GERASIMOV ANDREY SERGEEVICH (RU)
LUKIN ALEKSEY YURIEVICH (RU)
BAHOLDINA ANNA GENNADIEVNA (RU)
KRASAVIN MIKHAIL YURIEVICH (RU)
WO2013131018A1 | 2013-09-06 | |||
WO2016016292A1 | 2016-02-04 | |||
WO2008052907A1 | 2008-05-08 | |||
WO2008046757A1 | 2008-04-24 |
CA2856204A1 | 2013-07-18 |
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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. |
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/CHCl 3 ). 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/CHCl 3 ). 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(PPh 3 ) 4 and 0.03 eq. of PdCl 2 (PPh 3 ) 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/CHCl 3 ). 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 С 11 H 14 N 4 O [M+H+] 219.1240 Da, calculated 219.1240 Da. 1 H 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). 13 C 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). 13 C 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 С 11 H 11 F 3 N 4 O [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). 13 C 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 С 8 H 10 N 4 S [M+H + ] 195.0699 Da, calculated 195.0699 Da. 1 H 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). 13 C 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 С 17 H 18 N 4 O [M+H+] 295.1553 Da, calculated 295.1553 Da. 1 H 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). 13 C 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 С 10 H 11 BrN 4 [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). 13 C 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 С 10 H 10 Cl 2 N 4 [M+H + ] 257.0355 Da, calculated 257.0355 Da. 1 H 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). 13 C 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 С 10 H 12 N 4 [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). 13 C 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 С 11 H 14 N 4 [M+H + ] 203.1291 Da, calculated 203.1291 Da. 1 H 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). 13 C 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 С 12 H 16 N 4 O [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). 13 C 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 С 10 H 11 ClN 4 [M+H + ] 223.0745 Da, calculated 223.0745 Da. 1 H 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). 13 C 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 С 10 H 11 BrN 4 [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). 13 C 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 С 12 H 17 N 5 [M+H + ] 232.1557 Da, calculated 232.1557 Da. 1 H 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). 13 C 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 С 12 H 16 N 4 [M+H + ] 217.1448 Da, calculated 217.1448 Da. 1 H 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). 13 C 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 С 10 H 11 FN 4 [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). 13 C 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 С 10 H 11 N 5 O 2 [M+H + ] 234.0986 Da, calculated 234.0986 Da. 1 H 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). 13 C 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 С 14 H 20 N 4 O [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). 13 C 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 С 17 H 17 FN 4 O [M+H+] 313.1459 Da, calculated 313.1459 Da. 1 H 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). 13 C 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 С 17 H 17 FN 4 O [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). 13 C 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 С 17 H 17 FN 4 O [M+H+] 313.1459 Da, calculated 313.1459 Da. 1 H 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). 13 C 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 С 18 H 19 FN 4 O [M+H + ] 327.1616 Da, calculated 327.1616 Da. 1 H 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). 13 C 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 С 18 H 19 FN 4 O [M+H + ] 327.1616 Da, calculated 327.1616 Da. 1 H 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). 13 C 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 С 17 H 18 N 4 O [M+H + ] 295.1553 Da, calculated 295.1553 Da. 1 H 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). 13 C 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 С 17 H 15 F 3 N 4 O [M+H + ] 349.1271 Da, calculated 349.1271 Da. 1 H 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). 13 C 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 С 16 H 15 FN 4 [M+H + ] 283.1354 Da, calculated 283.1354 Da. 1 H 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). 13 C 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 С 16 H 14 F 2 N 4 [M+H + ] 301.1259 Da, calculated 301.1259 Da. 1 H 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). 13 C 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 С 16 H 15 ClN 4 [M+H + ] 299.1058 Da, calculated 299.1058 Da. 1 H 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). 13 C 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 С 18 H 20 N 4 O 2 [M+H + ] 325.1659 Da, calculated 325.1659 Da. 1 H 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). 13 C 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 С 16 H 14 F 2 N 4 [M+H + ] 301.1259 Da, calculated 301.1259 Da. 1 H 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). 13 C 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 С 17 H 15 F 3 N 4 O [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). 13 C 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 С 17 H 18 N 4 O [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). 13 C 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 Ca 2+ and Mg 2+ 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 (ЕС 50 ) 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. 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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.