WO2023033679A1

WO2023033679A1 - (azacycloalkyl)methoxy-substituted benzamides as modulators of trace amine-associated receptor 1 (taar1)

Info

Publication number: WO2023033679A1
Application number: PCT/RU2022/050270
Authority: WO
Inventors: Raul Radikovich GAINETDINOV; Andrey Sergeevich GERASIMOV; Aleksey Yurievich LUKIN; Nikolay Ilyich ZHURILO; 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: WO2023033679A4

Abstract

(Azacycloalkyl)methoxy-substituted benzamides 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

(AZACYCLOALKYL)METHOXY-SUBSTITUTED BENZAMIDES AS MODULATORS OF TRACE AMINE-ASSOCIATED RECEPTOR 1 (TAAR1)

Field of the invention

The present invention relates to (azacycloalkyl)methoxy-substituted benzamides 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 T AAR 1 -knockout mouse strain (TAAR1-KO mice) have recently been developed [CA2856204; WO2016016292A1; 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 (azacycloalkyl)methoxy-substituted benzamides 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 (azacycloalkyl)methoxy-substituted benzamides, 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 the compound of formula 1,

or a pharmaceutically acceptable salt thereof, where n is 0, 1 or 2; m is 0 if n is 2, or m is 1 if n is 0 or 1;

R¹ and R² are independently: hydrogen atom;

Ci-Cio alkyl optionally substituted with C3-C10 cycloalkyl;

C3-C10 cycloalkyl; or R¹ and R² together with the nitrogen atom to which they are attached form a 5- or 6- membered saturated heterocyclyl containing 1 nitrogen atom and optionally substituted with C1-C10 alkyl; or R¹ and R² together with the nitrogen atom to which they are attached form a 6- membered saturated heterocyclyl containing 1 nitrogen atom and 1 heteroatom selected from oxygen, sulfur and nitrogen.

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

(a) contacting an ester of hydroxybenzoic acid with the compound of formula 3

followed by alkaline hydrolysis of the resulting ester to form the compound of formula 5

(b) contacting the compound of formula 5 obtained in step (a) with amines of general formula R'R^H followed by removal of the protective tert-butoxycarbonyl group to form the 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 the 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 the 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 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 the 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 a part of 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, bicyclic or polycyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and etc.

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 of the invention, heterocyclic groups contain 1 or 2 heteroatoms selected from N, O, S. Heterocyclyl may have one or more substituents such as Ci- Cio alkyl, C3-C10 cycloalkyl. Nitrogen and sulfur atoms within heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Examples of heterocyclyls include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and etc. An example of substituted heterocyclyl is piperidinyl substituted with C1-C10 alkyl.

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 1-3 substituents. The terms «optionally substituted» and «substituted or unsub stituted» may be used interchangeably.

One of skill 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 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 substances that are not biologically or otherwise undesirable, for example, a substance 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. The terms «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 or 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 (azacycloalkyl)methoxy-substituted benzamides exhibiting properties of a trace amine receptor TAAR1 agonist, i.e. compounds of general formula 1

or pharmaceutically acceptable salts thereof, where n is 0, 1 or 2; m is 0 if n is 2, or m is 1 if n is 0 or 1;

R¹ and R² are independently: hydrogen atom;

Ci-Cio alkyl optionally substituted with C3-C10 cycloalkyl; or

In one embodiment of the invention, R¹ and R² cannot simultaneously be hydrogen.

In another embodiment of the invention, R¹ and R² are simultaneously hydrogen.

In another embodiment of the invention, R¹ is hydrogen and R² is Ci-Cio alkyl, preferably Ci-Ce alkyl.

In another embodiment of the invention, R¹ is hydrogen and R² is C3-C10 cycloalkyl, preferably C3-C8 cycloalkyl.

In another embodiment of the invention, R¹ and R² together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidinyl or morpholinyl.

In another embodiment of the invention, R¹ and R² together with the nitrogen atom to which they are attached form pyrrolidinyl or piperidinyl substituted with C1-C10 alkyl.

In some embodiments of the invention, the amide group within benzene ring of the compound of formula 1 is located at para- or meta-position relative to the methoxy substituent.

The following compounds are preferred: (piperidin-l-yl)[4-(piperidin-3-ylmethoxy)phenyl]methanone (1.1, TRX-0001):

7V-isopropyl-4-(piperidin-3-ylmethoxy)benzamide (1.2, TRX-0002):

4 )-7V-cyclopropylbenzamide (1.3, TRX-0003):

7 morpholino[4-(piperidin-3-ylmethoxy)phenyl]methanone (1.4, TRX-0004):

[4-(piperidin-3-ylmethoxy)phenyl](pyrrolidin-l-yl)methanone (1.5, TRX-0005):

(4-m ethylpiperi din- 1 -yl)[3 -(piperi din-3 -ylmethoxy)phenyl]methanone (1.6, TRX-0006):

[3-(piperidin-3-ylmethoxy)phenyl](pyrrolidin-l-yl)methanone (1.7, TRX-0007):

( eridin-3-ylmethoxy)phenyl]methanone (1.8, TRX-0008):

7V-isopropyl-4-(pyrrolidin-2-ylmethoxy)benzamide (1.9, TRX-0009): xy)-7V-cyclopropylbenzamide (1.10, TRX-0010):

morpholino[4-(pyrrolidin-2-ylmethoxy)phenyl]methanone (1.11, TRX-0011):

(pyrrolidin-l-yl)[4-(pyrrolidin-2-ylmethoxy)phenyl]methanone (1.12, TRX-0012): 4-ylmethoxy)phenyl]methanone (1.13, TRX-0013):

(4-methylpiperidin-l-yl)[4-(piperidin-4-ylmethoxy)phenyl]methanone (1.14, TRX-0014):

(piperidin-l-yl)[4-(piperidin-4-ylmethoxy)phenyl]methanone (1.15, TRX-0015):

7V-isopropyl-4-(piperidin-4-ylmethoxy)benzamide (1.16, TRX-0016):

7

[4-(piperidin-4-ylmethoxy)phenyl](pyrrolidin-l-yl)methanone (1.18, TRX-0018):

In some embodiments, the compound of formula 1 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of approximately 0.1 mg to approximately 1000 mg, preferably approximately 1 mg to approximately 800 mg, more preferably approximately 10 mg to approximately 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 approximately 1 wt.% to approximately 99 wt.%, preferably approximately 5 wt.% to approximately 98 wt.%, more preferably approximately 15 wt.% to approximately 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 approximately 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.

In another aspect, the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof for using 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 approximately 0.1 mg/day to 1000 mg/day, preferably approximately 1 mg/day to approximately 800 mg/day, more preferably approximately 10 mg/day to approximately 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 a mental disorder, a cognitive disorder, a metabolic disorder, a neurological and a 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 the 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 formula 1 or a pharmaceutically acceptable salt thereof comprising:

(a) contacting an ester of hydroxybenzoic acid with the compound of formula 3

7

(b) contacting the compound of formula 5 obtained in step (a) with amines of general formula R¹R²NH followed by removal of the protective tert-butoxycarbonyl group to form the compound of formula 1, where n, m, R¹ and R² are as defined above for the compound of formula 1.

In some embodiments, contacting an ester of hydroxybenzoic acid with the compound of formula 3 in step (a) is carried out in the presence of triphenylphosphine (PPhs) and diisopropyl azodi carboxylate (DIAD) at room temperature.

In some embodiments, conversion of the compound of formula 5 obtained in step (a) to the corresponding amide by contacting its with amines of general formula R¹R²NH in step (b) is carried out in the presence of N,N’ -carbonyl diimidazole (CDI) at room temperature.

An ester of hydroxybenzoic acid is alkyl ester of ortho-, meta-, or para-hydroxybenzoic acid. Preferably, an ester of hydroxybenzoic acid is ethyl ester of para- or meta-hydroxybenzoic acid.

Preferably, amines of general formula R¹R²NH are selected from the group including piperidine, 4-methylpiperidine, isopropylamine, cyclopropylamine, morpholine, pyrrolidine. 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 scheme below:

Compound 5. DIAD (60 g, 0.26 mol) was added dropwise to the solution of alcohol 3 (49.5 g, 0.23 mol), phenol 2 (39.5 g, 0.26 mol) and triphenylphosphine (68.2 g, 0.26 mol). Left overnight under stirring. The reaction mass was poured into 500 ml of water and extracted with chloroform. The pooled extracts were dried over anhydrous Na2SO4, evaporated, and the residue was analyzed by chromatography on silica gel with elution by the mixture of diethyl etherhexane 1 : 1. Fractions containing the product were evaporated and dissolved in 500 ml of methanol, then an aqueous KOH solution (22 g, 0.4 mol) was added dropwise, stirred overnight, the reaction mass was evaporated, the residue was dissolved in 300 ml of water and extracted 2 times with 200 ml of diethyl ether, the organic phases were discarded, the aqueous phase was acidified with 5% aqueous HC1 solution to pH 4, the precipitate was filtered off and air-dried.

4-{ [ l -(/c/7-Butoxycarbonyl)piperidin-3-yl]methoxyJbenzoic acid. The yield was 58.6 g (76%).

4-{ [l-(te/7-Butoxycarbonyl)piperidin-4-yl]methoxy (benzoic acid. The yield was 64.7 g (84%).

3-{ [l-(te/7-Butoxycarbonyl)piperidin-4-yl]methoxy (benzoic acid. The yield was 51.6 g (67%).

4-{ [l-(te/7-Butoxycarbonyl)pyrrolidin-2-yl]methoxy (benzoic acid. The yield was 36.2 g (49%).

Compound 1. CDI (9.7 g, 0.06 mol) was added portionwise to compound 5 solution (16.8 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 dissolved in 25 ml of «dry» dioxane and 25 ml of 4M HC1 solution in dioxane was added dropwise. Stirring was conducted overnight, the precipitate was filtered off and recrystallized from ethanol.

Example 2. Preparation of (piperidin-l-yl)[4-(piperidin-3-ylmethoxy)phenyl]methanone hydrochloride (1.1, TRX-001). It was obtained as colorless crystals.

The yield was 9.1 g (54%).

'H NMR (300 MHz, DMSO-d6) 8 9.44 - 9.22 (m, 1.9H), 7.34 - 7.28 (m, 2H), 7.02 - 6.95 (m, 2H), 3.99 - 3.84 (m, 2H), 3.49 - 3.15 (m, 6H), 2.81 - 2.66 (m, 2H), 2.33 - 2.20 (m, 1H), 1.85 - 1.28 (m, 10H).

¹³C NMR (75 MHz, DMSO-d6) 8 168.8, 159.1, 128.7, 128.6, 114.1, 69.4, 45.3, 45.2, 43.5, 43.2, 32.9, 25.7, 24.7, 24.1, 22.1, 21.1.

MS m/z 303.4 (M+H⁺).

Example 3. Preparation of 7V-isopropyl-4-(piperidin-3-ylmethoxy)benzamide hydrochloride (1.2, TRX-0002). It was obtained as colorless crystals.

The yield was 13.8 g (74%).

'H NMR (300 MHz, DMSO-d6) 8 9.56 - 9.24 (m, 1.9H), 8.13 (d, J = 7.8 Hz, 1H), 7.86 - 7.79 (m, 2H), 6.99 - 6.93 (m, 2H), 4.11 - 3.86 (m, 3H), 3.37 - 3.11 (m, 2H), 2.84 - 2.62 (m, 2H), 2.40 - 2.20 (m, 1H), 1.89 - 1.63 (m, 3H), 1.44 - 1.22 (m, 1H), 1.12 (d, J = 6.6 Hz, 6H).

¹³C NMR (75 MHz, DMSO-d6) 8 164.8, 160.5, 129.1, 127.2, 113.8, 69.4, 45.3, 43.2, 40.9, 33.0, 24.7, 22.4, 21.1.

MS m/z il A (M+H⁺).

Example 4. Preparation of 4-(piperi din-3 -ylmethoxy)-7V-cy cl opropylbenzamide hydrochloride (1.3, TRX-0003). It was obtained as colorless crystals.

The yield was 7.3 g (47%).

'H NMR (300 MHz, DMSO-d6) 8 9.46 - 9.16 (m, 2H), 8.51 (d, J = 4.2 Hz, 1H), 7.44 - 7.29 (m, 3H), 7.08 - 7.03 (m, 1H), 4.01 - 3.85 (m, 2H), 3.38 - 3.10 (m, 2H), 2.86 - 2.66 (m, 3H), 2.38 - 2.19 (m, 1H), 1.84 - 1.66 (m, 3H), 1.41 - 1.28 (m, 1H), 0.69 - 0.55 (m, 4H).

¹³C NMR (75 MHz, DMSO-d6) 8 167.1, 158.2, 135.8, 129.4, 119.8, 117.3, 113.1, 69.4,

45.3, 43.2, 33.0, 24.7, 23.1, 21.2, 5.7. MS m/z 275.3 (M+H⁺).

Example 5. Preparation of m orpholino[4-(piperi din-3 -ylmethoxy)phenyl]methanone hydrochloride (1.4, TRX-0004). It was obtained as colorless crystals.

The yield was 13 g (76%).

'H NMR (300 MHz, DMSO-d6) 8 9.41 - 9.26 (m, 2H), 7.39 - 7.32 (m, 2H), 7.01 - 6.94 (m, 2H), 4.01 - 3.84 (m, 2H), 3.81 - 3.75 (m, 1H), 3.54 - 3.37 (m, 6H), 3.33 - 3.26 (m, 1H), 3.22 - 3.16 (m, 1H), 3.05 - 3.01 (m, 1H), 2.78 - 2.68 (m, 2H), 2.34 - 2.22 (m, 1H), 1.85 - 1.70 (m, 3H), 1.39 - 1.27 (m, 1H).

¹³C NMR (75 MHz, DMSO-d6) 8 169.0, 159.3, 129.2, 127.7, 114.2, 69.4, 63.2, 45.2,

43.2, 42.6, 32.9, 24.7, 21.1.

MS m/z 305.4 (M+H⁺).

Example 6. Preparation of [4-(piperidin-3-ylmethoxy)phenyl](pyrrolidin-l-yl)methanone hydrochloride (1.5, TRX-0005). It was obtained as colorless crystals.

The yield was 9.9 g (61%).

'H NMR (300 MHz, DMSO-d6) 8 9.38 - 9.23 (m, 2H), 7.50 - 7.45 (m, 2H), 6.97 - 6.92 (m, 2H), 4.01 - 3.85 (m, 2H), 3.45 - 3.37 (m, 4H), 3.33 - 3.26 (m, 1H), 3.22 - 3.16 (m, 1H), 2.81 - 2.66 (m, 2H), 2.32 - 2.26 (m, 1H), 1.89 - 1.71 (m, 7H), 1.40 - 1.28 (m, 1H).

¹³C NMR (75 MHz, DMSO-d6) 8 167.9, 159.4, 129.5, 129.2, 113.9, 69.4, 46.1, 45.3,

44.3, 43.2, 33.0, 26.1, 24.7, 23.8, 21.1.

MS m/z 289.4 (M+H⁺).

Example 7. Preparation of (4-m ethylpiperi din- l-yl)[3-(piperi din-3 - ylmethoxy)phenyl]methanone hydrochloride (1.6, TRX-0006). It was obtained as colorless crystals.

The yield was 14.2 g (80%).

'H NMR (300 MHz, DMSO-d6) 8 9.45 - 9.13 (m, 2H), 7.34 - 7.28 (m, 2H), 6.99 - 6.92 (m, 2H), 4.03 - 3.82 (m, 2H), 3.52 - 3.12 (m, 6H), 2.83 - 2.66 (m, 2H), 2.36 - 2.20 (m, 1H), 1.88 - 1.48 (m, 6H), 1.39 - 1.28 (m, 1H), 1.07 - 0.95 (m, 2H), 0.89 (d, J = 6.1 Hz, 3H).

¹³C NMR (75 MHz, DMSO-d6) 8 168.8, 159.08, 128.7, 128.6, 114.1, 69.4, 45.3, 43.2, 43.0, 33.8, 32.9, 30.5, 30.1, 24.7, 21.6, 21.1.

MS m/z 317.4 (M+H⁺).

Example 8. Preparation of [3-(piperidin-3-ylmethoxy)phenyl](pyrrolidin-l-yl)- methanone hydrochloride (1.7, TRX-0007). It was obtained as colorless crystals.

The yield was 13.5 g (83%).

'H NMR (300 MHz, DMSO-d6) 8 9.46 - 9.15 (m, 2H), 7.35 - 7.28 (m, 1H), 7.05 - 6.97 (m, 3H), 4.00 - 3.81 (m, 2H), 3.43 - 3.39 (m, 1H), 3.36 - 3.28 (m, 3H), 3.23 - 3.16 (m, 2H), 2.79 - 2.66 (m, 2H), 2.38 - 2.18 (m, 1H), 1.92 - 1.61 (m, 7H), 1.43 - 1.22 (m, 1H).

¹³C NMR (75 MHz, DMSO-d6) 8 167.9, 158.1, 138.7, 129.5, 119.3, 116.1, 112.8, 69.4,

48.9, 45.9, 45.3, 43.2, 33.0, 25.9, 24.7, 23.8, 21.1.

MS m/z 289.5 (M+H⁺).

Example 9. Preparation of (piperidin-l-yl)[3-(piperidin-3-ylmethoxy)phenyl]methanone hydrochloride (1.8, TRX-0008). It was obtained as colorless crystals.

The yield was 6.2 g (37%).

'H NMR (300 MHz, DMSO-d6) 8 9.41 - 9.27 (m, 2H), 7.36 - 7.28 (m, 1H), 7.01 - 6.95 (m, 1H), 6.90 - 6.85 (m, 2H), 3.97 - 3.82 (m, 2H), 3.54 - 3.44 (m, 4H), 3.32 - 3.16 (m, 4H), 2.85 - 2.66 (m, 2H), 2.38 - 2.19 (m, 1H), 1.89 - 1.66 (m, 2H), 1.58 - 1.31 (m, 6H).

¹³C NMR (75 MHz, DMSO-d6) 8 168.5, 158.2, 138.0, 129.7, 118.8, 115.5, 112.4, 69.4, 48.0, 45.3, 43.2, 42.2, 33.0, 26.0, 25.3, 24.7, 24.1, 21.1.

MS m/z 301.4 (M+H⁺).

Example 10. Preparation of 7V-isopropyl-4-(pyrrolidin-2-ylmethoxy)benzamide hydrochloride (1.9, TRX-0009). It was obtained as colorless crystals.

The yield was 7.8 g (52%).

'H NMR (300 MHz, DMSO-d6) 8 9.98 (s, 0.9H), 9.33 (s, 0.9H), 8.14 (d, J = 7.8 Hz, 1H), 7.88 - 7.82 (m, 2H), 7.04 - 6.98 (m, 2H), 4.31 - 4.20 (m, 2H), 4.12 - 4.01 (m, 1H), 3.92 - 3.86 (m, 1H), 3.25 - 3.14 (m, 2H), 2.16 - 1.66 (m, 4H), 1.14 (d, J = 6.6 Hz, 6H).

¹³C NMR (75 MHz, DMSO-d6) 8 164.7, 159.9, 129.1, 127.6, 114.0, 66.9, 57.7, 44.9,

40.9, 26.4, 23.3, 22.4.

MS m/z 263.4 (M+H⁺).

Example 11. Preparation of 4-(pyrrolidin-2-ylmethoxy)-7V-cyclopropylbenzamide hydrochloride (1.10, TRX-0010). It was obtained as colorless crystals.

The yield was 11.2 g (75%).

'H NMR (300 MHz, DMSO-d6) 8 10.06 - 10.01 (m, 1H), 9.46 - 9.35 (m, 1H), 9.03 - 8.97 (m, 1.5H), 7.86 - 7.81 (m, 2H), 6.70 - 6.95 (m, 2H), 4.29 - 4.20 (m, 2H), 3.90 - 3.79 (m, 1H), 3.22 - 3.10 (m, 2H), 2.84 - 2.77 (m, 1H), 2.14 - 1.64 (m, 4H), 0.66 - 0.53 (m, 4H).

¹³C NMR (75 MHz, DMSO-d6) 8 167.0, 160.1, 129.2, 127.2, 114.1, 67.0, 57.8, 44.9, 26.5, 23.4, 23.2, 5.8.

MS m/z 261.3 (M+H⁺).

Example 12. Preparation of morpholino[4-(pyrrolidin-2-ylmethoxy)phenyl]methanone hydrochloride (1.11, TRX-0011). It was obtained as colorless crystals.

The yield was 10.5 g (64%).

'H NMR (300 MHz, DMSO-d6) 8 10.04 - 9.42 (m, 2H), 7.43 - 7.36 (m, 2H), 7.06 - 7.00 (m, 2H), 4.31 - 4.22 (m, 2H), 3.91 - 3.75 (m, 2H), 3.52 - 3.35 (m, 7H), 3.25 - 3.10 (m, 2H), 2.16 - 2.05 (m, 1H), 2.02 - 1.83 (m, 2H), 1.78 - 1.66 (m, 1H).

¹³C NMR (75 MHz, DMSO-d6) 8 168.9, 158.8, 129.1, 128.1, 114.5, 66.9, 63.1, 57.8, 44.9, 42.6, 26.4, 23.3.

MS m/z 291.3 (M+H⁺).

Example 13. Preparation of (pyrrolidin-l-yl)[4-(pyrrolidin-2- ylmethoxy)phenyl]methanone hydrochloride (1.12, TRX-0012). It was obtained as colorless crystals.

The yield was 9 g (58%).

'H NMR (300 MHz, DMSO-d6) 8 9.60 (s, 1.8H), 7.57 - 7.46 (m, 2H), 7.06 - 6.95 (m, 2H), 4.30 - 4.19 (m, 2H), 3.92 - 3.83 (m, 1H), 3.50 - 3.35 (m, 4H), 3.23 - 3.14 (m, 2H), 2.16 - 2.05 (m, 1H), 2.00 - 1.69 (m, 7H).

¹³C NMR (75 MHz, DMSO-d6) 8 167.8, 158.8, 129.9, 129.1, 114.1, 66.8, 57.7, 49.04, 46.06, 44.9, 26.3, 26.1, 23.9, 23.3.

MS m/z 275.6 (M+H⁺).

Example 14. Preparation of morpholino[4-(piperidin-4-ylmethoxy)phenyl]methanone hydrochloride (1.13, TRX-0013). It was obtained as colorless crystals.

The yield was 8.2 g (48%).

'H NMR (300 MHz, DMSO-d6) 8 9.37 (s, 0.9H), 9.08 (s, 0.9H), 7.35 - 7.31 (m, 2H), 6.99 - 6.92 (m, 2H), 3.84 (d, J = 6.3 Hz, 2H), 3.62 - 3.52 (m, 4H), 3.45 - 3.37 (m, 4H), 3.29 - 3.14 (m, 2H), 2.90 - 2.78 (m, 2H), 2.11 - 1.93 (m, 1H), 1.92 - 1.79 (m, 2H), 1.58 - 1.42 (m, 2H).

¹³C NMR (75 MHz, DMSO-d6) 8 169.0, 159.5, 129.2, 127.5, 114.2, 71.3, 66.1, 42.5, 33.1, 25.1.

MS m/z 305.5 (M+H⁺).

Example 15. Preparation of (4-methylpiperidin-l-yl)[4-(piperidin-4-ylmethoxy)- phenyl]methanone hydrochloride (1.14, TRX-0014). It was obtained as colorless crystals.

The yield was 8.9 g (50%).

'H NMR (300 MHz, DMSO-d6) 8 9.36 (s, 0.9H), 9.04 (s, 0.9H), 7.31 - 7.26 (m, 2H), 6.97 - 6.92 (m, 2H), 4.32 - 4.28 (m, 1H), 3.85 (d, J = 6.3 Hz, 2H), 3.64 - 3.59 (m, 1H), 3.26 - 3.20 (m, 2H), 2.91 - 2.78 (m, 4H), 2.11 - 1.96 (m, 1H), 1.94 - 1.84 (m, 2H), 1.69 - 1.37 (m, 5H), 1.08 - 0.94 (m, 2H), 0.88 (d, J = 6.1 Hz, 3H).

¹³C NMR (75 MHz, DMSO-d6) 8 168.9, 159.3, 128.8, 128.6, 114.2, 71.4, 42.6, 33.9,

33.1, 30.5, 30.2, 25.1, 21.7.

MS m/z 317.5 (M+H⁺). Example 16. Preparation of (piperidin-l-yl)[4-(piperidin-4- ylmethoxy)phenyl]methanone hydrochloride (1.15, TRX-0015). It was obtained as colorless crystals.

The yield was 10 g (59%).

'H NMR (300 MHz, DMSO-d6) 8 9.25 (s, 0.9H), 8.88 (s, 0.9H), 7.37 - 7.27 (m, 2H), 7.07 - 6.86 (m, 2H), 3.87 (d, J = 6.2 Hz, 2H), 3.79 - 3.70 (m, 2H), 3.53 - 3.38 (m, 2H), 3.30 - 3.17 (m, 2H), 3.00 - 2.78 (m, 2H), 2.11 - 1.19 (m, 3H), 1.72 - 1.32 (m, 8H).

¹³C NMR (75 MHz, DMSO-d6) 8 168.8, 159.3, 128.7, 128.6, 114.1, 71.3, 42.5, 33.1, 25.7, 25.1, 24.1, 22.1.

MS m/z 303.2 (M+H⁺).

Example 17. Preparation of 7V-isopropyl-4-(piperidin-4-ylmethoxy)benzamide hydrochloride (1.16, TRX-0016). It was obtained as colorless crystals.

The yield was 10.6 g (71%).

'H NMR (300 MHz, DMSO-d6) 8 9.30 (s, 0.9H), 9.03 (s, 0.9H), 8.12 (d, J = 7.7 Hz, 1H), 7.84 - 7.79 (m, 2H), 6.97 - 6.92 (m, 2H), 4.11 - 4.00 (m, 1H), 3.87 (d, J = 6.3 Hz, 2H), 3.27 - 3.20 (m, 2H), 2.92 - 2.80 (m, 2H), 2.13 - 1.96 (m, 1H), 1.91 - 1.85 (m, 2H), 1.59 - 1.45 (m, 2H), 1.12 (d, J = 6.6 Hz, 6H).

¹³C NMR (75 MHz, DMSO-d6) 8 164.8, 160.7, 129.2, 127.1, 113.9, 71.4, 42.6, 40.9, 33.2, 25.1, 22.5.

MS m/z 263.6 (M+H⁺).

Example 18. Preparation of 4-(piperidin-4-ylmethoxy)-7V-cyclopropylbenzamide hydrochloride (1.17, TRX-0017). It was obtained as colorless crystals.

The yield was 94 g (60%).

'H NMR (300 MHz, DMSO-d6) 8 9.30 (s, 0.9H), 9.00 (s, 0.9H), 8.36 (d, J = 3.4 Hz, 1H), 7.85 - 7.78 (m, 2H), 6.97 - 6.92 (m, 2H), 3.87 (d, J = 5.6 Hz, 2H), 3.27 - 3.21 (m, 2H), 2.92 - 2.79 (m, 3H), 2.14 - 1.96 (m, 1H), 1.91 - 1.85 (m, 2H), 1.58 - 1.45 (m, 2H), 0.66 - 0.54 (m, 4H).

¹³C NMR (75 MHz, DMSO-d6) 8 166.9, 160.1, 129.0, 126.6, 113.8, 71.3, 42.5, 33.1, 25.1, 23.0, 5.7.

MS m/z 1 A (M+H⁺).

Example 19. Preparation of [4-(piperidin-4-ylmethoxy)phenyl](pyrrolidin-l- yl)methanone hydrochloride (1.18, TRX-0018). It was obtained as colorless crystals.

The yield was 9 g (54%).

'H NMR (300 MHz, DMSO-d6) 8 9.32 (s, 2H), 7.22 - 6.97 (m, 2H), 6.68 - 6.46 (m, 2H), 3.64 - 3.38 (m, 2H), 3.21 - 2.95 (m, 6H), 2.92 - 2.77 (m, 2H), 2.22 - 1.99 (m, 1H), 1.79 - 1.31 (m, 5H), 1.24 - 0.98 (m, 2H).

¹³C NMR (75 MHz, DMSO-d6) 8167.8, 159.5, 129.3, 129.1, 113.8, 71.2, 49.0, 46.0, 42.5, 33.0, 26.0, 25.1, 23.9.

MS m/z 289.4 (M+H⁺).

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

Materials and Methods.

The pchTAARl 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 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.

Data on the effective ligand concentration are presented 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 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

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 n is 0, 1 or 2; m is 0 if n is 2, or m is 1 if n is 0 or 1;

R¹ and R² are independently selected from the group consisting of: hydrogen atom;

Ci-Cio alkyl optionally substituted with C3-C10 cycloalkyl;

C3-C10 cycloalkyl; or R¹ and R² together with the nitrogen atom to which they are attached form a 5- or 6- membered saturated heterocyclyl containing 1 nitrogen atom and optionally substituted with C1-C10 alkyl; or R¹ and R² together with the nitrogen atom to which they are attached form a 6-membered saturated heterocyclyl containing 1 nitrogen atom and 1 heteroatom selected from oxygen, sulfur and nitrogen.

2. The compound of claim 1, wherein R¹ is hydrogen and R² is C1-C10 alkyl.

3. The compound of claim 1, wherein R¹ is hydrogen and R² is C3-C10 cycloalkyl.

4. The compound of claim 1, wherein R¹ and R² together with the nitrogen atom to which they are attached form pyrrolidinyl or piperidinyl optionally substituted with C1-C10 alkyl.

5. The compound of claim 1, wherein R¹ and R² together with the nitrogen atom to which they are attached form morpholinyl.

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

(piperidin-l-yl)[4-(piperidin-3-ylmethoxy)phenyl]methanone,

7V-isopropyl-4-(piperidin-3-ylmethoxy)benzamide,

4-(piperidin-3-ylmethoxy)-7V-cyclopropylbenzamide, morpholino[4-(piperidin-3-ylmethoxy)phenyl]methanone,

[4-(piperidin-3-ylmethoxy)phenyl](pyrrolidin-l-yl)methanone,

(4-m ethylpiperi din- 1 -yl)[3-(piperi din-3 -ylmethoxy)phenyl]methanone,

22 [3-(piperidin-3-ylmethoxy)phenyl](pyrrolidin-l-yl)methanone, (piperidin-l-yl)[3-(piperidin-3-ylmethoxy)phenyl]methanone, 7V-isopropyl-4-(pyrrolidin-2-ylmethoxy)benzamide, 4-(pyrrolidin-2-ylmethoxy)-7V-cyclopropylbenzamide, morpholino[4-(pyrrolidin-2-ylmethoxy)phenyl]methanone, (pyrrolidin-l-yl)[4-(pyrrolidin-2-ylmethoxy)phenyl]methanone, morpholino[4-(piperidin-4-ylmethoxy)phenyl]methanone, (4-methylpiperidin-l-yl)[4-(piperidin-4-ylmethoxy)phenyl]methanone, (piperidin-l-yl)[4-(piperidin-4-ylmethoxy)phenyl]methanone, 7V-isopropyl-4-(piperidin-4-ylmethoxy)benzamide, 4-(piperidin-4-ylmethoxy)-7V-cyclopropylbenzamide, [4-(piperidin-4-ylmethoxy)phenyl](pyrrolidin-l-yl)methanone.

7. 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.

8. 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.

9. 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:

where n is 0, 1 or 2; m is 0 if n is 2, or m is 1 if n is 0 or 1;

C1-C10 alkyl optionally substituted with C3-C10 cycloalkyl;

10. The pharmaceutical composition of claim 9, wherein the excipient is selected from the group including a pharmaceutically acceptable carrier, diluent, filler and solvent.

11. The pharmaceutical composition of claim 9 or claim 10, 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 pharmaceutical composition of claim 9 or claim 10, 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.

13. The pharmaceutical composition of any one of claims 9-12, 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.