5-(2-bromophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.12, TRX-0048); 5-(4-(dimethylamino)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.13, TRX-0049); 5-(3,5-dimethylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.14, TRX-0050); 5-(4-fluorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.15, TRX-0051); 5-(3-nitrophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.16, TRX-0052); 5-(4-butoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.17, TRX-0053); 5-(4-((2-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.18, TRX- 0054); 5-(4-((3-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.19, TRX- 0055); 5-(4-((4-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.20, TRX- 0056); 5-(3-methyl-4-((3-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.21, TRX-0057); 5-(3-methyl-4-((4-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.22, TRX-0058); 5-(4-(4-methoxyphenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.23, TRX- 0059); 5-(4-(4-trifluoromethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.24, TRX-0060); 5-(4-(3-fluorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.25, TRX-0061); 5-(4-(2,4-difluorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.26, TRX- 0062); 5-(4-(4-chlorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.27, TRX-0063); 5-(4-(3,4-dimethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.28, TRX- 0064); 5-(4-(3,5-difluorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.29, TRX- 0065); 5-(3-(4-trifluoromethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.30, TRX-0066); 5-(4-(4-methylphenoxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.31, TRX- 0067). 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. 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 a pharmaceutically acceptable carrier, diluent, filler and 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 dosage forms selected from the group including tablets, powders, granules, pills, suspension, pellets, capsules, sachets and injectable solution. In another aspect, the present invention provides the 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 a 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. 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. Typically, the therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof is about 0.1 mg/day to about 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 of the invention, said disease, disorder or condition mediated by trace amine receptors TAAR1 is selected from the group including a mental disorder, cognitive disorder, metabolic disorder, neurological and neurodegenerative disease. In some embodiments of the invention, 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, as well as 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 a method for preparing the compound of general formula 1 or a pharmaceutically acceptable salt thereof comprising the following steps: (a) obtaining the compound of formula 5

by a method selected from: contacting the compound of formula 4

with hydrazine hydrate; or heating the compound of formula 11:

or the compounds of formula 15:

to the melting temperature of said compounds; (b) removing the tert-butoxycarbonyl protecting group, to obtain the compound of formula 1 where the values of R are as described in claim 1. In another embodiment of the invention, the method described above additionally comprises after step (a) the step of attaching the tetrahydropyranyl protecting group to the cyclic secondary nitrogen atom of the compound of formula 5, where R is phenyl substituted with halogen, followed by the Suzuki reaction, wherein step (b) further includes removing the tetrahydropyranyl protecting group. Various synthetic approaches to the production of the compound of formula 1 depending on the nature of substituent R are detailed below. Method A. Synthesis of 1,2,4-triazoles from imino ethers and anhydride (2).

N-acylated imino ether 4 is obtained by reacting poorly stable anhydride 2 with imino ether hydrochloride in alkaline medium; its treatment with hydrazine hydrate yields triazole 5. Removing the Boc-protection yields the desired compound 1.1. Method B. Synthesis of 1,2,4-triazole derivatives from amidrazones.

Keto ester 9 is obtained by reacting N-Boc-protected 3-aminopropanoic acid (6) with N- methylmorpholine (7) and isobutyl chloroformate (8) in inert atmosphere. Its interaction with amidrazones (10) yields compounds 11 which spontaneously cyclized to triazoles 5 when heated to their melting temperature. Deprotection of amino group is conducted in the final stage. Method C. Synthesis of triazole derivatives from imino ethers and 3-tert-butyl-(3- aminopropanehydrazide)carbamate.

Compounds 11 are obtained in one step by reacting imino ether 3 with protected 3- aminopropanoic acid hydrazide 12. Thereafter, synthesis is carried out similarly to the method B. Method D. Synthesis of 1,2,4-triazoles from amidine and hydrazides.

Compound 15 is obtained by reacting hydrazides 14 with amidine trifluoroacetate 13 in the presence of sodium methylate. The subsequent steps are carried out similarly to the method B. Method E. Synthesis of 1,2,4-triazole derivatives by the Suzuki reaction.

In the first stage, the tetrahydropyranyl protection is attached to the cyclic secondary nitrogen atom. Next, protected compounds 17 are introduced into the Suzuki reaction, and the treatment of biaryl-substituted triazoles 18 by hydrochloric acid in dioxane led to the simultaneous removal of both protective groups. 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 of the invention, 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 2.30 g of 3-aminopropionic acid (336.7 mmol) was added 14.83 g of sodium hydroxide (370.4 mmol) dissolved in the mixture of water:isopropanol 1:1 (150:150 ml) and 66.13 g of di-tert-butyl dicarbonate (303 mmol) and left for 12 hours under stirring. The progress of the reaction was monitored by TLC. Once the reaction has completed, isopropanol was evaporated. The aqueous layer was extracted 2 times with ethyl acetate, the aqueous phase was acidified with 3% HCl to pH=2, the resulting precipitate was filtered, and the remaining water was extracted with ethyl acetate. The organic layer was passed through sodium sulfate and evaporated on a rotary evaporator. The substance remained on the filter was dried in a desiccator over alkali. The yield was 44.5 g (78%). 30 mmol of 3-(tert-butoxycarbonyl)aminopropionic acid (5.601 g) was dissolved in anhydrous methylene chloride, added 17.5 mmol of dicyclohexylcarbodiimide (DCC) (1.562 g) and left overnight under stirring. The resulting precipitate was filtered, and a stock solution was used immediately in the next stage. Synthesis of 1,2,4-triazoles according to the method A. 1 eq. of imino ether was suspended in dry methylene chloride, added 3 eq. of triethylamine and allowed to mix well. In 10 minutes, 1 eq. of N,N-di-tert-butoxycarbonyl-3-aminopropionic acid anhydride (2) was added dropwise. The progress of the reaction was monitored by TLC (2% methanol in chloroform), then the reaction mixture was extracted with water, the organic layer was passed through sodium sulfate and evaporated on a rotary evaporator. Methylene chloride was added with the following gentle dropwise addition of 3 eq. of hydrazine hydrate. Once the reaction has completed, the reaction mixture was extracted successively with water, 5% potassium carbonate solution, 3% citric acid solution. The organic layer was passed through sodium sulfate and evaporated on a rotary evaporator. Purification was carried out using normal phase column chromatography on silica gel in the system chloroform:methanol (3:1). The Boc-protecting group was removed with hydrochloric acid in dioxane. Synthesis of 1,2,4-triazoles according to the method B. (Step 1 - synthesis of amidrazones) 1 eq. of imino ether (as free base) was dissolved in tetrahydrofuran and added 1.5 eq. of hydrazine hydrate, left for 48 hours under stirring. The reaction mixture was evaporated on a rotary evaporator and reevaporated with toluene. (Step 2) The flask was purged with argon and added compound (6), tetrahydrofuran and 1.1 eq. of N-methylmorpholine. The reaction mixture was cooled to -30°C and 1 eq. of isobutyl chloroformate was slowly added dropwise. Cooling was stopped 10 minutes after dropwise addition. When the temperature reached 0°C, the precipitate was quickly filtered off. 1 eq. of amidrazone was immediately added to the stock solution and left for 16 hours under stirring. The progress of the reaction was monitored by TLC (1% MeOH/CHCl₃). Next, the precipitate was filtered off. For the cyclization of triazole ring, the substance was melted in an oil bath at a temperature of 110–180°C. Purification was carried out using normal phase column chromatography on silica gel in the system chloroform:methanol 5%. Hydrochloric acid in dioxane was used to remove the Boc-protecting group. Synthesis of 1,2,4-triazoles according to the method C. 1 eq. of imino ether was dissolved in 2 eq. of triethylamine and added 1 eq. of 3-tert-butyl-(3- aminopropanehydrazide)carbamate. The reaction was left for 48 hours under stirring. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was passed through sodium sulfate and evaporated on a rotary evaporator. For the cyclization of triazole ring the substance was melted in an oil bath at a temperature of 180-200°C. Purification was carried out using normal phase column chromatography in the system chloroform:methanol 2%. The Boc-protecting group was removed by adding hydrochloric acid in dioxane. Synthesis of 1,2,4-triazoles according to the method D.1.2 eq. of compound (13) was dissolved in a small amount of dry methanol, added 1.2 eq. of freshly prepared sodium methylate and in 15 minutes – 1 eq. of hydrazide. The reaction mass was left ^{for 24-48 hours} under stirring^. The progress of the reaction was monitored by TLC (2% MeOH/CHCl₃). Once th_{e reaction has} completed, the reaction mixture was evaporated on a rotary evaporator and melted at a temperature of 180-200 °C in an oil bath with a reflux condenser. Purification was carried out using normal phase column chromatography on silica gel in the system ethyl acetate:light petroleum 1:1. The Boc-protecting group was removed with hydrochloric acid in dioxane. Synthesis of 1,2,4-triazoles according to the method E (Step 1 – creation of tetrahydropyranyl protection) compound (5) (2.06 mmol, 1 eq.) was dissolved in dry tetrahydrofuran, then 3,4-dihydro-2H-pyran (0.93 ml, 10.3 mmol, 5 eq.) and para- toluenesulfonic acid (0.035 g, 0.21 mmol, 0.1 eq.) were added and boiled with a reflux condenser for 5 hours. The progress of the reaction was monitored by TLC (chloroform). Next, sequential extraction was carried out using ethyl acetate with water, 5% potassium carbonate solution, 3% citric acid solution. The organic layer was passed through sodium sulfate and evaporated on a rotary evaporator. The yield is quantitative. (Step 2) The flask was purged with argon, and 1 eq. of compound (17) in argon flow was dissolved in 30 ml of dioxane followed by addition of 3.5 ml of 20% sodium carbonate solution in distilled water and 2 eq. of boronic acid. In 15 minutes, 0.03 eq. of Pd(PPh₃)₄ and 0.03 eq. of PdCl₂(PPh₃)₂ were added. Boiling was conducted with a reflux condenser in argon flow for 3-4 hours. The progress of the reaction was monitored by TLC (2% MeOH/CHCl₃). Once the reaction has completed, the reaction _{mixture was extracted} with ethyl acetate and successively with water and 5% potassium carbonate solution. The organic layer was passed through sodium sulfate and evaporated on a rotary evaporator. Purification was carried out using normal phase column chromatography on silica gel in the system ethyl acetate:light petroleum 1:1. THP- and Boc-protections were removed from the purified product with hydrochloric acid in dioxane. Example 2. Synthesis of 5-(3-methoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.1, TRX-0037). The yield was 0.924 g (48%). Tm=235-236°C. HRMS (ESI) found for С₁₁H₁₄N₄O [M+H+] 219.1240 Da, calculated 219.1240 Da. ¹H NMR (300 MHz, DMSO) δ 8.27 (br.s, 3H), 7.71-7.66 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.11 – 7.05 (m, 1H), 3.82 (s, 3H), 3.33-3.24 (m, 2H), 3.22-3.14 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 159.6, 156.1, 155.6, 130.2, 128.7, 118.6, 116.3, 111.4, 55.4, 36.8, 24.3. Example 3. Synthesis of 5-(3-trifluoromethylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.2, TRX-0038). The yield was 0.110 g (22%). T_m=242-244 °C. H^{RMS (ESI) found for} _С11H11F3N4 ^{[M+H+] 257.1009 Da, calculated 257.1009} _Da. ¹ _H NMR (300 MHz, DMSO) δ 8.35 (br.s, 5H), 7.89 – 7.67 (m, 2H), 3.35 – 3.14 (m, 4H).¹³C NMR (75 MHz, DMSO) δ 156.9, 155.6, 130.4, 130.3, 130.0 (q, J = 31.8 Hz), 129.9, 126.2 (q, J = 3.5 Hz), 124.1 (q, J = 272.4 Hz), 122.4 (q, J = 3.8 Hz), 36.8, 24.2. Example 4. Synthesis of 5-(4-trifluoromethoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.3, TRX-0039). The yield was 0.054 g (12%). T_m=253-254°C. HRMS (ESI) found for С₁₁H₁₁F₃N₄O [M+H+] 273.0958 Da, calculated _{273.0958 Da.} 1_H NMR (300 MHz, DMSO) δ 8.28 (br.s, 3H), 8.20 – 8.14 (m, 2H), 7.53 – 7.47 (m, 2H), 3.30 – 3.21 (m, 2H), 3.20 – 3.12 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 157.1, 155.9, 149.1 (q, J = 1.6 Hz), 128.6, 128.1, 121.5, 118.4 (q, J = 256.7 Hz), 36.9, 24.4. Example 5. Synthesis of 5-(2-thiophene)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.4, TRX-0040). The yield was 0.164 g (24%). T_m=248-250 °C. HRMS (ESI) found for С₈H₁₀N₄S [M+H⁺] 195.0699 Da, calculated 195.0699 Da. ¹H NMR (300 MHz, DMSO) δ 8.17 (br.s, 3H), 7.71 – 7.62 (m, 2H), 7.19 – 7.14 (m, 1H), 3.27 – 3.15 (m, 2H), 3.13 – 3.04 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 155.1, 153.3, 130.8, 127.6, 127.3, 126.1, 36.3, 23.7. Example 6. Synthesis of 5-(4-(benzyloxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.5, TRX-0041). The yield was 4.568 g (54%). Tm= 238-240°C. HRMS (ESI) found for С₁₇H₁₈N₄O [M+H+] 295.1553 Da, calculated 295.1553 Da. ¹H NMR (300 MHz, DMSO) δ 8.24 (br.s, 3H), 8.10 – 8.05 (m, 2H), 7.50 – 7.31 (m, 5H), 7.22 – 7.17 (m, 2H), 5.19 (s, 2H), 3.33 – 3.22 (m, 2H), 3.20 – 3.13 (m, 1H). ¹³C NMR (75 MHz, DMSO) δ 160.0, 155.3, 155.0, 136.4, 128.2, 128.0, 127.8, 127.7, 118.9, 115.2, 69.3, 36.6, 24.1. Example 7. Synthesis of 5-(3-bromophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.6, TRX-0042). The yield was 4.060 g (45%). T_m=239-241 °C. HRMS (ESI) found for С₁₀H₁₁BrN₄ [M+H+]] 269.0240 Da, calculated 269.0240 Da. 1H NMR (300 MHz, DMSO) δ 8.33 (br.s, 3H), 8.24 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.51 – 7.44 (m, 1H), 3.32 – 3.22 (m, 2H), 3.21 – 3.14 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 156.4, 155.6, 132.5, 131.2, 131.1, 128.6, 125.1, 122.2, 36.8, 24.2. Example 8. Synthesis of 5-(3,5-dichlorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.7, TRX-0043). The yield was 0.102 g (36%). T_m=222-224°C. HRMS (ESI) found for С₁₀H₁₀Cl₂N₄ [M+H⁺] 257.0355 Da, calculated 257.0355 Da. ¹H NMR (300 MHz, DMSO) δ 8.31 (br.s, 3H), 8.02 (d, J = 1.8 Hz, 2H), 7.70 – 7.68 (m, 1H), 3.29 – 3.20 (m, 2H), 3.19 – 3.11 (m, 2H).¹³C NMR (75 MHz, DMSO) δ 156.6, 155.8, 134.7, 133.3, 128.7, 124.3, 36.8, 24.1. Example 9. Synthesis of 5-(phenyl-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.8, TRX-0044). The yield was 0.04 g (8%). T_m=250-252 °C. HRMS (ESI) found for С₁₀H₁₂N₄ [M+H+] 189.1135 Da, calculated 189.1135 Da. 1H NMR (300 MHz, DMSO) δ 8.17 (br.s, 3H), 8.08 – 8.02 (m, 2H), 7.55 – 7.44 (m, 3H), 3.32 – 3.20 (m, 2H), 3.17 – 3.09 (m, 2H).¹³C NMR (75 MHz, DMSO) δ 156.6, 154.1, 129.9, 129.0, 128.5, 126.1, 37.2, 24.6. Example 10. Synthesis of 5-(2-methylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.9, TRX-0045)^. The yield was 0.110 g (22%). T_m=244-245°C. HRMS (ESI) found for С₁₁H₁₄N₄ [M+H⁺] 203.1291 Da, calculated 203.1291 Da. ¹H NMR (300 MHz, DMSO) δ 8.25 (br.s, 3H), 7.78 (d, J = 7.4 Hz, 1H), 7.43 – 7.29 (m, 3H), 3.33 – 3.22 (m, 2H), 3.21 – 3.14 (m, 2H), 2.53 (s, 3H). ¹³C NMR (75 MHz, DMSO) δ 157.1, 155.1, 136.6, 131.1, 129.0, 129.2, 127.5, 125.9, 36.8, 30.6, 24.3. Example 11. Synthesis of 5-(4-ethoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.10, TRX-0046). The yield was 0.051 g (44%). T_m=226-228 °C. HRMS (ESI) found for С₁₂H₁₆N₄O [M+H+] 233.1397 Da, calculated 233.1397 _Da. 1_H NMR (300 MHz, DMSO) δ 8.16 (br.s, 3H), 8.01 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.10 (q, J = 6.9 Hz, 2H), 3.31 – 3.19 (m, 2H), 3.17 – 3.08 (m, 2H), 1.34 (t, J = 6.9 Hz, 3H).¹³C NMR (75 MHz, DMSO) δ 160.3, 156.8, 156.4, 128.1, 120.1, 115.1, 63.6, 37.3, 24.9, 14.8. Example 12. Synthesis of 5-(4-chlorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.11, TRX-0047). The yield was 0.025 g (13%). T_m=239-241°C. HRMS (ESI) found for С₁₀H₁₁ClN₄ [M+H⁺] 223.0745 Da, calculated 223.0745 Da. ¹H NMR (300 MHz, DMSO) δ 8.12 (s, 2H), 8.05 – 8.00 (m, 2H), 7.58 – 7.53 (m, 2H), 3.29 – 3.17 (m, 2H), 3.14 – 3.05 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 157.7, 156.4, 134.3, 129.2, 128.3, 127.9, 37.2, 24.6. Example 13. Synthesis of 5-(2-bromophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.12, TRX-0048). The yield was 0.044 g (33%). T_m=194-196 °C. HRMS (ESI) found for С₁₀H₁₁BrN₄ [M+H+] 267.0240 Da, calculated 267.0240 _Da. 1_H NMR (300 MHz, DMSO) δ 8.25 (s, 3H), 7.79 – 7.73 (m, 2H), 7.53 – 7.46 (m, 1H), 7.44 – 7.38 (m, 1H), 3.29 – 3.11 (m, 4H). ¹³C NMR (75 MHz, DMSO) δ 157.4, 155.8, 133.8, 131.9, 131.4, 131.0, 128.0, 121.3, 37.2, 24.6. Example 14. Synthesis of 5-(4-(dimethylamino)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.13, TRX-0049). The yield was 0.017 g (9%). Tm=244.5-246°C. HRMS (ESI) found for С₁₂H₁₇N₅ [M+H⁺] 232.1557 Da, calculated 232.1557 Da. ¹H NMR (300 MHz, DMSO) δ 8.20 (s, 3H), 8.02 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 3.35 – 3.24 (m, 2H), 3.21 – 3.12 (m, 2H), 3.03 (s, 6H). ¹³C NMR (75 MHz, DMSO) δ 154.2, 154.1, 151.8, 128.2, 112.3, 36.6, 25.5, 24.1. Example 15. Synthesis of 5-(3,5-dimethylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.14, TRX-0050). The yield was 0.138 g (41%). T_m=232-234 °C. HRMS (ESI) found for С₁₂H₁₆N₄ [M+H⁺] 217.1448 Da, calculated 217.1448 Da. ¹H NMR (300 MHz, DMSO) δ 8.34 (br.s, 3H), 7.76 (s, 2H), 7.17 (s, 1H), 3.37 – 3.16 (m, 4H), 2.33 (s, 6H).¹³C NMR (75 MHz, DMSO) δ 155.7, 155.2, 138.4, 132.2, 126.5, 124.3, 36.7, 24.2, 21.0. Example 16. Synthesis of 5-(4-fluorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride ₍1.15, _TRX-0051). The yield was 0.028 g (16%). T_m=253-256°C. HRMS (ESI) found for С₁₀H₁₁FN₄ [M+H+] 207.1041 Da, calculated 207.1041 Da. 1_H NMR (300 MHz, DMSO) δ 8.25 – 8.04 (m, 5H), 7.46 – 7.27 (m, 2H), 3.30 – 3.19 (m, 2H), 3.17 – 3.08 (m, 2H).¹³C NMR (75 MHz, DMSO) δ 162.93 (d, J = 246.5 Hz), 156.89, 155.93, 128.38 (d, J = 8.7 Hz), 125.56, 115.97 (d, J = 22.0 Hz), 36.94, 24.45. Example 17. Synthesis of 5-(3-nitrophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.16, TRX-0052). The yield was 0.057 g (48%). T_m=214-216 °C. HRMS (ESI) found for С₁₀H₁₁N₅O₂ [M+H⁺] 234.0986 Da, calculated 234.0986 Da. ¹H NMR (300 MHz, DMSO) δ 8.78 – 8.76 (m, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.28 (dd, J = 8.2, 1.6 Hz, 1H), 8.18 (br.s, 3H), 7.79 (t, J = 8.0 Hz, 1H), 3.32 – 3.20 (m, 2H), 3.19 – 3.11 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 157.9, 156.1, 148.5, 132.2, 132.0, 131.0, 124.2, 120.5, 37.2, 24.5. Example 18. Synthesis of 5-(4-butoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.17, TRX-0053). The yield was 0.019 g (15%). T_m=205-207 °C. HRMS (ESI) found for С₁₄H₂₀N₄O [M+H+] 261.1710 Da, calculated 261.1710 _Da. 1_H NMR (300 MHz, DMSO) δ 8.32 (br.s, 3H), 8.06 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.04 (t, J = 6.4 Hz, 2H), 3.33 – 3.12 (m, 4H), 1.76 – 1.65 (m, 2H), 1.50 – 1.37 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). ¹³C NMR (75 MHz, DMSO) δ 160.4, 155.7, 155.6, 128.1, 119.2, 114.9, 67.4, 36.8, 30.6, 24.4, 18.7, 13.7. Example 19. Synthesis of 5-(4-((2-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride ^(1.18, TRX-0054). The yield was 0.023 g (15%). Tm=232-235 ^C. HRMS (ESI) found for С₁₇H₁₇FN₄O [M+H+] 313.1459 Da, calculated 313.1459 Da. ¹H NMR (300 MHz, DMSO) δ 8.16 (br.s, 3H), 8.06 – 8.00 (m, 2H), 7.59 (t, J = 7.0 Hz, 1H), 7.49 – 7.40 (m, 1H), 7.32 – 7.17 (m, 4H), 5.22 (s, 2H), 3.31 – 3.19 (m, 2H), 3.17 – 3.08 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 160.5 (d, J = 246.2 Hz), 159.5, 156.6, 156.4, 130.9 (d, J = 4.0 Hz), 130.6 (d, J = 8.2 Hz), 127.8, 124.6 (d, J = 3.4 Hz), 123.4 (d, J = 14.5 Hz), 120.8, 115.5 (d, J = 21.0 Hz), 115.1, 63.8, 37.1, 24.7. Example 20. Synthesis of 5-(4-((3-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride (1.19, TRX-0055). The yield was 0.051 g (31%). Tm=214-216 ^C. HRMS (ESI) found for С₁₇H₁₇FN ₄O [M+H+] 313.1459 Da, calculated _{313.1459 Da.} 1_H NMR (300 MHz, DMSO) δ 8.20 (br.s, 3H), 8.08 – 8.02 (m, 2H), 7.51 – 7.40 (m, 1H), 7.35 – 7.28 (m, 2H), 7.23 – 7.13 (m, 3H), 5.21 (s, 2H), 3.32 – 3.20 (m, 2H), 3.18 – 3.10 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 162.7 (d, J = 243.6 Hz), 160.1, 156.8, 156.6, 140.1 (d, J = 7.5 Hz), 131.0 (d, J = 8.3 Hz), 128.3, 124.1 (d, J = 1.6 Hz), 120.9, 115.8, 115.2 (d, J = 21.0 Hz), 114.8 (d, J = 21.7 Hz), 69.0, 37.5, 25.0. Example 21. Synthesis of 5-(4-((4-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride (1.20, TRX-0056). The yield was 0.070 g (46%). T_m=220.5-222 °C. HRMS (ESI) found for С₁₇H₁₇FN₄O [M+H+] 313.1459 Da, calculated 313.1459 Da. ¹H NMR (300 MHz, DMSO) δ 8.20 (s, 3H), 8.08 – 8.01 (m, 2H), 7.53 (dd, J = 8.6, 5.6 Hz, 2H), 7.28 – 7.15 (m, 4H), 5.17 (s, 2H), 3.32 – 3.20 (m, 2H), 3.18 – 3.09 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 162.3 (d, J = 243.8 Hz), 160.4, 156.3, 156.2, 133.4 (d, J = 3.0 Hz), 130.6 (d, J = 8.3 Hz), 128.5, 120.3, 115.8 (d, J = 21.4 Hz), 115.8, 69.2, 37.3, 24.9. Example 22. Synthesis of 5-(3-methyl-4-((3-fluorobenzyl)oxy)phenyl)-4H-1,2,4- triazole)-3-ethanamine hydrochloride (1.21, TRX-0057). The yield was 0.053 g (32%). T_m=215- 216 °C. HRMS (ESI) found for С₁₈H₁₉FN₄O [M+H⁺] 327.1616 Da, calculated 327.1616 Da. ¹H NMR (300 MHz, DMSO) δ 8.19 (br.s, 3H), 7.97 – 7.89 (m, 2H), 7.51 – 7.42 (m, 1H), 7.37 – 7.28 (m, 2H), 7.22 – 7.13 (m, 2H), 5.24 (s, 2H), 3.33 – 3.19 (m, 2H), 3.18 – 3.09 (m, 2H), 2.28 (s, 3H).¹³C NMR (75 MHz, DMSO) δ 163.2 (d, J = 243.6 Hz), 159.2, 156.1, 155.8, 140.8 (d, J = 7.4 Hz), 131.5 (d, J = 8.3 Hz), 129.8, 127.9, 126.9, 124.2 (d, J = 2.7 Hz), 119.1, 115.6 (d, J = 20.9 Hz), 114.9 (d, J = 21.9 Hz), 113.1, 69.5, 37.6, 25.1, 17.1. Example 23. Synthesis of 5-(3-methyl-4-((4-fluorobenzyl)oxy)phenyl)-4H-1,2,4- triazole)-3-ethanamine hydrochloride (1.22, TRX-0058). The yield was 0.020 g (12%). T_m=182- 183°C. HRMS (ESI) found for С₁₈H₁₉FN₄O [M+H⁺] 327.1616 Da, calculated 327.1616 Da. ¹H NMR (300 MHz, DMSO) δ 8.12 (br.s, 3H), 7.90 – 7.85 (m, 2H), 7.57 – 7.48 (m, 2H), 7.28 – 7.14 (m, 3H), 5.18 (s, 2H), 3.30 – 3.15 (m, 2H), 3.12 – 3.04 (m, 2H), 2.24 (s, 3H).¹³C NMR (75 MHz, DMSO) δ 161.6 (d, J = 243.6 Hz), 157.5, 156.7, 156.4, 133.1 (d, J = 3.0 Hz), 129.5 (d, J = 8.3 Hz), 128.2, 126.5, 125.1, 120.2, 115.1 (d, J = 21.4 Hz), 111.9, 68.5, 37.0, 24.6, 16.0. Example 24. Synthesis of 5-(4-(4-methoxyphenyl)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride (1.23, TRX-0059). The yield was 0.065 g (50%). T_m=300-301 ^C. HRMS (ESI) found for С₁₇H₁₈N₄O [M+H⁺] 295.1553 Da, calculated 295.1553 Da. ¹H NMR (300 MHz, DMSO) δ 8.23 (br.s, 3H), 8.13 (d, J = 8.2 Hz, 2H), 7.84 – 7.76 (m, 2H), 7.74 – 7.67 (m, 2H), 7.05 (d, J = 8.5 Hz, 2H), 3.81 (s, 3H), 3.33 – 3.22 (m, 2H), 3.20 – 3.12 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 159.5, 157.0, 156.6, 141.3, 131.6, 128.0, 126.9, 126.7, 126.6, 114.7, 55.4, 37.2, 24.7. Example 25. Synthesis of 5-(4-(4-trifluoromethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride (1.24, TRX-0060). The yield was 0.060 g (35%). T_m=299-300 °C. HRMS (ESI) found for С₁₇H₁₅F₃N₄O [M+H⁺] 349.1271 Da, calculated 349.1271 Da. ¹H NMR (300 MHz, DMSO) δ 8.25 (br.s, 3H), 8.17 (d, J = 8.3 Hz, 2H), 7.87 (t, J = 8.1 Hz, 4H), 7.48 (d, J = 8.3 Hz, 2H), 3.34 – 3.22 (m, 2H), 3.21 – 3.13 (m, 2H).¹³C NMR (75 MHz, DMSO) δ 157.3, 156.6, 148.1, 140.0, 138.7, 128.8, 128.3, 127.5, 126.9, 121.7, 120.3 (d, J = 256.3 Hz), 37.2, 24.6. Example 26. Synthesis of 5-(4-(3-fluorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.25, TRX-0061). The yield was 0.040 g (26%). T_m=260-262 ^C. HRMS (ESI) found for С₁₆H₁₅FN₄ [M+H⁺] 283.1354 Da, calculated 283.1354 Da. ¹H NMR (300 MHz, DMSO) δ 8.20 (br.s, 3H), 8.15 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.67 – 7.47 (m, 3H), 7.29 – 7.18 (m, 1H), 3.33 – 3.21 (m, 2H), 3.19 – 3.10 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 163.1 (d, J = 243.4 Hz), 157.4, 156.7, 142.1 (d, J = 8.0 Hz), 140.3, 131.4 (d, J = 8.4 Hz), 128.7, 127.8, 127.1, 123.2 (d, J = 2.4 Hz), 115.1 (d, J = 21.4 Hz), 113.9 (d, J = 22.2 Hz), 37.4, 25.0. Example 27. Synthesis of 5-(4-(2,4-difluorophenyl)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride (1.26, TRX-0062). The yield was 0.059 g (44%). T_m=251-253 °C. HRMS (ESI) found for С₁₆H₁₄F₂N₄ [M+H⁺] 301.1259 Da, calculated 301.1259 Da. ¹H NMR (300 MHz, DMSO) δ 8.12 (m, 5H), 7.73 – 7.60 (m, 3H), 7.45 – 7.34 (m, 1H), 7.29 – 7.18 (m, 1H), 3.32 – 3.20 (m, 2H), 3.18 – 3.09 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 162.0 (dd, J = 208.5, 12.3 Hz), 158.7 (dd, J = 210.1, 12.4 Hz), 156.4, 155.7, 135.5, 131.8 (dd, J = 9.7, 4.6 Hz), 129.1 (d, J = 2.7 Hz), 127.6, 126.2, 123.9 (dd, J = 13.1, 3.8 Hz), 112.1 (dd, J = 21.1, 3.6 Hz), 104.7 (t, J = 26.6 Hz), 36.7, 24.2. Example 28. Synthesis of 5-(4-(4-chlorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride (1.27, TRX-0063). The yield was 0.047 g (36%). T_m=247-249 °C. HRMS (ESI) found for С₁₆H₁₅ClN₄ [M+H⁺] 299.1058 Da, calculated 299.1058 Da. ¹H NMR (300 MHz, DMSO) δ 8.23 – 8.09 (m, 5H), 7.87 – 7.74 (m, 4H), 7.58 – 7.51 (m, 2H), 3.32 – 3.20 (m, 2H), 3.18 – 3.09 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 157.1, 156.4, 139.1, 138.0, 132.7, 129.0, 128.4, 128.1, 127.0, 126.7, 37.0, 24.6. Example 29. Synthesis of 5-(4-(3,4-dimethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride ^(1.28, TRX-0064). The yield was 0.046 g (32%). Tm=199-201°C. HRMS (ESI) found for С₁₈H₂₀N₄O₂ [M+H⁺] 325.1659 Da, calculated 325.1659 Da. ¹H NMR (300 MHz, DMSO) δ 8.28 (br.s, 3H), 8.16 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.33 – 7.27 (m, 2H), 7.08 – 7.03 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.35 – 3.25 (m, 2H), 3.23 – 3.16 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 156.2, 155.9, 149.2, 149.1, 141.8, 131.8, 126.8, 126.7, 125.8, 119.1, 112.3, 110.4, 55.8, 55.7, 36.9, 24.5. Example 30. Synthesis of 5-(4-(3,5-difluorophenyl)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride (1.29, TRX-0065). The yield was 0.050 g (38%). T_m=260-262°C. HRMS (ESI) found for С₁₆H₁₄F₂N₄ [M+H⁺] 301.1259 Da, calculated 301.1259 Da. ¹H NMR (300 MHz, DMSO) δ 8.32 (br.s, 3H), 8.22 – 8.17 (m, 2H), 7.95 – 7.90 (m, 2H), 7.59 – 7.49 (m, 2H), 7.31 – 7.22 (m, 1H), 3.35 – 3.16 (m, 4H). ¹³C NMR (75 MHz, DMSO) δ 162.2 (dd, J = 205.6, 12.3 Hz), 158.9 (dd, J = 207.4, 12.3 Hz), 157.5, 156.3, 135.3, 131.9 (dd, J = 9.7, 4.7 Hz), 129.2 (d, J = 2.9 Hz), 128.5, 126.2, 124.2 (dd, J = 13.3, 3.8 Hz), 112.2 (dd, J = 21.2, 3.6 Hz), 104.6 (dd, J = 26.9, 25.9 Hz), 37.0, 24.6. Example 31. Synthesis of 5-(3-(4-trifluoromethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride (1.30, TRX-0066). The yield was 0.045 g (28%). T_m=253-257 °C. HRMS (ESI) found for С₁₇H₁₅F₃N₄O [M+H+] 349.1271 Da, calculated 349.1271 Da. 1H NMR (300 MHz, DMSO) δ 8.38 – 8.35 (m, 1H), 8.18 (br.s, 3H), 8.09 – 8.04 (m, 1H), 7.91 – 7.85 (m, 2H), 7.82 – 7.77 (m, 1H), 7.66 – 7.59 (m, 1H), 7.53 – 7.47 (m, 2H), 3.31 – 3.21 (m, 2H), 3.18 – 3.11 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 157.1, 156.5, 148.1 (q, J = 1.7 Hz), 139.4, 138.8, 129.8, 129.4, 128.8, 128.2, 125.5, 124.4, 121.6, 120.2 (q, J = 256.4 Hz), 37.0, 24.6. Example 32. Synthesis of 5-(4-(4-methylphenoxy)phenyl)-4H-1,2,4-triazole)-3- ethanamine hydrochloride (1.31, TRX-0067). The yield was 0.030 g (13%). T_m=234.5-236 °C. HRMS (ESI) found for С₁₇H₁₈N₄O [M+H+] 295.1553 Da, calculated 295.1553 _Da. 1_H NMR (300 MHz, DMSO) δ 8.16 (br.s, 3H), 8.06 – 8.00 (m, 2H), 7.28 – 7.21 (m, 2H), 7.09 – 6.96 (m, 4H), 3.30 – 3.19 (m, 2H), 3.16 – 3.07 (m, 2H), 2.31 (s, 3H). ¹³C NMR (75 MHz, DMSO) δ 158.9, 156.7, 156.3, 153.3, 133.5, 130.7, 128.1, 122.9, 119.6, 117.9, 37.0, 24.6, 20.4. Example 33. Construction of expression plasmids, TAAR and stably transfected cell lines. Materials and methods. The pchTAAR1 expression vector containing the human TAAR1 receptor gene was obtained 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 Gαs 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 Gαs 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: pchTAAR1 (3– 5 µg) and pcEPAC (3–5 µg) 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 pchTAAR1 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 µl of PBS buffer containing Ca²⁺ and Mg²⁺ ions, 10 µl of 2 mM IBMX solution (Sigma) and 10 µl of 50 µM 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 (ЕС₅₀) ligand solutions diluted from 0.1 nM to 10 μM were added and incubated for another 5 minutes at room temperature. A non-selective agonist of β2-adrenergic receptor, isoprotenerol (assessment of biosensor performance), at a concentration of 100 nM, as well as beta- phenylethylamine (a natural agonist of TAAR1 receptor) at concentrations 0.1 nM to 10 μM 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. Data on the effective ligand concentration are presented in Table 1. Table 1. TAAR1 receptor activation by compounds 1.1 – 1.31

Therefore, it can be concluded based on the data obtained that the compounds of formula 1 according to the present invention have excellent agonistic activity on TAAR1 receptor and can be used to treat diseases mediated by trace amine receptors TAAR1 such as mental disorders, cognitive disorders, neurological and neurodegenerative diseases, 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

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:

Formula 1 where R is: С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group consisting of: С₁-С₁₀ alkyl optionally substituted with 1-3 halogen atoms, С₁-С₁₀ alkoxy optionally substituted with 1-3 halogen atoms or С₆-С₁₄ aryl optionally substituted with a halogen atom, С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group including halogen and С₁-С₁₀ alkoxy optionally substituted with 1-3 halogen atoms, a halogen, amino group of formula -N(R¹)₂ where each R¹ is independently hydrogen or С₁-С₁₀ alkyl_, nitro group, and C₆-C₁₄ aryloxy optionally substituted with С₁-С₁₀ alkyl; or 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen or sulfur.

2. The compound of claim 1, wherein R is С₆-С₁₄ aryl substituted with 1-2 substituents selected from the group including methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy and phenyloxy optionally substituted with С₁-С₁₀ alkyl.

3. The compound of claim 1, wherein R is С₆-С₁₄ aryl substituted with С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group including halogen, methoxy, ethoxy, propoxy, butoxy and trifluoromethoxy.

4. The compound of claim 1, wherein R is С₆-С₁₄ aryl substituted with 1-2 substituents selected from the group including methyl, ethyl, propyl, butyl and trifluoromethyl.

5. The compound of claim 1, wherein R is С₆-С₁₄ aryl substituted with 1-2 substituents selected from the group including fluoride, chloride and bromide.

6. The compound of claim 1, wherein R is С₆-С₁₄ aryl substituted with an amino group selected from the group including methylamino, dimethylamino and diethylamino.

7. The compound of claim 1, wherein R is thiophene.

8. The compound of claim 1, wherein the compound of formula 1 is selected from the group including: 5-(3-methoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(3-trifluoromethylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-trifluoromethoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(2-thiophene)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(benzyloxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(3-bromophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(3,5-dichlorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(phenyl-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(2-methylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-ethoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-chlorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(2-bromophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(dimethylamino)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(3,5-dimethylphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-fluorophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(3-nitrophenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-butoxyphenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-((2-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-((3-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-((4-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(3-methyl-4-((3-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(3-methyl-4-((4-fluorobenzyl)oxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(4-methoxyphenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(4-trifluoromethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(3-fluorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(2,4-difluorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(4-chlorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(3,4-dimethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(3,5-difluorophenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(3-(4-trifluoromethoxyphenyl)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride; 5-(4-(4-methylphenoxy)phenyl)-4H-1,2,4-triazole)-3-ethanamine hydrochloride.

9. 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 disorder and a neurodegenerative disorder.

10. The compound of claim 1, wherein the disease, disorder or condition 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.

11. 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:

Formula 1 where R is: С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group consisting of: С₁-С₁₀ alkyl optionally substituted with 1-3 halogen atoms, С₁-С₁₀ alkoxy optionally substituted with 1-3 halogen atoms or С₆-С₁₄ aryl optionally substituted with a halogen atom, С₆-С₁₄ aryl optionally substituted with 1-2 substituents selected from the group including halogen and С₁-С₁₀ alkoxy optionally substituted with 1-3 halogen atoms, halogen, amino group of formula -N(R¹)₂ where each R¹ is independently hydrogen or С₁-С₁₀ alkyl, nitro group, and C₆-C₁₄ aryloxy optionally substituted with С₁-С₁₀ alkyl; or 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen or sulfur.

12. The pharmaceutical composition of claim 11, wherein the excipient is selected from the group including a pharmaceutically acceptable carrier, diluent, filler and solvent.

13. The pharmaceutical composition of claim 11 or claim 12, 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.

14. The pharmaceutical composition of claim 11 or claim 12, wherein the disease, disorder or condition 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.

15. The pharmaceutical composition of any one of claims 11-14, 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.