Methods for treating trace amine-associated receptor 1 (TAAR1)-associated diseases or disorders comprising administration of novel TAAR1 agonists or pharmaceutical compositions thereof

Abstract

The present disclosure relates to methods for treating trace amine-associated receptor 1 (TAAR1)-associated diseases or disorders comprising administration of novel TAAR1 agonists or pharmaceutical compositions thereof.

Description

[0001] Methods for treating trace amine-associated receptor 1 (TAARI)-associated diseases or disorders comprising administration of novel TAAR1 agonists or pharmaceutical compositions thereof

[0002] Technical field

[0003] The present disclosure relates to methods for treating trace amine-associated receptor 1 (TAARI)-associated diseases or disorders, comprising administering to the subject a therapeutically effective amount of compounds of formula (I) that are TAAR1 agonists. TAAR1 -associated diseases or disorders include a mental disease or disorder, a cognitive disease or disorder, a neurological disease or disorder, a psychiatric disease or disorder, a neurodegenerative disease or disorder, and a substance-related and / or addictive disorder.

[0004] Background

[0005] The trace amine-associated receptor-1 (TAAR1) is a constituent of the Class A (Rhodopsin-like) family of GPCRs and demonstrates widespread distribution throughout the mammalian brain and gastrointestinal system, participating in a spectrum of neuronal processes (Halff et al., 2023). Various endogenous trace amines (TA), including tyramine, p-phenethylamine (P-PEA) and catecholamine metabolites such as 3-methoxytyramine (Berry et al., 2017), engage TAAR1 signalling pathways via distinct G protein subtypes (Halff et al., 2023).

[0006] TAAR1 has garnered significant clinical interest over the last decade as a potential therapeutic target for several neuropsychiatric disorders, in particular schizophrenia (Halff et al., 2023; Berry et al., 2017). Activation of TAAR1 in dopaminergic, serotonergic, and glutamatergic neurons appears to have an overall inhibitory effect on cell firing, and complementary behavioural observations suggest that agonists could be effective in the treatment of drug addiction, bipolar disorder and schizophrenia (Mantas et al., 2021; Halff et al., 2023).

[0007] A burgeoning category of antipsychotic agents, TAAR1 agonists, holds promise in the treatment of neuropsychiatric disorders. Two TAAR1 agonists, Ulotaront (SEP-363856; Sunovion; WO20118032 A1 ; WO21211489 A1) and Ralmitaront (RG-7906 and RO- 6889450; Hoffman-La Roche; W014041106 A1), have advanced into early clinical trials for the treatment of several conditions including narcolepsy (Szabo et al., 2023), psychosis in Parkinson’s disease (Isaacson et al., 2023) and schizophrenia (Koblan et al., 2020).

[0008] Until recently, knowledge of the TAAR1 structure has been based on other models of GPCRs (Nair et al., 2022). In view of the newly developed structural and biochemical observations of TAAR1 , including the functional selectivity of TAAR1 signalling (Nair et al., 2024), development of novel TAAR1 agonists for TAAR1 are very relevant.

[0009] Summary

[0010] As outlined above, TAAR1 agonists have shown therapeutic potential for the treatment of neuropsychiatric diseases and disorders. In view of the newly developed structural and biochemical observations of TAAR1 , development of novel, TAAR1 are very relevant.

[0011] The present inventors have found that novel compounds of formula (I) exhibit TAAR1 agonism with surprisingly improved potency compared with TAAR1 agonists known in the art and can be used to treat diseases or disorders associated with TAAR1.

[0012] Accordingly, one aspect of the present disclosure provides for a compound of Formula (I):

[0013] Formula (I) wherein

[0014] R1is H, Ci-4alkyl, CH2F, CHF2, or CF3;

[0015] R3is H, C1-4 alkyl or cyclopropyl;

[0016] R2is phenyl substituted with one or more independently selected R4, or a 5- or 6- membered heteroaryl selected from the group consisting of

[0017] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl , 1 ,2,5-thiadiazol-3-yl , 1 ,3,4-thiadiazol-2-yl , pyrazol-4-yl, pyrazol-3-yl, pyrazol-1-yl, pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0018] • thiazol-2-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0019] • thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0020] • oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0021] R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of:

[0022] 3-(3,4-dimethoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0023] 3-(3-methoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0024] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0025] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine,or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder.

[0026] In one aspect, the present invention relates to a compound selected from the group consisting of:

[0027] or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder.

[0028] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound as described herein for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder. Description of Drawings Figure 1. Structure-activity relationships and selectivity profile of TAAR1 agonists. (A) Heatmap of screening results using PRESTO-TANGO for 27 aminergic GPCRs for Ulotaront, and compounds 1 and 2 with on 3-6 technical replicates per receptor. p-Arrestin recruitment was normalized as a percentage of the signal emitted by the positive controls for each receptor. (B) Concentration-response curves from the PRESTO-TANGO assay for compounds 1, 2, and controls at the 5-HT1 D, D2, a2A, and M2 receptors. (5-hydroxytryptamine, 5-HT; Quinpirole, Epinephrine, Acetylcholine, Ach). Data represents the mean ± SEM of three independent experiments.

[0029] Figure 2. In vivo testing of compound 2 for TAAR1 agonism and antipsychoticlike efficacy. (A) Changes in CBT following i.p. administration of increasing doses of compound 2 (0.1 - 1 mg / kg, n=6-7 mice per group). (B) CBT measurements were taken at 30-minute intervals over a 120-minute period post-injection of various doses of compound 2 or vehicle in both genotypes. (C) The average shift in CBT (from Figure 2B) is represented. Statistical significance: *p<0.05, **p<.005 (2 vs. vehicle) based on a 2-way ANOVA, Bonferroni’s multiple comparison test. (D) PPI was assessed in mice (n= 7) following i.p. injection of compound 2 (1 mg / kg), risperidone (0.2 mg / kg), or vehicle. (E) PPI% at each pre-pulse intensity. Statistical significance: *p<.05, **p<.005, ***p<.001 (compound 2 or risperidone vs. vehicle) based on 2-way ANOVA, Bonferroni’s multiple comparison test. (F) The average change in PPI (%) across all pre-pulses in wildtype (WT) mice. Statistical significance: *p<.05, ***p<.001 (compound 2 or risperidone vs. vehicle) based on 1-way ANOVA, Bonferroni’s multiple comparison test. (G) Locomotion experiments (n=10 mice). (H) The impact of compound 2 (1 mg / kg) or risperidone (0.03 mg / kg) on baseline locomotion in the OFT. Statistical significance: *p<.05 (2 or risperidone vs. vehicle) based on 1-way ANOVA, Bonferroni’s multiple comparison test. Baseline locomotion was assessed for 10 minutes before MK-801 injections (0.35 mg / kg), as depicted in panel (I) where time-bins represent 5- minute intervals. (J) The effects of compound 2 or vehicle on the inhibition of MK-801- induced hyperlocomotion. Statistical significance: **p<.005, ***p<.001 (65 or risperidone vs. vehicle) based on 1 -way ANOVA, Bonferroni’s multiple comparison test.

[0030] Figure 3. In vivo testing of compounds for TAAR1 agonism. Changes in CBT following i.p. administration of vehicle or compounds 35, 33, 30, 28, 29( 1 mg / kg, n=4-6 mice per group) in TAAR1-WT mice. CBT measurements were taken at 30-minute intervals over a 120-minute period post-injection of compounds or vehicle. Definitions

[0031] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0032] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.

[0033] The terms “C1-3 alkyl”, “C2-3 alkyl”, and “C1-4 alkyl” as used herein refer to a straight or branched hydrocarbon chains containing from 1 to 3, 2 to 3 and 1 to 4 carbon atoms, respectively. Representative examples of C1-3 alkyl, C2-3 alkyl, and C1-4 alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.

[0034] The term “C1-3 alkoxy” as used herein refer to -OR#, wherein R#represents a C1-3 alkyl as defined herein. C1-3 alkoxy include methoxy, ethoxy, n-propoxy, and iso-propoxy.

[0035] The term “CN” is used herein to indicate a cyano group ( ).

[0036] The term “halogen” as used herein refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0037] The term “5-membered heteroaryl” or “6-membered heteroaryl” as used herein refers to a 5 or 6-membered heterocycle with two or three double bonds containing one ring heteroatom selected from N, S, and O and optionally one or two further ring N atoms. Representative examples of a 5-membered heteroaryl include, but are not limited to, furanyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of a 6-membered heteroaryl include, but are not limited to, pyridinyl, pyrimidyl, pyrazyl, and pyridazyl. In some embodiments, the 5- or e- membered heteroaryl is selected from the group consisting of furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, ,2,4-thiadiazol-5-yl , 1 ,2,5- thiadiazol-3-yl , 1 ,3,4-thiadiazol-2-yl , pyrazol-4-yl, ,2,4-thiadiazol-5-yl , 1 ,2,5-thiadiazol- 3-yl , 1 ,3,4-thiadiazol-2-yl , pyrazol-4-yl, pyrazol-3-yl , pyrazol-1-yl, pyrimidin-2-yl, thiazol-2-yl, oxazol-4-yl, thiazol-5-yl and thiazol-4-yl. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0038] As described herein, compounds of the present invention may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position, i.e. the substituent may be individually / independently selected from a group of substituents. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0039] As used herein, “TAAR1” refers to trace amine-associated receptor 1 , and can be used interchangeably with “TA1T, “TAR1”, “TRAR1” and / or “trace amine receptor”.

[0040] As used herein, the term ‘reference compound’ refers to a reference agonist or antagonist of a GPCR receptor, such as an agonist or antagonist of TAAR1 , 5- hydroxytryptamine receptor 1 D (5-HTID), 5-hydroxytryptamine receptor 1 E (5-HTIE), the a 2A adrenergic receptor (O2A), the dopamine D2 receptor (D2), the histamine H1 receptor (H 1), and / or a member of the muscarinic acetylcholine receptor family, such as the M2 receptor. In some embodiments, the reference compound is a serotonin agonist, such as an agonist of the 5-hydroxytryptamine receptor 2A (5-HT2A) receptor. In some embodiments, the reference compound is ritanserin, Tiserton, or R55667. In some embodiments, the reference compound is a dopamine D2 receptor (D2) antagonist or agonist. In some embodiments, the reference compound is quinpirole. In some embodiments, the reference compound is a TAAR1 antagonist or agonist. In some embodiments, the reference compound is RTI-7470-44, p-Methylphenethylamine or amphetamine. Detailed description

[0041] Medical use

[0042] In one aspect, the present invention relates to a compound of Formula (I):

[0043] Formula (I) wherein

[0044] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0045] R3is H, C1-4 alkyl or cyclopropyl;

[0046] R2is phenyl substituted with one or more independently selected R4, or a 5- or 6-membered heteroaryl selected from the group consisting of

[0047] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl , 1 ,2,5-thiadiazol-3-yl , 1 ,3,4-thiadiazol-2-yl , pyrazol-4-yl, pyrazol-3-yl , pyrazol-1-yl , pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0048] • thiazol-2-yl, thiazol-5-yl , each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0049] • thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0050] • oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0051] R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of: 3-(3,4-dimethoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0052] 3-(3-methoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0053] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0054] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAAR1)- associated disorder.

[0055] In one aspect, the present invention relates to a compound of Formula (I):

[0056] Formula (I) wherein

[0057] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0058] R3is H, C1-4 alkyl or cyclopropyl;

[0059] R2is phenyl substituted with one or more independently selected R4, or a 5- or 6- membered heteroaryl selected from the group consisting of

[0060] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, pyrazol-1-yl , pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0061] • thiazol-2-yl, thiazol-5-yl , each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0062] • thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0063] • oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0064] R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of:

[0065] 3-(3,4-dimethoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0066] 3-(3-methoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0067] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0068] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder.

[0069] In one aspect, the present invention relates to a compound of Formula (I):

[0070] Formula (I) wherein

[0071] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0072] R3is H, C1-4 alkyl or cyclopropyl;

[0073] R2is phenyl optionally substituted with one or more independently selected R4, or a 5- or 6-membered heteroaryl selected from the group consisting of

[0074] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0075] • thiazol-2-yl, thiazol-4-yl , each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and • oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN,; and

[0076] R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of:

[0077] 3-(3,4-dimethoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0078] 3-(3-methoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0079] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0080] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine,or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder.

[0081] As used herein, the terms "treat," "treating" and "treatment," contemplate an action that occurs while a patient is suffering from or susceptible to a specified disease, disorder or condition, which delays onset of and / or reduces the frequency or severity of one or more symptoms or features of the disease disorder or condition. Thus, "treat", "treating", and "treatment" refer to any type of treatment that imparts a benefit to a subject afflicted with a disease, disorder or condition, including improvement in the condition of the subject (e.g., in one or more symptoms), delay in the progression of the disease, disorder or condition, prevention or delay of the onset of the disease, disorder or condition, etc.

[0082] The terms “preventative treatment”, “prevent,” “preventing,” and “prevention” (and grammatical variations thereof) refer to prevention and / or delay of the onset of a disease, disorder and / or a clinical symptom(s) in a subject and / or a reduction in the severity of the onset of the disease, disorder and / or clinical symptom(s) relative to what would occur in the absence of the methods of the invention. The prevention can be complete, e.g., the total absence of the disease, disorder and / or clinical symptom(s). The prevention can also be partial, such that the occurrence of the disease, disorder and / or clinical symptom(s) in the subject and / or the severity of onset is less than what would occur in the absence of the present invention. With respect to a TAAR1 - associated disorder, the term refers to, e.g., preventing the TAAR1 -associated disorder from occurring if the treatment is administered prior to the onset of the disorder. Those skilled in the art will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject.

[0083] A “subject” of the invention includes any animal that has or is susceptible to a TAAR1 - associated disorder or is in need of treatment of a TAAR1 -associated disorder. Such a subject is generally a mammalian subject (e.g., a laboratory animal such as a rat, mouse, guinea pig, rabbit, primate, etc.), a farm or commercial animal (e.g., a cow, horse, goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog, ferret, etc.). In particular embodiments, the subject is a primate subject, a non-human primate subject (e.g., a chimpanzee, baboon, monkey, gorilla, etc.) or a human. Subjects include males and / or females of any age, including neonates, juveniles, adolescents, adults, and geriatric subjects.

[0084] As used herein the term "trace amine-associated receptor 1 (TAARI)-associated disorder" refers to any condition or pathology in which dysregulation, malfunction, or modulation of TAAR1, e.g., inhibition of TAAR1 activity or modulation of TAAR1 ligands is implicated as a contributing factor or potential therapeutic target. TAAR1 is a G protein-coupled receptor primarily expressed in the brain and is involved in modulating neurotransmitter systems such as dopamine and serotonin. Disorders associated with TAAR1 dysfunction may include psychiatric disorders (e.g., schizophrenia, bipolar disorder, depression), substance use disorders (e.g., addiction), and neurodegenerative diseases. Therapeutic interventions targeting TAAR1 may include agonists, antagonists, or modulators, wherein administration of said therapeutic intervention results in the restoration of normal receptor function and / or ameliorating associated symptoms or pathologies and / or the treatment of one or more symptoms of the disorder in the subject.

[0085] The term “prophylactic treatment” as used herein to describe the present invention, refers to the treatment of subjects having, or at risk of having a specified condition or symptom of the condition, but not presently having or experiencing the symptoms of the condition. The term “ameliorative treatment” as used herein to describe the present invention, refers to the treatment of subjects having, or at risk of having a specified symptom, wherein the subjects are presently having or experiencing the symptoms of the condition.

[0086] The term “symptomatic treatment” as used herein to describe the present invention, refers to ameliorating a specified condition or disorder or symptoms accompanied therewith to a significant extent.

[0087] In some embodiments, R1is H, C1-4 alkyl, CH2F, CHF2, or CF3; R3is H, Me or cyclopropyl; and R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0088] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl,

[0089] 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol- 4-yl, pyrazol-3-yl, pyrazol-1-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0090] • thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0091] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0092] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy.

[0093] In some embodiments, R1is H, C1-4 alkyl, CH2F, CHF2, or CF3; R3is H, Me or cyclopropyl; and R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0094] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of Ci-3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0095] • thiazol-2-yl, thiazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0096] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy.

[0097] In some embodiments, R1is H, C1-4 alkyl, CH2F, CHF2, or CF3; R3is H, Me or cyclopropyl; and R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0098] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, or pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0099] • thiazol-2-yl or thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0100] • thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0101] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0102] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy.

[0103] In some embodiments, R1is H, C1-4 alkyl, CH2F, CHF2, or CF3; R3is H, Me or cyclopropyl; and R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0104] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; • thiazol-2-yl, thiazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0105] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0106] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, provided that the compound is not selected from the group consisting of:

[0107] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0108] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine.

[0109] In some embodiments, R1is C1-4 alkyl. In some embodiments, R1is selected from the group consisting of Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, and t-Bu. In some embodiments, R1is Me. In some embodiments, R1is H.

[0110] In some embodiments, R3is H. In some embodiments, R3is C1-4 alkyl. In some embodiments, R3is Me. In some embodiments, R3is Et.

[0111] In some embodiments, R1is H or Me, and R3is H, Me, or Et. In some embodiments, R1is H or Me, and R3is H or Me. In some embodiments, R1is H or Me, and R3is H. In some embodiments, R1is Me and R3is H. In some embodiments, R1is H and R3is H. In some embodiments, R1is H and R3is Me. In some embodiments, R1is H and R3is Et.

[0112] In some embodiments, R2is phenyl optionally substituted with one or more R4, and wherein R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, with the proviso that said phenyl is not substituted with methoxy in the meta position. In some embodiments, R2is phenyl. In some embodiments, R2is phenyl optionally substituted with one or more R4, and wherein R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, with the proviso that said phenyl is not substituted with C1-3 alkoxy in the meta position. In some embodiments, R2is not phenyl. In some embodiments, R2is phenyl substituted with one or more R4, and wherein R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, with the proviso that said phenyl is not substituted with C1-3 alkoxy in the meta position. In some embodiments, R2is phenyl substituted with one or more R4, and wherein R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, with the proviso that said phenyl is not substituted with methoxy in the meta position. In some embodiments, R2is phenyl substituted with one or more R4, and wherein R4is F, Cl, or Br. In some embodiments, R4is F. In some embodiments, R4is Cl. In some embodiments, R4is Br. In some embodiments, R2is 2-fluorophenyl. In some embodiments, R2is 2-chlorophenyl. In some embodiments, R2is 3-fluorophenyl. In some embodiments, R2is 3-chlorophenyl. In some embodiments, R2is 4- fluorophenyl. In some embodiments, R2is 4-chlorophenyl.

[0113] In some embodiments, R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0114] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0115] • thiazol-2-yl, thiazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0116] • oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of:

[0117] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0118] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine. In some embodiments, R2is furanyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments,

[0119] R2is furanyl substituted with CN. In some embodiments, embodiments, the furanyl is furan-2-yl. In some embodiments, the furanyl is furan-3-yl. In some embodiments, R2is furanyl. In some embodiments, R2is furan-2-yl. In some embodiments, R2is furan-3-yl.

[0120] In some embodiments, R2is thienyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is thienyl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, F, Cl, Br, and CN. In some embodiments, R2is thienyl substituted with C1-3 alkyl. In some embodiments, R2is thienyl substituted with Me. In some embodiments, R2is thienyl substituted with F. In some embodiments, R2is thienyl substituted with Cl. In some embodiments, R2is thienyl substituted with Br. In some embodiments, R2is thienyl substituted with CN. In some embodiments, the thienyl is thien-2-yl. In some embodiments, the thienyl is thien-3-yl. In some embodiments, R2is . In some embodiments, R2is

[0121] In some embodiments, . In some embodiments,

[0122] . In some embodiments, some embodiments, some embodiments, R2is . In some embodiments, R2is . In some embodiments, some embodiments, some embodiments, some embodiments, R2is thienyl. In some embodiments, R2is thien-3-yl. In some embodiments, R2is thien-2-yl.

[0123] In some embodiments, R2is thiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, the compound is not 3-(4-methylthiazol-2-yl) 1 ,2,5,6-tetrahydropyridine or 1 -methyl 3- (4-methylthiazol-2-yl) 1 ,2,5,6-tetrahydropyridine. In some embodiments, R2is not 4- methylthiazol. In some embodiments, R2is thiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is thiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, and Br. In some embodiments, R2is thiazol-2-yl substituted with Cl. In some embodiments, . In some embodiments,

[0124] R2is . In some embodiments, R2is thiazol-2-yl substituted with C1-3 alkoxy. In some embodiments, some embodiments, R2is thiazol-2-yl substituted with cyclopropyl. In some embodiments, R2is In some embodiments, R2is thiazol-2-yl.

[0125] In some embodiments, R2is thiazol-4-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not 1-methyl-3-[4-(2-methyl-1 ,3- thiazol)-yl]-1 ,2,5,6-tetrahydropyridine or 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6- tetrahydropyridine. In some embodiments, R2is thiazol-4-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that R2is not 2-methyl-1 ,3- thiazol-4-yl. In some embodiments, R2is thiazol-4-yl substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, and Br.

[0126] In some embodiments, R2is thiazol-4-yl substituted with C1-3 alkyl. In some embodiments, R2is thiazol-4-yl substituted with Me. In some embodiments, R2is

[0127] In some embodiments, R2is thiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, and Br. In some embodiments, R2is thiazol-5-yl optionally substituted with cyclopropyl. In some embodiments, R2is . In some embodiments, R2is thiazol-5-yl.

[0128] In some embodiments, R2is isothiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is isothiazol-3-yl. In some embodiments, R2is isothiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is isothiazol-5-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl. In some embodiments, R2is isothiazol-

[0129] 5-yl substituted with Me. In some embodiments, some embodiments, R2is isothiazol-5-yl.

[0130] In some embodiments, R2is 1 ,2,4-thiadiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is 1 ,2,4-thiadiazol-3-yl substituted with C1-3 alkyl. In some embodiments, R2is 1 ,2,4- thiadiazol-3-yl substituted with Me. In some embodiments,

[0131] In some embodiments, R2is 1 ,2,4-thiadiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is 1 ,2,4-thiadiazol-5-yl substituted with C1-3 alkyl. In some embodiments, R2is 1 ,2,4- thiadiazol-5-yl substituted with Me. In some embodiments, R2is . In some embodiments, R2is 1 ,2,4-thiadiazol-5-yl.

[0132] In some embodiments, R2is 1 ,2,5-thiadiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is 1 ,2,5-thiadiazol-3-yl. In some embodiments, R2is 1 ,3,4-thiadiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is 1 ,3,4-thiadiazol-2-yl.

[0133] In some embodiments, R2is pyrazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is pyrazol-4-yl.

[0134] In some embodiments, R2is pyrazol-1-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is pyrazol-1-yl.

[0135] In some embodiments, R2is pyrazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is pyrazol-3-yl substituted with one or more substituents each independently selected from C1-3 alkyl. In some embodiments, R2is pyrazol-3-yl substituted with Me. some embodiments, R2is pyrazol-3-yl.

[0136] In some embodiments, R2is pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl and C1-3 alkoxy. In some embodiments, R2is pyrimidin-2-yl. In some embodiments, R2is oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, and Br. In some embodiments, R2is oxazol-4-yl. thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol-4-yl, pyrazol-1-yl, , pyrazol-3-yl, pyrimidin-2-yl, or oxazol-4-yl. In some embodiments, R2is

[0137]

[0138] In some embodiments, the compound for use is selected from the group consisting of: 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0139] 5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine;

[0140] 2-(5,6-dihydro-2H-1l2-pyridin-3-yl)furan-3-carbonitrile;

[0141] 5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine;

[0142] 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0143] 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0144] 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;

[0145] 5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0146] 5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0147] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;

[0148] 5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0149] 5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0150] 5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0151] 5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0152] 5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine; 4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0153] 5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0154] 4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0155] 5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0156] 5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0157] 5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0158] 5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0159] 4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0160] 4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0161] 5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0162] 4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0163] 4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0164] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0165] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0166] 4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0167] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0168] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0169] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0170] 2-methyl-4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0171] 5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0172] 4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine;

[0173] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine; and

[0174] 5-phenyl-1,2,3,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof.

[0175] In one aspect, the present invention relates to a compound selected from the group consisting of:

[0176] 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0177] 5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine;

[0178] 2-(5,6-dihydro-2H-1l2-pyridin-3-yl)furan-3-carbonitrile;

[0179] 5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine;

[0180] 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0181] 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0182] 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;

[0183] 5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine; 5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0184] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;

[0185] 5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0186] 5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0187] 5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0188] 5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0189] 5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0190] 4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0191] 5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0192] 4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0193] 5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0194] 5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0195] 5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0196] 5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0197] 4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0198] 4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0199] 5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0200] 4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0201] 4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0202] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0203] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0204] 4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0205] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0206] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0207] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0208] 2-methyl-4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0209] 5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0210] 4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine;

[0211] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine;

[0212] 5-phenyl-1,2,3,6-tetrahydropyridine;

[0213] 4.5-dimethyl-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0214] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;

[0215] 4.5-dimethyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0216] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0217] 4-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0218] 5-(1-methyl-1 H-pyrazol-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0219] 4-methoxy-2-(4-methyl-1,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0220] 5-methyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0221] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0222] 3-methyl-5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0223] 5-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0224] 5-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0225] 5-(1 H-pyrazol-1-yl)-1 ,2,3,6-tetrahydropyridine;

[0226] 3-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;

[0227] 4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0228] 5-methyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0229] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0230] 4-cyclopropyl-2-(4-methyl-1,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0231] 2-cyclopropyl-5-(4-methyl-1,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0232] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole; 3-(1 ,2,5,6-tetrahydropyridin-3- yl)isothiazole;

[0233] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0234] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,3,4-thiadiazole;

[0235] 5-(2-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;

[0236] 5-(3-fluorophenyl)-1 ,2,3,6-tetrahydropyridine;

[0237] 5-(4-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;

[0238] 5-(3-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;

[0239] 5-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyridine; and

[0240] 5-(2-fluorophenyl)-1 ,2,3,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof

[0241] In one aspect, the present invention relates to a compound selected from the group consisting of:

[0242]

[0243] 10 pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder. In one aspect, the present invention relates to a pharmaceutical composition comprising a compound as described herein for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder.

[0244] While the compound of Formula (I) of the present invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0245] In some embodiments, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and / or prophylactic ingredients, known and used in the art. The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0246] Aminergic GPCR agonism

[0247] The present invention provides for compound(s) or a pharmaceutically acceptable salt(s) thereof, for use in the treatment, prevention and / or alleviation of a trace amine- associated receptor 1 (TAARI)-associated disorder, as aforementioned in section ‘medical use’. The pathophysiology underlying a trace amine-associated receptor 1 (TAARI)-associated disorder(s) is associated with dysfunctional aminergic receptor signalling. In some embodiments, the compound(s) or a pharmaceutically acceptable salt(s) thereof modulates monoaminergic and / or glutamatergic receptor signalling.

[0248] In some embodiments, the compound(s) or a pharmaceutically acceptable salt(s) thereof has a multi-target selectivity profile. In some embodiments, the compound has a multi-target selectivity profile, wherein the compound has agonist activity and / or antagonist activity for at least one aminergic GPCR. In some embodiments, the compound has a multi-target selectivity profile, wherein the compound has agonist activity for at least one aminergic GPCR. In some embodiments, the compound has a multi-target selectivity profile, wherein the compound has antagonist activity for at least one aminergic GPCR. In some embodiments the compound has agonist activity and / or antagonist activity for at least one aminergic GPCR, such as a receptor selected from the group comprising: TAAR1, 5-hydroxytryptamine receptor 1 D (5-HTID), 5-hydroxytryptamine receptor 1E (5-HTIE), the a 2A adrenergic receptor (O2A), the dopamine D2 receptor (D2), the histamine H1 receptor (Hi), and / or a member of the muscarinic acetylcholine receptor family, such as the M2 receptor.

[0249] As used herein, reference to an "agonist" of a given protein refers to any compound that is characterized by the ability to agonize (e.g., stimulate, induce, increase, enhance, or mimic) the biological activity of a naturally occurring protein or reference protein (including the protein itself), and includes any homologue, binding protein (e.g., an antibody), or agent that interacts with a protein or receptor bound by the protein, or any suitable product of drug / compound / peptide design or selection which is characterized by its ability to agonize (e.g., stimulate, induce, increase, enhance) the biological activity of the protein. Such agonists can include, but are not limited to, a protein, peptide, or nucleic acid (including ribozymes, RNAi, aptamers, and antisense), antibodies and antigen binding fragments thereof, or product of drug / compound / peptide design or selection that provides the agonist effect. Accordingly, as used herein, the term “agonist activity” refers to the functional property of biological activity or processes (e.g., enzyme activity or receptor binding) of an agonist, such biological activity or processes may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, receptor internalization, and / or may be manifested only in particular cell types.

[0250] As used herein, reference to an "antagonist" refers to any compound which inhibits (e.g., antagonizes, reduces, decreases, blocks, reverses, or alters) the biological activity of a given agonist of a protein (including the protein itself), and includes any homologue, binding protein (e.g., an antibody), or agent that interacts with a protein or receptor bound by the protein, or any suitable product of drug / compound / peptide design or selection which is characterized by its ability to antagonise or inhibit the biological activity of the protein. Such antagonists can include, but are not limited to, a protein, peptide, or nucleic acid (including ribozymes, RNAi, aptamers, and antisense), antibodies and antigen binding fragments thereof, or product of drug / compound / peptide design or selection that provides the antagonistic effect. Accordingly, as used herein, the term “antagonist activity” refers to the functional property of biological activity or processes (e.g., enzyme activity or receptor binding) of an antagonist, such biological activity or processes may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, receptor internalization, and / or may be manifested only in particular cell types.

[0251] As used herein, the term “potency” or “biological potency” refers to the biological activity of a compound. Potency can be expressed in terms of the concentration or amount or dose required to produce a defined effect, such as a pharmacological effect of a given intensity. A highly potent drug exhibits a given response at low concentrations, whereas a drug with lower potency evokes the same response at higher concentrations. Potency can be defined by various methods of measurement, including effective dose (ED50), median lethal dose (LD50), median toxic dose (TD50), half maximal effective concentration (EC50) and / or half maximal effective inhibitory concentration (IC50).

[0252] As used herein, the term half maximal effective concentration (EC50) generally refers to the concentration which induces a response halfway between the baseline and maximum, by reference to the dose response curve. EC50 is used as a measure of the potency of a compound and represents the concentration where 50% of its maximal effect is observed. As used herein, The term pECso means the absolute value of the log(EC50) wherein EC50 is the concentration of the test compound that elicits half- maximal (50 %) effect compared to the compound's maximally attainable effect. The values can be determined according to any conventional methods known by the skilled person, e.g. those described in the working examples, and such as a luminescencecomplementation G protein recruitment assay and / or the PRESTO-TANGO method. Values can be determined using a software program such as Graphpad Prism 4.03 (GraphPad, San Diego, CA). In some embodiments, the EC50 and / or the pECso is determined by a luminescence-complementation G protein recruitment assay. In some embodiments, the EC50 and / or the pECso is determined a PRESTO-TANGO assay.

[0253] In some embodiments, the compound reduces core body temperature by between 0.1- 3°C in vivo, such as between 0.5-2°C, such as between 0.5-1.5°C, such as between 0.5-1 °C. In some embodiments, the receptors are human.

[0254] In some embodiments, the compound is a TAAR1 agonist.

[0255] In some embodiments, the compound is a TAAR1 agonist, with a pEC50 for TAAR1 between 5.0 and 7.6, such as between 5.0 and 7, such as between 5.0 and 6.8, such as between 5.0 and 6.6, such as between 5.0 and 6.4, such as between 5.0 and 6.2, such as between 5.0 and 6.0, such as between 5.1 and 7.6, such as between 5.2 and

[0256] 7.6, such as between 5.3 and 7.6, such as between 5.4 and 7.6, such as between 5.5 and 7.6, such as between 5.6 and 7.6, such as between 5.7 and 7.6, such as between 5.8 and 7.6, such as between 5.9 and 7.6, such as between 6 and 7.6, such as between 6.1 and 7.6, such as between 6.2 and 7.6, such as between 6.3 and 7.6, such as between 6.4 and 7.6, such as between 6.5 and 7.6, such as between 6.6 and 7.6, such as between 6.7 and 7.6, such as between 6.8 and 7.6, such as between 6.9 and

[0257] 7.6.

[0258] In some embodiments, the compound is a TAAR1 agonist, with a pEC50 for TAAR1 with a pEC50 for TAAR1 of at least 5.0, such as at least 5.2, such as at least 5.4, such as at least 5.6, such as at least 5.8, such as at least 6, such as at least 6.2, such as at least 6.4, such as at least 6.6, such as at least 6.8, such as at least 7.

[0259] In some embodiments, the compound is a TAAR1 agonist, with a pEC50 for TAAR1 of at least 6.4, such as at least 6.6, such as at least 6.8, such as at least 7.

[0260] In some embodiments, the compound is a TAAR1 agonist, with an EC50 ranging from 0.03-12 jiM, such as ranging from 0.06-12 .M, such as ranging from 0.08-12 .M, such as ranging from 0.1-12 .M, such as ranging from 0.2-12 .M, such as ranging from 0.4- 12 jiM, such as ranging from 0.6-12 .M, such as ranging from 0.8-12 .M, such as ranging from 1-12 .M, such as ranging from 2-12 .M, such as ranging from 4-12 .M, such as ranging from 6-12 .M.

[0261] In some embodiments, the compound has a pEC50 for the dopamine D2 receptor (D2) of at the most 6.0, such as at the most 5.5, such as at the most 5.0, such as at the most 4.5. In some embodiments, the compound has a pEC50 for the 5-HTID receptor of at the most 6.0, such as at the most 5.5, such as at the most 5.0, such as at the most 4.5.

[0262] In some embodiments, the compound has a pEC50 for the a2A receptor of at the most 6.0, such as at the most 5.5, such as at the most 5.0, such as at the most 4.5.

[0263] In some embodiments, the compound has a pEC50 for M2 receptor of at the most 5.0, such as at the most 4.5, such as at the most 4.0.

[0264] In some embodiments, the compound reduces core body temperature by between 0.1- 1.5°C in vivo, such as between 0.5-1 °C.

[0265] Trace amine-associated receptor 1 (TAARI)-associated disorders

[0266] In one aspect, the present invention relates to the compound(s) of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder.

[0267] A "trace amine-associated receptor 1 (TAARI)-associated disorder" refers to any condition or pathology in which dysregulation or malfunction of the TAAR1 receptor is implicated as a contributing factor or potential therapeutic target. TAAR1 is a G protein- coupled receptor primarily expressed in the brain and is involved in modulating neurotransmitter systems such as dopamine and serotonin. Disorders associated with TAAR1 dysfunction may include psychiatric disorders (e.g., schizophrenia, bipolar disorder, depression), substance use disorders (e.g., addiction), neurodegenerative diseases, and metabolic disorders. Therapeutic interventions targeting TAAR1 may include agonists, antagonists, or modulators aimed at restoring normal receptor function and ameliorating associated symptoms or pathologies.

[0268] In one embodiment, the TAAR1 -associated disorder is selected from the group comprising a mental disease or disorder, a cognitive disease or disorder, a neurological disease or disorder, a psychiatric disease or disorder, a neurodegenerative disease or disorder, and a substance-related and / or addictive disorder.

[0269] In one embodiment, the disease or disorder is a mental disease or disorder.

[0270] In one embodiment, the disease or disorder is a cognitive disease or disorder. In one embodiment, the disease or disorder is a neurological disease or disorder and / or a psychiatric disease or disorder and / or a neurodegenerative disease or disorder.

[0271] In one embodiment, the disease or disorder is a neurological disease or disorder.

[0272] In one embodiment, the disease or disorder is a psychiatric disease or disorder.

[0273] In one embodiment, the disease or disorder is a neurodegenerative disease or disorder.

[0274] In one embodiment, the disease or disorder is a substance-related and / or addictive disorder.

[0275] In one embodiment, the disease or disorder is selected from the group comprising: Schizophrenia, Psychosis, Psychosis in Schizophrenia, psychosis in neurodegenerative diseases, Psychosis in Dementia with Lewy Bodies, Psychosis in Alzheimer’s disease, Psychosis in Parkinson’s disease, Psychosis in frontotemporal dementia, Psychosis in vascular dementia, Psychosis in Huntington’s disease, Bipolar disorder, Major depressive disorder, anxiety, generalized anxiety disorder, stress- induced disorder, Attention deficit hyperactive disorder (ADHD), autism spectrum disorder, obsessive-compulsive disorder, L-dopa-induced dyskinesias in Parkinson’s disease, Chorea in Huntington’s disease, Nicotine abuse, Cocaine abuse, Amphetamine abuse, Opioid abuse, Alcohol abuse, Sleep disorders, Excessive daytime sleepiness, narcolepsy, cataplexy, idiopathic hypersomnia, shift work sleep disorder, Fatigue, REM sleep behavioural disorder (RBD).

[0276] Pharmaceutical composition

[0277] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I):

[0278] Formula (I) wherein

[0279] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0280] R3is H, Me or cyclopropyl;

[0281] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0282] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4- thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol-4-yl, pyrazol-3-yl, pyrazol-1-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0283] • thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0284] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0285] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0286] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I):

[0287] Formula (I) wherein

[0288] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0289] R3is H, Me or cyclopropyl;

[0290] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0291] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, pyrazol-1-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; • thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0292] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0293] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0294] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I):

[0295] Formula (I) wherein

[0296] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0297] R3is H, Me or cyclopropyl;

[0298] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0299] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F,CHF2, CF3, F, Cl, Br, and CN;

[0300] • thiazol-2-yl, thiazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0301] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0302] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, R1is H, C1-4 alkyl, CH2F, CHF2, or CF3; R3is H, Me or cyclopropyl; and R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0304] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, or pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0305] • thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0306] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0307] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy.

[0308] In some embodiments, the pharmaceutical composition further comprises one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0309] In some embodiments, R1is C1-4 alkyl. In some embodiments, R1is selected from the group consisting of Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, and t-Bu. In some embodiments, R1is Me. In some embodiments, R1is H.

[0310] In some embodiments, R3is H. In some embodiments, R3is Me. In some embodiments, R1is H or Me, and R3is H or Me. In some embodiments, R1is H or Me, and R3is H. In some embodiments, R1is Me and R3is H. In some embodiments, R1is H and R3is H. In some embodiments, R1is H and R3is Me.

[0311] In some embodiments, R2is furanyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is furanyl substituted with CN. In some embodiments, some embodiments, the furanyl is furan-2-yl. In some embodiments, the furanyl is furan-3-yl. In some embodiments, R2is furanyl. In some embodiments, R2is furan-2-yl. In some embodiments, R2is furan-3-yl.

[0312] In some embodiments, R2is thienyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is thienyl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, F, Cl, Br, and CN. In some embodiments, R2is thienyl substituted with C1-3 alkyl. In some embodiments, R2is thienyl substituted with Me. In some embodiments, R2is thienyl substituted with F. In some embodiments, R2is thienyl substituted with Cl. In some embodiments, R2is thienyl substituted with Br. In some embodiments, the thienyl is thien-2-yl. In some embodiments, the thienyl is thien-3-yl. In some embodiments, R2 embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, R2is thienyl. In some embodiments, R2is thien-3-yl. In some embodiments, R2is thien-2-yl.

[0313] In some embodiments, R2is thiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is thiazol-2-yl substituted with Cl. In some embodiments, . In some embodiments, R2is In some embodiments, R2is thiazol-2-yl substituted with C1-3 alkoxy. In some embodiments, some embodiments, R2is thiazol-2-yl. In some embodiments, R2is thiazol-4-yl substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is thiazol-4-yl. In some embodiments, R2is thiazol-5-yl substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is thiazol-5-yl.

[0314] In some embodiments, R2is isothiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is isothiazol-3- yi.

[0315] In some embodiments, R2is isothiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is isothiazol-5- yi.

[0316] In some embodiments, R2is isothiazol-5-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl. In some embodiments, R2is isothiazol-5-yl substituted with Me. In some embodiments, R2is

[0317] In some embodiments, R2is 1 ,2,4-thiadiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is 1 ,2,4- thiadiazol-3-yl substituted with C1-3 alkyl. In some embodiments, R2is 1 ,2,4-thiadiazol-

[0318] 3-yl substituted with Me. In some embodiments,

[0319] In some embodiments, R2is 1 ,2,4-thiadiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is 1 ,2,4-thiadiazol-5-yl substituted with C1-3 alkyl. In some embodiments, R2is 1 ,2,4- thiadiazol-5-yl substituted with Me. In some embodiments, R2is . In some embodiments.R2is 1 ,2,4-thiadiazol-5-yl.

[0320] In some embodiments, R2is 1 ,2,5-thiadiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is 1 ,2,5-thiadiazol-3-yl.

[0321] In some embodiments, R2is 1 ,3,4-thiadiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is 1 ,3,4-thiadiazol-2-yl.

[0322] In some embodiments, R2is pyrazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is pyrazol-4-yl.

[0323] In some embodiments, R2is pyrazol-1-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is pyrazol-1-yl.

[0324] In some embodiments, R2is pyrazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments, R2is pyrazol-3-yl substituted with one or more substituents each independently selected from C1-3 alkyl. In some embodiments, R2is pyrazol-3-yl substituted with Me. In some embodiments, some embodiments, R2is pyrazol-3-yl.

[0325] In some embodiments, R2is pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl and C1- 3 alkoxy. In some embodiments, R2is pyrimidin-2-yl.

[0326] In some embodiments, R2is oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. In some embodiments,

[0327] R2is oxazol-4-yl. isothiazol-5-yl, , pyrazol-4-yl, pyrimidin-2-yl, or oxazol-4-yl. In some embodiments, pharmaceutical composition comprises a compound is selected from the group consisting of:

[0328] 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0329] 5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine;

[0330] 2-(5,6-dihydro-2H-1l2-pyridin-3-yl)furan-3-carbonitrile;

[0331] 5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine;

[0332] 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0333] 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0334] 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;

[0335] 5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0336] 5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0337] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;

[0338] 5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0339] 5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0340] 5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0341] 5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0342] 5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0343] 4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0344] 5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0345] 4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0346] 5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0347] 5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0348] 5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0349] 5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0350] 4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0351] 4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0352] 5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0353] 4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0354] 4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0355] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0356] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0357] 4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0358] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0359] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole; 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0360] 5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0361] 4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine; and 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine, or a pharmaceutically acceptable salt thereof.

[0362] In one aspect, the present invention relates to a pharmaceutical composition comprising acompound is selected from the group consisting of:

[0363] 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0364] 5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine;

[0365] 2-(5,6-dihydro-2H-1l2-pyridin-3-yl)furan-3-carbonitrile;

[0366] 5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine;

[0367] 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0368] 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0369] 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;

[0370] 5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0371] 5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0372] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;

[0373] 5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0374] 5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0375] 5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0376] 5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0377] 5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0378] 4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0379] 5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0380] 4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0381] 5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0382] 5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0383] 5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0384] 5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0385] 4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0386] 4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0387] 5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0388] 4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0389] 4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine; 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0390] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0391] 4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0392] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0393] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0394] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0395] 5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0396] 4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine;

[0397] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine;

[0398] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;

[0399] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0400] 4-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0401] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0402] 5-(1-methyl-1 H-pyrazol-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0403] 4-methoxy-2-(4-methyl-1,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0404] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0405] 3-methyl-5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0406] 5-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0407] 5-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0408] 5-(1 H-pyrazol-1-yl)-1 ,2,3,6-tetrahydropyridine;

[0409] 3-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;

[0410] 4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0411] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0412] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0413] 3-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0414] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; and

[0415] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,3,4-thiadiazole, or a pharmaceutically acceptable salt thereof, and one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0416] Compounds of the present invention may be prepared according to any conventional methods of chemical synthesis known by the skilled person, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods known by the skilled artisan from commercially available chemicals. The end products of the reactions described herein may be isolated by conventional technique such as extraction, crystallisation, distillation, chromatography etc.

[0417] In some embodiments, the pharmaceutical composition according to the present invention is for use in the treatment, prevention and / or alleviation of a trace amine- associated receptor 1 (TAARI)-associated disorder, as defined in sections ‘medical use’, ‘aminergic GPCR antagonism’ and / or ‘trace amine-associated receptor 1 (TAARI)-associated disorders’.

[0418] Items

[0419] 1. A compound of Formula (I):

[0420] Formula (I) wherein

[0421] R1is H, Ci-4alkyl, CH2F, CHF2, or CF3;

[0422] R3is H, C1-4 alkyl or cyclopropyl;

[0423] R2is phenyl substituted with one or more independently selected R4, or a 5- or 6-membered heteroaryl selected from the group consisting of

[0424] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl , 1 ,2,5-thiadiazol-3-yl , 1 ,3,4-thiadiazol-2-yl , pyrazol-4-yl, pyrazol-3-yl , pyrazol-1-yl , pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0425] • thiazol-2-yl, thiazol-5-yl , each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0426] • thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0427] • oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0428] R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of:

[0429] 3-(3,4-dimethoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0430] 3-(3-methoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0431] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0432] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAAR1)- associated disorder. A compound of Formula (I):

[0433] Formula (I) wherein

[0434] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0435] R3is H, C1-4 alkyl or cyclopropyl;

[0436] R2is phenyl substituted with one or more independently selected R4, or a 5- or 6-membered heteroaryl selected from the group consisting of

[0437] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, pyrazol-1-yl , pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0438] • thiazol-2-yl, thiazol-5-yl , each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0439] • thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0440] • oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0441] R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of:

[0442] 3-(3,4-dimethoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0443] 3-(3-methoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0444] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0445] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAAR1)- associated disorder.

[0446] 3. A compound of Formula (I):

[0447] Formula (I) wherein

[0448] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0449] R3is H, C1-4 alkyl or cyclopropyl;

[0450] R2is phenyl optionally substituted with one or more independently selected R4, or a 5- or 6-membered heteroaryl selected from the group consisting of

[0451] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0452] • thiazol-2-yl, thiazol-4-yl , each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0453] • oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0454] R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of:

[0455] 3-(3,4-dimethoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0456] 3-(3-methoxyphenyl)-1 ,2,5,6-tetrahydropyridine;

[0457] 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and

[0458] 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAAR1)- associated disorder. The compound for use according any one of the preceding items, wherein R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0459] R3is H, Me or cyclopropyl;

[0460] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0461] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl,

[0462] 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol- 4-yl, pyrazol-3-yl, pyrazol-1-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; • thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0463] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0464] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof. The compound for use according any one of the preceding items, wherein R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0465] R3is H, Me or cyclopropyl;

[0466] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0467] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0468] • thiazol-2-yl, thiazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0469] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0470] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof. The compound for use according any one of the preceding items, wherein

[0471] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0472] R3is H, Me or cyclopropyl;

[0473] R2is a 5- or 6-membered heteroaryl selected from the group consisting of • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0474] • thiazol-2-yl, thiazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0475] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof. The compound for use according to any one of the preceding items, wherein R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0476] R3is H, Me or cyclopropyl;

[0477] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0478] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, or pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0479] • thiazol-2-yl or thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0480] • thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0481] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0482] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof. 8. The compound for use according to any one of the preceding items, wherein R1is C1-4 alkyl.

[0483] 9. The compound for use according to any one of the preceding items, wherein R1is selected from the group consisting of Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, and t-Bu.

[0484] 10. The compound for use according to any one of the preceding items, wherein R1is Me.

[0485] 11 . The compound for use according to any one of the preceding items, wherein R1is H.

[0486] 12. The compound for use according to any one of the preceding items, wherein R3is H.

[0487] 13. The compound for use according to any one of the preceding items, wherein R3is C1-4 alkyl.

[0488] 14. The compound for use according to any one of the preceding items, wherein R3is Me.

[0489] 15. The compound for use according to any one of the preceding items, wherein R3is Et.

[0490] 16. The compound for use according to any one of the preceding items, wherein R1is Me and R3is H.

[0491] 17. The compound for use according to any one of the preceding items, wherein R1is H and R3is H.

[0492] 18. The compound for use according to any one of the preceding items, wherein R1is H and R3is Me.

[0493] 19. The compound for use according to any one of the preceding items, wherein R1is H and R3is Et.

[0494] 20. The compound for use according to any one of the preceding items, wherein R1is H or Me, and R3is H, Me, or Et.

[0495] 21. The compound for use according to any one of the preceding items, wherein R1is H or Me, and R3is H or Me.

[0496] 22. The compound for use according to any one of the preceding items, wherein R1is H or Me, and R3is H.

[0497] 23. The compound for use according to any one of the preceding items, wherein R2is phenyl substituted with one or more R4, and wherein R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CFs, F, Cl, Br, and CN, with the proviso that said phenyl is not substituted with methoxy in the meta position.

[0498] 24. The compound for use according to any one of the preceding items, wherein R2is phenyl substituted with one or more R4, and wherein R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, with the proviso that said phenyl is not substituted with C1-3 alkoxy in the meta position.

[0499] 25. The compound for use according to any one of the preceding items, wherein R2is phenyl.

[0500] 26. The compound for use according to any one of the preceding items, wherein R2is phenyl substituted with one or more R4, and wherein R4is F, Cl, or Br.

[0501] 27. The compound for use according to any one of the preceding items, wherein R4is F.

[0502] 28. The compound for use according to any one of the preceding items, wherein R4is Cl.

[0503] 29. The compound for use according to any one of the preceding items, wherein R4is Br.

[0504] 30. The compound for use according to any one of the preceding items, wherein R2is 2-fluorophenyl.

[0505] 31 . The compound for use according to any one of the preceding items, wherein R2is 2-chlorophenyl.

[0506] 32. The compound for use according to any one of the preceding items, wherein R2is 3-fluorophenyl.

[0507] 33. The compound for use according to any one of the preceding items, wherein R2is 3-chlorophenyl.

[0508] 34. The compound for use according to any one of the preceding items, wherein R2is 4-fluorophenyl.

[0509] 35. The compound for use according to any one of the preceding items, wherein R2is 4-chlorophenyl.

[0510] 36. The compound for use according to any one of the preceding items, wherein R2is furanyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0511] 37. The compound for use according to any one of the preceding items, wherein R2is furanyl substituted with CN. 38. The compound for use according to any one of the preceding items, wherein R2

[0512] 39. The compound for use according to any one of the preceding items, wherein the furanyl is furan-2-yl.

[0513] 40. The compound for use according to any one of the preceding items, wherein the furanyl is furan-3-yl.

[0514] 41. The compound for use according to any one of the preceding items, wherein R2is furanyl.

[0515] 42. The compound for use according to any one of the preceding items, wherein R2is furan-2-yl.

[0516] 43. The compound for use according to any one of the preceding items, wherein R2is furan-3-yl.

[0517] 44. The compound for use according to any one of the preceding items, wherein R2is thienyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0518] 45. The compound for use according to any one of the preceding items, wherein R2is thienyl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, F, Cl, Br, and CN.

[0519] 46. The compound for use according to any one of the preceding items, wherein R2is thienyl substituted with C1-3 alkyl.

[0520] 47. The compound for use according to any one of the preceding items, wherein R2is thienyl substituted with Me.

[0521] 48. The compound for use according to any one of the preceding items, wherein R2is thienyl substituted with F.

[0522] 49. The compound for use according to any one of the preceding items, wherein R2is thienyl substituted with Cl.

[0523] 50. The compound for use according to any one of the preceding items, wherein R2is thienyl substituted with Br.

[0524] 51. The compound for use according to any one of the preceding items, wherein R2is thienyl substituted with CN.

[0525] 52. The compound for use according to any one of the preceding items, wherein the thienyl is thien-2-yl. 53. The compound for use according to any one of the preceding items, wherein the thienyl is thien-3-yl.

[0526] 54. The compound for use according to any one of the preceding items, wherein R2 55. The compound for use according to any one of the preceding items, wherein R2

[0527] 56. The compound for use according to any one of the preceding items, wherein R2

[0528] 57. The compound for use according to any one of the preceding items, wherein R2

[0529] 58. The compound for use according to any one of the preceding items, wherein R2

[0530] 59. The compound for use according to any one of the preceding items, wherein R2

[0531] 60. The compound for use according to any one of the preceding items, wherein R2 61. The compound for use according to any one of the preceding items, wherein R2 is

[0532] 62. The compound for use according to any one of the preceding items, wherein R2

[0533] 63. The compound for use according to any one of the preceding items, wherein R2

[0534] 64. The compound for use according to any one of the preceding items, wherein R2

[0535] 65. The compound for use according to any one of the preceding items, wherein R2

[0536] 66. The compound for use according to any one of the preceding items, wherein R2

[0537] 67. The compound for use according to any one of the preceding items, wherein R2is thienyl.

[0538] 68. The compound for use according to any one of the preceding items, wherein R2is thien-3-yl.

[0539] 69. The compound for use according to any one of the preceding items, wherein R2is thien-2-yl.

[0540] 70. The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0541] 71. The compound for use according to any one of the preceding items, wherein the compound is not 3-(4-methylthiazol-2-yl) 1 ,2,5,6-tetrahydropyridine or 1- methyl 3-(4-methylthiazol-2-yl) 1 ,2,5,6-tetrahydropyridine.

[0542] 72. The compound for use according to any one of the preceding items, wherein R2is not 4-methylthiazol.

[0543] 73. The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0544] 74. The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, and Br.

[0545] 75. The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl substituted with Cl.

[0546] 76. The compound for use according to any one of the preceding items, wherein R2

[0547] 77. The compound for use according to any one of the preceding items, wherein R2

[0548] 78. The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl.

[0549] 79. The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl substituted with one or two Me.

[0550] 80. The compound for use according to any one of the preceding items, wherein R2

[0551] 81 . The compound for use according to any one of the preceding items, wherein R2 is The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl substituted with C1-3 alkoxy. The compound for use according to any one of the preceding items, wherein R2 The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl substituted with cyclopropyl. The compound for use according to any one of the preceding items, wherein R2 The compound for use according to any one of the preceding items, wherein R2is thiazol-2-yl. The compound for use according to any one of the preceding items, wherein R2is thiazol-4-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of: 1-methyl-3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and 3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine. The compound for use according to any one of the preceding items, wherein R2is thiazol-4-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that R2is not 2-methyl-1 ,3-thiazol-4-yl. The compound for use according to any one of the preceding items, wherein R2is thiazol-4-yl substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, and Br. The compound for use according to any one of the preceding items, wherein R2 is thiazol-4-yl substituted with C1-3 alkyl.

[0552] 91. The compound for use according to any one of the preceding items, wherein R2is thiazol-4-yl substituted with Me.

[0553] 92. The compound for use according to any one of the preceding items, wherein R2

[0554] 93. The compound for use according to any one of the preceding items, wherein R2is thiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, and Br.

[0555] 94. The compound for use according to any one of the preceding items, wherein R2is thiazol-5-yl optionally substituted with cyclopropyl.

[0556] 95. The compound for use according to any one of the preceding items, wherein R2

[0557] 96. The compound for use according to any one of the preceding items, wherein R2is thiazol-5-yl.

[0558] 97. The compound for use according to any one of the preceding items, wherein R2is isothiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0559] 98. The compound for use according to any one of the preceding items, wherein R2is isothiazol-3-yl.

[0560] 99. The compound for use according to any one of the preceding items, wherein R2is isothiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0561] 100. The compound for use according to any one of the preceding items, wherein R2is isothiazol-5-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl.

[0562] 101 . The compound for use according to any one of the preceding items, wherein R2is isothiazol-5-yl substituted with Me.

[0563] 102. The compound for use according to any one of the preceding items, wherein

[0564] 103. The compound for use according to any one of the preceding items, wherein R2is isothiazol-5-yl.

[0565] 104. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0566] 105. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-3-yl substituted with C1-3 alkyl.

[0567] 106. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-3-yl substituted with Me.

[0568] 107. The compound for use according to any one of the preceding items, wherein

[0569] 108. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0570] 109. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-5-yl substituted with C1-3 alkyl.

[0571] 110. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-5-yl substituted with Me.

[0572] 111. The compound for use according to any one of the preceding items, wherein

[0573] 112. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-5-yl.

[0574] 113. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,5-thiadiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0575] 114. The compound for use according to any one of the preceding items, wherein R2is 1 ,2,5-thiadiazol-3-yl.

[0576] 115. The compound for use according to any one of the preceding items, wherein R2is 1 ,3,4-thiadiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0577] 116. The compound for use according to any one of the preceding items, wherein R2is 1 ,3,4-thiadiazol-2-yl.

[0578] 117. The compound for use according to any one of the preceding items, wherein R2is pyrazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0579] 118. The compound for use according to any one of the preceding items, wherein R2is pyrazol-4-yl.

[0580] 119. The compound for use according to any one of the preceding items, wherein R2is pyrazol-1-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0581] 120. The compound for use according to any one of the preceding items, wherein R2is pyrazol-1-yl.

[0582] 121 . The compound for use according to any one of the preceding items, wherein R2is pyrazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0583] 122. The compound for use according to any one of the preceding items, wherein R2is pyrazol-3-yl substituted with one or more substituents each independently selected from C1-3 alkyl.

[0584] 123. The compound for use according to any one of the preceding items, wherein R2is pyrazol-3-yl substituted with Me.

[0585] 124. The compound for use according to any one of the preceding items, wherein . The compound for use according to any one of the preceding items, wherein R2is pyrazol-3-yl. . The compound for use according to any one of the preceding items, wherein R2is pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. . The compound for use according to any one of the preceding items, wherein R2is pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl and C1-3 alkoxy. . The compound for use according to any one of the preceding items, wherein R2is pyrimidin-2-yl. . The compound for use according to any one of the preceding items, wherein R2is oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. . The compound for use according to any one of the preceding items, wherein R2is oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, and Br. . The compound for use according to any one of the preceding items, wherein R2is oxazol-4-yl. . The compound for use according to any one of the preceding items,

[0586] thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol-4-yl, pyrazol-

[0587] 5 pyrazol-3-yl, pyrimidin-2-yl, or oxazol-4-yl.

[0588] 133. The compound for use according to any one of the preceding items, isothiazol-3-yl, , isothiazol-5-yl, , pyrazol-4-yl, pyrimidin-2-yl, or oxazol-4-yl. . The compound for use according to any one of the preceding items, wherein the compound is selected from the group consisting of: 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0589] 5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine;

[0590] 2-(5,6-dihydro-2H-1l2-pyridin-3-yl)furan-3-carbonitrile;

[0591] 5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine;

[0592] 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0593] 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0594] 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;

[0595] 5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0596] 5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0597] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;

[0598] 5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0599] 5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0600] 5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0601] 5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0602] 5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0603] 4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0604] 5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0605] 4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0606] 5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0607] 5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0608] 5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0609] 5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0610] 4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0611] 4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0612] 5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0613] 4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0614] 4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0615] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0616] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; 4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0617] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0618] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0619] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0620] 2-methyl-4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0621] 5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0622] 4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine;

[0623] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine;

[0624] 5-phenyl-1 ,2,3,6-tetrahydropyridine;

[0625] 4.5-dimethyl-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0626] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;

[0627] 4.5-dimethyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0628] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0629] 4-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0630] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0631] 5-(1-methyl-1 H-pyrazol-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0632] 4-methoxy-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0633] 5-methyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0634] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0635] 3-methyl-5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0636] 5-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0637] 5-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0638] 5-(1 H-pyrazol-1-yl)-1 ,2,3,6-tetrahydropyridine;

[0639] 3-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;

[0640] 4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0641] 5-methyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0642] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0643] 4-cyclopropyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0644] 2-cyclopropyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0645] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole; 3-(1 ,2,5,6-tetrahydropyridin-

[0646] 3-yl)isothiazole;

[0647] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0648] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,3,4-thiadiazole;

[0649] 5-(2-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;

[0650] 5-(3-fluorophenyl)-1 ,2,3,6-tetrahydropyridine; 5-(4-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;

[0651] 5-(3-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;

[0652] 5-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyridine; and 5-(2-fluorophenyl)-1 ,2,3,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof. . The compound for use according to any one of the preceding items, wherein the compound is selected from the group consisting of: 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0653] 5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine;

[0654] 2-(5,6-dihydro-2H-1l2-pyridin-3-yl)furan-3-carbonitrile;

[0655] 5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine;

[0656] 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0657] 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0658] 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;

[0659] 5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0660] 5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0661] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;

[0662] 5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0663] 5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0664] 5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0665] 5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0666] 5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0667] 4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0668] 5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0669] 4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0670] 5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0671] 5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0672] 5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0673] 5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine; 4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0674] 4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0675] 5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0676] 4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine; 4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0677] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0678] 4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0679] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0680] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0681] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole; 2-methyl-4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; 5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0682] 4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine;

[0683] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine; and

[0684] 5-phenyl-1,2,3,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof.

[0685] 136. The compound for use according to any one of the preceding items, wherein the compound modulates monoaminergic and / or glutamatergic receptor signalling.

[0686] 137. The compound for use according to any one of the preceding items, wherein the compound has a multi-target selectivity profile, wherein the compound has agonist activity and / or antagonist activity for at least one aminergic GPCR.

[0687] 138. The compound for use according to any one of the preceding items, wherein the compound has a multi-target selectivity profile, wherein the compound has agonist activity and / or antagonist activity for at least one aminergic GPCR, such as a receptor selected from the group comprising: TAAR1, 5-hydroxytryptamine receptor 1 D (5-HTID), 5-hydroxytryptamine receptor 1E (5-HTIE), the a 2A adrenergic receptor (O2A), the dopamine D2 receptor (D2), the histamine H1 receptor (Hi), and / or a member of the muscarinic acetylcholine receptor family, such as the M2 receptor.

[0688] 139. The compound for use according to items 136 to 138, wherein the receptors are human.

[0689] 140. The compound for use according to any one of the preceding items, wherein the compound is a TAAR1 agonist.

[0690] 141. The compound for use according to any one of the preceding items, wherein the compound is a TAAR1 agonist, with a pEC50 for TAAR1 between 5.0 and 7.6, such as between 5.0 and 7.0. 142. The compound for use according to any one of the preceding items, wherein the compound is a TAAR1 agonist, with a pEC50 for TAAR1 with a pEC50 for TAAR1 of at least 5.0, such as at least 5.2, such as at least 5.4, such as at least 5.6, such as at least 5.8, such as at least 6, such as at least 6.2, such as at least 6.4, such as at least 6.6, such as at least 6.8, such as at least 7.

[0691] 143. The compound for use according to any one of the preceding items, wherein the compound is a TAAR1 agonist, with a pEC50 for TAAR1 of at least

[0692] 6.4, such as at least 6.6, such as at least 6.8, such as at least 7.

[0693] 144. The compound for use according to any one of the preceding items, wherein the compound is a TAAR1 agonist, with an EC50 ranging from 0.03-12 pM.

[0694] 145. The compound for use according to any one of the preceding items, wherein the compound has a pEC50 for the dopamine D2 receptor (D2) of at the most 6.0, such as at the most 5.5, such as at the most 5.0, such as at the most

[0695] 4.5.

[0696] 146. The compound for use according to any one of the preceding items, wherein the compound has a pEC50 for the 5-HTID receptor of at the most 6.0, such as at the most 5.5, such as at the most 5.0, such as at the most 4.5.

[0697] 147. The compound for use according to any one of the preceding items, wherein the compound has a pEC50 for the C(2A receptor of at the most 6.0, such as at the most 5.5, such as at the most 5.0, such as at the most 4.5.

[0698] 148. The compound for use according to any one of the preceding items, wherein the compound has a pEC50 for M2 receptor of at the most 5.0, such as at the most 4.5, such as at the most 4.0.

[0699] 149. The compound for use according to any one of the preceding items, wherein the pECso is determined by a luminescence-complementation G protein recruitment assay.

[0700] 150. The compound for use according to any one of the preceding items, wherein the pECso is determined by a PRESTO-TANGO assay.

[0701] 151 . The compound for use according to any one of the preceding items, wherein the compound reduces core body temperature by between 0.1 -3°C in vivo, such as between 0.5-2°C, such as between 0.5-1.5°C, such as between 0.5-1 °C. 152. The compound for use according to any one of the preceding items, wherein the compound reduces core body temperature by between 0.1-1.5°C in vivo, such as between 0.5-1 °C.

[0702] 153. The compound for use according to any one of the preceding items, wherein the disease or disorder is selected from the group comprising a mental disease or disorder, a cognitive disease or disorder, a neurological disease or disorder, a psychiatric disease or disorder, a neurodegenerative disease or disorder, and a substance-related and / or addictive disorder.

[0703] 154. The compound for use according to any one of the preceding items, wherein the disease or disorder is a mental disease or disorder.

[0704] 155. The compound for use according to any one of the preceding items, wherein the disease or disorder is a cognitive disease or disorder.

[0705] 156. The compound for use according to any one of the preceding items, wherein the disease or disorder is a neurological disease or disorder and / or a psychiatric disease or disorder and / or a neurodegenerative disease or disorder.

[0706] 157. The compound for use according to any one of the preceding items, wherein the disease or disorder is a neurological disease or disorder.

[0707] 158. The compound for use according to any one of the preceding items, wherein the disease or disorder is a psychiatric disease or disorder.

[0708] 159. The compound for use according to any one of the preceding items, wherein the disease or disorder is a neurodegenerative disease or disorder.

[0709] 160. The compound for use according to any one of the preceding items, wherein the disease or disorder is a substance-related and / or addictive disorder.

[0710] 161. The compound for use according to any one of the preceding items, wherein the disease or disorder is selected from the group comprising: Schizophrenia, Psychosis, Psychosis in Schizophrenia, psychosis in neurodegenerative diseases, Psychosis in Dementia with Lewy Bodies, Psychosis in Alzheimer’s disease, Psychosis in Parkinson’s disease, Psychosis in frontotemporal dementia, Psychosis in vascular dementia, Psychosis in Huntington’s disease, Bipolar disorder, Major depressive disorder, anxiety, generalized anxiety disorder, stress-induced disorder, Attention deficit hyperactive disorder (ADHD), autism spectrum disorder, obsessive-compulsive disorder, L-dopa-induced dyskinesias in Parkinson’s disease, Chorea in Huntington’s disease, Nicotine abuse, Cocaine abuse, Amphetamine abuse, Opioid abuse, Alcohol abuse, Sleep disorders, Excessive daytime sleepiness, narcolepsy, cataplexy, idiopathic hypersomnia, shift work sleep disorder, Fatigue, REM sleep behavioural disorder (RBD).

[0711] 162. A pharmaceutical composition comprising a compound of Formula (I):

[0712] Formula (I) wherein

[0713] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0714] R3is H, Me or cyclopropyl;

[0715] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0716] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl,

[0717] 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol- 4-yl, pyrazol-3-yl, pyrazol-1-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0718] • thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0719] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0720] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0721] 163. A pharmaceutical composition comprising a compound of Formula (I):

[0722] Formula (I) wherein

[0723] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0724] R3is H, Me or cyclopropyl;

[0725] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0726] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, pyrazol-1-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0727] • thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0728] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0729] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof. . A pharmaceutical composition comprising a compound of Formula (I):

[0730] Formula (I) wherein

[0731] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0732] R3is H, Me or cyclopropyl;

[0733] R2is a 5- or 6-membered heteroaryl selected from the group consisting of • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0734] • thiazol-2-yl, thiazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0735] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0736] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0737] 165. The pharmaceutical composition according to any one of the preceding items, wherein

[0738] R1is H, C1-4 alkyl, CH2F, CHF2, or CF3;

[0739] R3is H, Me or cyclopropyl; and

[0740] R2is a 5- or 6-membered heteroaryl selected from the group consisting of

[0741] • furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, or pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0742] • thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;

[0743] • oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and

[0744] • pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof. 166. The pharmaceutical composition according to any one of the preceding items, wherein R1is C1-4 alkyl.

[0745] 167. The pharmaceutical composition according to any one of the preceding items, wherein R1is selected from the group consisting of Me, Et, n-Pr, i-Pr, n- Bu, i-Bu, s-Bu, and t-Bu.

[0746] 168. The pharmaceutical composition according to any one of the preceding items, wherein R1is Me.

[0747] 169. The pharmaceutical composition according to any one of the preceding items, wherein R1is H.

[0748] 170. The pharmaceutical composition according to any one of the preceding items, wherein R3is H.

[0749] 171. The pharmaceutical composition according to any one of the preceding items, wherein R3is Me.

[0750] 172. The pharmaceutical composition according to any one of the preceding items, wherein R1is Me and R3is H.

[0751] 173. The pharmaceutical composition according to any one of the preceding items, wherein R1is H and R3is H.

[0752] 174. The pharmaceutical composition according to any one of the preceding items, wherein R1is H and R3is Me.

[0753] 175. The pharmaceutical composition according to any one of the preceding items, wherein R1is H or Me, and R3is H or Me.

[0754] 176. The pharmaceutical composition according to any one of the preceding items, wherein R1is H or Me, and R3is H.

[0755] 177. The pharmaceutical composition according to any one of the preceding items, wherein R2is furanyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0756] 178. The pharmaceutical composition according to any one of the preceding items, wherein R2is furanyl substituted with CN.

[0757] 179. The compound for use according to any one of the preceding items, wherein R2is 180. The pharmaceutical composition according to any one of the preceding items, wherein the furanyl is furan-2-yl.

[0758] 181 . The pharmaceutical composition according to any one of the preceding items, wherein the furanyl is furan-3-yl.

[0759] 182. The compound for use according to any one of the preceding items, wherein R2is furanyl.

[0760] 183. The pharmaceutical composition according to any one of the preceding items, wherein R2is furan-2-yl.

[0761] 184. The pharmaceutical composition according to any one of the preceding items, wherein R2is furan-3-yl.

[0762] 185. The pharmaceutical composition according to any one of the preceding items, wherein R2is thienyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0763] 186. The pharmaceutical composition according to any one of the preceding items, wherein R2is thienyl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, F, Cl, Br, and CN.

[0764] 187. The pharmaceutical composition according to any one of the preceding items, wherein R2is thienyl substituted with C1-3 alkyl.

[0765] 188. The pharmaceutical composition according to any one of the preceding items, wherein R2is thienyl substituted with Me.

[0766] 189. The pharmaceutical composition according to any one of the preceding items, wherein R2is thienyl substituted with F.

[0767] 190. The pharmaceutical composition according to any one of the preceding items, wherein R2is thienyl substituted with Cl.

[0768] 191 . The pharmaceutical composition according to any one of the preceding items, wherein R2is thienyl substituted with Br.

[0769] 192. The pharmaceutical composition according to any one of the preceding items, wherein the thienyl is thien-2-yl.

[0770] 193. The pharmaceutical composition according to any one of the preceding items, wherein the thienyl is thien-3-yl. 194. The pharmaceutical composition according to any one of the preceding items, wherein

[0771] 195. The pharmaceutical composition according to any one of the preceding items, wherein

[0772] 196. The pharmaceutical composition according to any one of the preceding items, wherein

[0773] 197. The pharmaceutical composition according to any one of the preceding items, wherein

[0774] 198. The pharmaceutical composition according to any one of the preceding items, wherein

[0775] 199. The pharmaceutical composition according to any one of the preceding items, wherein

[0776] 200. The pharmaceutical composition according to any one of the preceding items, wherein R2is

[0777] 201 . The pharmaceutical composition according to any one of the preceding items, wherein 202. The pharmaceutical composition according to any one of the preceding items, wherein

[0778] 203. The pharmaceutical composition according to any one of the preceding items, wherein

[0779] 204. The pharmaceutical composition according to any one of the preceding items, wherein

[0780] 205. The pharmaceutical composition according to any one of the preceding items, wherein

[0781] 206. The pharmaceutical composition according to any one of the preceding items, wherein

[0782] 207. The pharmaceutical composition according to any one of the preceding items, wherein R2is thienyl.

[0783] 208. The pharmaceutical composition according to any one of the preceding items, wherein R2is thien-3-yl.

[0784] 209. The pharmaceutical composition according to any one of the preceding items, wherein R2is thien-2-yl.

[0785] 210. The pharmaceutical composition according to any one of the preceding items, wherein R2is thiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0786] 211. The pharmaceutical composition according to any one of the preceding items, wherein R2is thiazol-2-yl substituted with Cl. . The compound for use according to any one of the preceding items, wherein . The pharmaceutical composition according to any one of the preceding items, wherein . The pharmaceutical composition according to any one of the preceding items, wherein R2is thiazol-2-yl substituted with C1-3 alkoxy. . The pharmaceutical composition according to any one of the preceding items, wherein R2is . The pharmaceutical composition according to any one of the preceding items, wherein R2is thiazol-2-yl. . The pharmaceutical composition according to any one of the preceding items, wherein R2is thiazol-4-yl substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. . The pharmaceutical composition according to any one of the preceding items, wherein R2is thiazol-4-yl. . The pharmaceutical composition according to any one of the preceding items, wherein R2is thiazol-5-yl substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. . The pharmaceutical composition according to any one of the preceding items, wherein R2is thiazol-5-yl. . The pharmaceutical composition according to any one of the preceding items, wherein R2is isothiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN. . The pharmaceutical composition according to any one of the preceding items, wherein R2is isothiazol-3-yl. 223. The pharmaceutical composition according to any one of the preceding items, wherein R2is isothiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0787] 224. The pharmaceutical composition according to any one of the preceding items, wherein R2is isothiazol-5-yl.

[0788] 225. The pharmaceutical composition according to any one of the preceding items, wherein R2is isothiazol-5-yl substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl.

[0789] 226. The pharmaceutical composition according to any one of the preceding items, wherein R2is isothiazol-5-yl substituted with Me.

[0790] 227. The pharmaceutical composition according to any one of the preceding items, wherein

[0791] 228. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0792] 229. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-3-yl substituted with C1-3 alkyl.

[0793] 230. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-3-yl substituted with Me.

[0794] 231 . The pharmaceutical composition according to any one of the preceding items, wherein

[0795] 232. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-5-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0796] 233. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-5-yl substituted with C1-3 alkyl. 234. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-5-yl substituted with Me.

[0797] 235. The pharmaceutical composition according to any one of the preceding items, wherein

[0798] 236. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,4-thiadiazol-5-yl.

[0799] 237. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,5-thiadiazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0800] 238. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,2,5-thiadiazol-3-yl.

[0801] 239. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,3,4-thiadiazol-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0802] 240. The pharmaceutical composition according to any one of the preceding items, wherein R2is 1 ,3,4-thiadiazol-2-yl.

[0803] 241 . The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0804] 242. The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrazol-4-yl.

[0805] 243. The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrazol-1-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0806] 244. The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrazol-1-yl.

[0807] 245. The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrazol-3-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0808] 246. The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrazol-3-yl substituted with one or more substituents each independently selected from C1-3 alkyl.

[0809] 247. The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrazol-3-yl substituted with Me.

[0810] 248. The pharmaceutical composition according to any one of the preceding items, wherein

[0811] 249. The compound for use according to any one of the preceding items, wherein R2is pyrazol-3-yl.

[0812] 250. The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl and C1-3 alkoxy.

[0813] 251 . The pharmaceutical composition according to any one of the preceding items, wherein R2is pyrimidin-2-yl.

[0814] 252. The pharmaceutical composition according to any one of the preceding items, wherein R2is oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN.

[0815] 253. The pharmaceutical composition according to any one of the preceding items, wherein R2is oxazol-4-yl.

[0816] 254. The pharmaceutical composition according to any one of the preceding items, wherein R2is furan-2-yl, furan-3-yl, NC , thien-2-yl,

[0817] pyrimidin-2-yl, or oxazol-4-yl. . The pharmaceutical composition according to any one of the preceding items, wherein the compound is selected from the group consisting of: 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0818] 5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine;

[0819] 2-(5,6-dihydro-2H-1l2-pyridin-3-yl)furan-3-carbonitrile;

[0820] 5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine;

[0821] 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0822] 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0823] 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;

[0824] 5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0825] 5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0826] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;

[0827] 5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0828] 5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0829] 5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0830] 5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0831] 5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0832] 4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0833] 5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine; 4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0834] 5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0835] 5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0836] 5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0837] 5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0838] 4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0839] 4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0840] 5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0841] 4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0842] 4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0843] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0844] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0845] 4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0846] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0847] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0848] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0849] 5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0850] 4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine;

[0851] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine;

[0852] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;

[0853] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0854] 4-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0855] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0856] 5-(1-methyl-1 H-pyrazol-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0857] 4-methoxy-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0858] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0859] 3-methyl-5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0860] 5-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0861] 5-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0862] 5-(1 H-pyrazol-1-yl)-1 ,2,3,6-tetrahydropyridine;

[0863] 3-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;

[0864] 4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0865] 3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0866] 5-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole; 3-(1 ,2,5,6-tetrahydropyridin- 3-yl)isothiazole; 5-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; and

[0867] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,3,4-thiadiazole, or a pharmaceutically acceptable salt thereof. . The pharmaceutical composition according to any one of the preceding items, wherein the compound is selected from the group consisting of: 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0868] 5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine;

[0869] 2-(5,6-dihydro-2H-1l2-pyridin-3-yl)furan-3-carbonitrile;

[0870] 5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine;

[0871] 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0872] 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0873] 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;

[0874] 5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0875] 5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0876] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;

[0877] 5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0878] 5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0879] 5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0880] 5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0881] 5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0882] 4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0883] 5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0884] 4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;

[0885] 5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0886] 5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0887] 5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0888] 5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0889] 4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0890] 4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0891] 5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;

[0892] 4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0893] 4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;

[0894] 2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0895] 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;

[0896] 4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; 5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0897] 5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;

[0898] 3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole; 5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;

[0899] 4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine; and 2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine, or a pharmaceutically acceptable salt thereof.

[0900] 257. The pharmaceutical composition according to any one of items 162 to256, wherein the composition further comprises one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0901] 258. The pharmaceutical composition according to any one of 162 to 256 for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAARI)-associated disorder.

[0902] Examples

[0903] Example 1: Preparation of compounds of Formula (I)

[0904] General synthetic procedures: All reagents were purchased from Fluorochem, Sigma- Aldrich, Enamine and Chemtronica. DCM, methanol, DMF, and acetonitrile (99.9%) were purchased from VWR International AB, whereas THF was purchased from Sigma- Aldrich. Reagents and solvents were used as such without further purification. All reactions involving air or moisture-sensitive reagents or intermediates were performed under a nitrogen atmosphere. Mainly LC / MS was used for monitoring reactions using an Agilent 1100 series HPLC having a C18 Atlantis T3 column (3.0 x 50 mm, 5 m). Acetonitrile-water (flow rate 0.75 mL / min over 6 min) was used as mobile phase and a Waters micromass ZQ (model code: MM1) mass spectrometer with electrospray ionization mode was used for detection of molecular ions. TLC (Merck, silica gel 60 F254 plates) was sometimes used for monitoring reactions, particularly in the purification of compounds. Visualization of the developed TLC was done using UV light (254 nm) and staining with ninhydrin or anisaldehyde stain. After workup, organic phases were dried over Na2SO4 / MgSC>4 and filtered before being concentrated under reduced pressure.1H and13C NMR spectra for the synthesized compounds were recorded at 298 K on an Agilent Technologies 400 MR spectrometer at 400 MHz or 100 MHz, respectively, or on Bruker Avarice Neo spectrometers at 500 / 600 MHz or 125 / 150 MHz, respectively. Chemical shifts are reported in parts per million (ppm, 5) and referenced to the residual1H resonance of the solvent (CD3OD 5 3.31) and the residual13C resonance of the solvent (CD3OD 5 49.0). Splitting patterns are designated as follows: s (singlet), d (doublet), t (triplet), m (multiplet) and br (broad). Coupling constants (J) are listed in hertz (Hz). Preparative reversed-phase HPLC was performed on a Kromasil C8 column (250 x 21.2 mm, 5 pm) on a Gilson HPLC equipped with a Gilson 322 pump, a UV / Visible- 156 detector and a 202 collector using acetonitrile-water gradients as eluents with a flow rate of 15 mL / min and detection at 210 or 254 nm.1H NMR spectroscopy (500 and 600 MHz) and LC / MS were used to determine the purity of the compounds which all had a purity >90%.

[0905] Procedure for Suzuki Coupling of 3-piperideine derivatives

[0906] R:H, Me

[0907] Briefly, compounds were synthesized starting from a N-Boc protected pinacol borane precursor (scheme above) using Suzuki coupling with heteroaryl bromides followed by Boc-deprotection by 4N HCI in dioxane.

[0908] General procedure: the mixture of the pinacol borane precursor (0.1 mmol, 1.3 eq, 31 mg), heteroaryl bromide (0.075 mmol, 1 eq), PdCldppf (2.5 mg, 0.05 eq), and Na2COs (16 mg, 2 eq) in dioxane: H2O (3:1 , v / v, 0.4 mL) was stirred at 100 °C for 2 hrs. After cooling and removal of solvent, the residue was dissolved in DMSO, filtered and purified by HPLC using 20-100% acetonitrile in H2O to afford the Boc-protected product. The later was dissolved in 4N HCI in dioxane (> 10 eq) and stirred at room temperature for 1 h. The solvent was then removed to afford desired product as a HCI salt or as formic acid salt after purification by hplc using 0-40% acetonitrile in H2O (H2O + 0.1 % formic acid). The following compounds (Table 1) were prepared according to the above general procedure:

[0909] Table 1. Compounds of formula (I) prepared according to the procedure of Example 1.

[0910] Example 2: Potencies of Compounds of Formula (I) at TAAR1 Materials and Methods

[0911] To investigate TAAR1 activation by compounds of formula (I), the following cell culture methods and G protein recruitment assay were utilised.

[0912] Cell culture: Expi293F cells were maintained in 8% CO2, 37 °C and 95% humidity and 125 mL shaking flasks (Corning) using Gibco Expi293 Expression Medium. HTLA cells were maintained in T175 flasks (Sarstedt) with Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS, GlutaMax, Sodium Pyruvate, HEPES, Non- Essential Amino Acids and Penicillin-Streptomycin. G-protein recruitment assay: A mammalian codon-optimized (GenSmart) human TAAR1 construct was engineered, featuring triple HA-tags and an additional 9 amino acids from the N-terminus of the beta2-adrenergic receptor on the N-terminus and a SmBiT linker on the C-terminus. Mini-Gas-393, tagged with LgBiT on the N-terminus and devoid of polyhistidine tags, was synthesized according to published sequences (Wan et al., 2018; Nehmea et al., 2017) at GenScript, and both constructs were inserted into a pcDNA 3.1+ backbone. Expi293F cells were transfected with vectors encoding LgBiT-tagged mini-Gas-393 and C-terminally SmBiT-tagged hTAARI at a gene ratio of 1:10, with a cDNA dose of 1 pg / mL, and cultured for 48 hours. Following transfection, cells were diluted to a total volume of 10 mL in Dulbecco's Phosphate Buffered Saline (dPBS), supplemented with 10 pM of coelenterazine-h (NanoLight), and then reseeded in solid white, 96-well plates (Corning) at 90 pL per well. Luminescence readings were acquired using SPARK 10M (Tecan, Sweden) for 5 minutes before compound addition to ensure signal stability. Compounds, diluted in 1X dPBS, were added at 10 pL per well, and luminescence was monitored for 10 minutes with a 100 ms read time per well. pEC50 values for Ulotaront and Ralmitaront were derived from Saarinen et al., 2022 and Agren et al., 2023. pEC50 values for ‘Wang compounds’ and ‘Merck compound’ were derived from Wang et al., 2023 and US5324723A, respectively.

[0913] Results

[0914] The potencies (pEC50 values) of compounds of formula (I) at TAAR1 are presented in Table 2. Example compound no. corresponds to that presented in Example 1. pEC50 values range from 5 to 7.7.

[0915] Compound example numbers 4, 24, 26, 27, 34, 36, 38, 40, 43, 44, and 47 exhibited improved potency for TAARI as compared with existing TAAR1 agonist; Ulotaront. Compound example numbers 3-5, 7, 9-13, 17-21, 23-27, 30-41, 43-48, 50-51 exhibited improved potency for TAAR1 as compared with existing TAAR1 agonist; Ralmitaront.

[0916] Compound example numbers 4-5, 7, 9-18, 20-21, 23-41, 43-48, 50-51 exhibited improved potency for TAAR1 as compared with existing TAAR1 agonists derived from Wang et al., 2023.

[0917] Compound example numbers 4-5, 7, 9-12, 17-18, 20-21, 24-27, 32, 34-41, 43-48, 50 exhibited improved potency for TAARI as compared with existing TAAR1 agonists derived from US5324723A. Table 2. The potencies, as defined by EC50 values, of example compounds of formula (I) at TAAR1. pEC50 values for Ulotaront and Ralmitaront were derived from Saarinen et al., 2022 and Agren et al., 2023. pEC50 values for ‘Wang compounds’ and ‘Merck compound’ were derived from Wang et al., 2023 and US5324723A, respectively.

[0918] Ref1 compound: Ulotaront (CAS Number Ref2 compound: Ralmitaront (CAS Number 2133417-13-5), racemic mixture of (2R)-2-(2-thienyl)morpholine and

[0919] (2S)-2-(2-thienyl)morpholine (also referred to herein as “Wang compounds”)

[0920] Ref4 compound: 3-[4-(2-Methyl-l, 3-thiazol)-yl]-l , 2, 5,6- tetrahydropyridine,

[0921] Conclusion

[0922] Compounds of Formula (I) exhibit improved potency compared with existing TAAR1 agonists Ulotaront and Ralmitaront.

[0923] Example 3: Multi-target Selectivity profile of Compounds of Formula (I)

[0924] Materials and Methods

[0925] Receptor activation by compounds 1 and 2 (as described in Table 1) at several aminergic receptors to determine compound selectivity was carried out using a modified version of the PRESTO-TANGO method. 5 pL of each TANGO-ized GPCR plasmid (10ng / pL, sourced via Addgene, Kit #1000000068) was spotted per well in 384-well plates (CulturPlate-384, White Opaque, PerkinElmer) using a liquid handling robot (Apricot S3, 610 SPT Labtech). Next, 5pL of polyethylenimine (PEI) derivative (Transporter™ 5, Polysciences) was added in a 1:4 cDNA to PEI ratio and incubated for 20 minutes at room temperature. The plate was then briefly spun down using a tabletop centrifuge. Following this, HTLA cells were washed twice with pre-warmed DPBS and then resuspended to 562 cells / pL in media consisting of FluoroBriteDMEM + 5% dialyzed FBS (One Shot™ format, Gibco™), 1% Penicillin-Streptomycin (10,000 11 / mL, Gibco™). Using an electronic multichannel pipette (E1-ClipTip, Thermo 618 Scientific™). Next, 40 pL of the cell resuspension was added to each well and incubated for 24h at 37 °C and 5% CO2 in a humidity chamber. After 24h of incubation, 5pL of compound to be tested (11x stock) was added with an electronic multichannel pipette and incubated for a further 16h at 37 °C and 5% CO2 in a humidity chamber. Following 16 hours of incubation with compound, 6 pL (1:10 dilution) of BrightGlo (Promega) was added. Luminescence signal was counted utilizing a plate-reader (SPARK, Tecan) with an integration time of 100 ms and a 100 ms pause between well readings. In subsequent concentration-response curve assessments, HTLA cells were transfected while suspended in media at a concentration of 1 pg cDNA / mL and 562 cells / pL. Each well of white 384-well plates received 50 pL of this suspension and was then incubated for 24 hours before being stimulated with compounds for 16 hours. For the antagonist mode, cells were pretreated with compounds for 15 minutes prior to the addition of an agonist concentration approximately corresponding to its EC80 at the receptor, determined experimentally in advance.

[0926] Results

[0927] Compounds 1 and 2 demonstrated promising selectivity profiles wherein agonism was observed agonism at 5-HT1 D, a2A, and D2 receptors (Figure 1A). Compound 1 exhibited agonist activity at the H1 receptor (70%) and activated several members of the muscarinic acetylcholine receptor family, such as the M2 receptor (55%). Specifically, potency evaluations were conducted on four aminergic receptors, including the D2 receptor (Figure 1 B). Both compounds 1 and 2 displayed activity at the D2 receptor (with Emax values of 54% and 59%, respectively). However, a low potency was observed (with pEC50 values <6 compared to the reference agonist quinpirole, which had a pEC50 of 9.0). Activity was also observed at the 5-HT 1 D receptor (with Emax values of 52% and 75% for compounds 1 and 2, respectively, with pEC50 < 6 for both. Compound 2 acted as a full agonist of the a2A receptor with low potency (pEC50 = 6.0, Emax = 110%), while compound 1 exhibited poor potency agonism at the M2 receptor (pEC50 = 5.0, Emax = 125%).

[0928] Conclusion

[0929] The compounds of the invention exhibit a multi-target selectivity profile for aminergic GPCRs. Example 4: In vivo efficacy and antipsychotic-like activity of compound Compounds of Formula (I)

[0930] Materials and Methods

[0931] Male and female mice (C57BL / 6), aged between 3-4 months for prepulse inhibition (PPI) experiments and 3-6 months for other tests, were employed. Distinct cohorts were used for various behavioural / physiological assessments, with separate groups for open field, core body temperature (CBT), and PPI tests, while repeated measures within individuals were applied for different treatment or dosage conditions. Housing maintained a stable environment (20°C, 53% humidity, 12-hour light / dark cycle), with ad libitum access to food and water, and experiments conducted during the light phase.

[0932] Compound preparation and dosing adhered to standardized procedures. Compounds (2, 35, 33, 30, 28, 29) were dissolved in 5% DMSO in saline and administered at doses ranging from 0.1 to 5 mg / kg, as specified. Risperidone (0.2 mg / kg for PPI tests, and 0.03 mg / kg for open field test (OFT)) and MK-801 hydrogen maleate (0.35mg / kg) were prepared similarly. Injection volumes were 10 ml / kg, administered intraperitoneally (i.p.).

[0933] CBT was monitored using rectal thermoprobes. Basal measurements were recorded before i.p. administration, with subsequent readings taken at 30-minute intervals over 2 hours. A one-week washout period between doses of compound 2 was observed, with injections initiated at the lowest dose.

[0934] PPI measurements utilized startle response chambers equipped with sound isolation features and Plexiglass animal enclosures. These chambers were equipped with a loudspeaker capable of emitting white noise and varied acoustic pulses. To minimize stress, the enclosures were designed to allow freedom of movement for the animals. Startle responses were captured by piezoelectric transducers and transformed into analog signals. Prior to experiments, calibration of transducers and speakers was conducted. Mice were habituated to the chambers over multiple sessions, including exposure to background white noise. PPI measurements were conducted across four sessions, with a randomized treatment order. Animals underwent habituation in the testing room before injections of compound 2, risperidone, or vehicle, followed by a five-minute background noise habituation period. The test session comprised four blocks of trials, each containing various trial types presented in a pseudorandomized order. Trial types included pulse-only, NOSTIM, and prepulse trials of different intensities. The test session concluded after 23 minutes, encompassing 60 trials in total. PPI data are represented as PPI %, calculated as [1 - (prepulse trials / startle-only trials)]*100. To determine the mean PPI, the average PPI% for all prepulse intensities (3, 6,12dB) was summed and divided by the number of prepulse intensities).

[0935] For OFT, mice underwent testing over four sessions spaced 96 hours apart. The initial session served as a mock test, with all mice receiving a vehicle injection to mitigate novelty effects in subsequent sessions. The following three sessions were true test sessions, where mice were pretreated with compound 2, risperidone, or vehicle, followed by MK-801. Treatment order across sex, genotype, and test session was randomized. After i.p. injection of compound 2 (1 mg / kg), risperidone, or vehicle, mice were immediately placed in the open field and recorded for 15 minutes. Subsequently, they received an i.p. injection of MK-801 and were recorded for an additional 60 minutes. The open field arena measured 46 x 46 cm with grey floor and walls, and the center brightness ranged from 30 to 50 lux. Between each animal, the arenas were cleaned with 70% ethanol. Video footage captured by a ceiling-mounted camera was analyzed using EthoVision XT11.5 software from Noldus.

[0936] Results

[0937] Due to the very strong potency in our in vitro assays, we conducted CBT measurements in mice at varying doses of compound 2 (0.1 , 0.5, and 1 mg / kg), (Figure 2A). Compound 2 elicited a decrease in CBT at doses of 0.5 and 1 mg / kg, peaking 30 minutes post-injection. Baseline was reached 2 hours after injection (Figure 2B). The reduction (~1°C) observed was statistically significant at both 30- and 60-minute intervals post-injection (Figure 2C). Therefore, we proceeded with compound 2 in behavioural assays at a dose of 1 mg / kg. Similarly, as compounds 35, 33, 30, 28 were tested for their ability to reduce CBT in TAAR1-WT mice at a dose of 1mg / kg. Similar to compound 2, all compounds were able to exert a reduction in CBT in TAAR1-WT mice.

[0938] To evaluate if compound 2 could exhibit antipsychotic-like effects, experiments utilizing the PPI behavioural assay we conducted, in aim to determine if compound 2 could increase sensorimotor gating (Figure 2D). Treatment with compound 2 increased PPI at both 3 and 6 dB pre-pulse levels (Figure 2E), similar to the atypical antipsychotic risperidone. Additionally, augmentation in overall PPI compared to the vehicle control was observed using either compound 2 or risperidone (Figure 2F).

[0939] Similarly, the locomotor effects of the compound were evaluated. Measurements of locomotion in mice pretreated with vehicle, compound 2, or risperidone before (baseline) and after treatment with the NMDA receptor antagonist MK-801 8 (Figure 2G) were conducted. A significant reduction in baseline locomotion was observed with risperidone and compound 2 (Figure 2H). Additionally, both compound 2 and risperidone treatment led to a significant decrease in MK-801-induced hyperlocomotion (Figure 2I).

[0940] Conclusion

[0941] Compound 2 exhibits antipsychotic-like therapeutic effects in vivo. Likewise, compounds 35, 33, 30, 28 exhibit TAAR1 agonism in vivo.

[0942] References

[0943] Wan Q, Okashah N, Inoue A, Nehme R, Carpenter B, Tate CG, et al. Mini G protein probes for active G protein-coupled receptors (GPCRs) in live cells. J Biol Chem. 2018;293:7466-7473.

[0944] Nehmea R, Carpenter B, Singhal A, Strege A, Edwards PC, White CF, et al. Mini-G proteins: Novel tools for studying GPCRs in their active conformation. PLoS One. 2017;12:1-26.

[0945] Halff EF, Rutigliano G, Garcia-Hidalgo A, Howes OD. Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders. Trends Neurosci. 2023;46:60-74.

[0946] M. D. Berry, R. R. Gainetdinov, M. C. Hoener, M. Shahid, Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges. Pharmacol. Ther. 180, 161-180 (2017).

[0947] I. Mantas, T. Vallianatou, Y. Yang, M. Shariatgorji, M. Kalomoiri, E. Fridjonsdottir, M. J. Millan, X. Zhang, P. E. Andren, P. Svenningsson, TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition. Biol. Psychiatry 90, 16-27 (2021).

[0948] S. T. Szabo, S. C. Hopkins, R. Lew, A. Loebel, T. Roth, K. S. Koblan, A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy. Sleep Med. 107, 202-211 (2023).

[0949] S. H. Isaacson, M. Goldstein, R. Pahwa, C. Singer, K. Klos, M. Pucci, Y. Zhang, D. Crandall, K. S. Koblan, B. Navia, for the Parkinson’s Psychosis TAAR1 Study Group, Ulotaront, a Trace Amine-Associated Receptor 1 / Serotonin 5-HT 1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study. Neurol. Clin. Pract. 13, e200175 (2023).

[0950] K. S. Koblan, J. Kent, S. C. Hopkins, J. H. Krystal, H. Cheng, R. Goldman, A. Loebel, A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia. N. Engl. J. Med. 382, 1497-1506 (2020).

[0951] Nair PC, Miners JO, McKinnon RA, Langmead CJ, Gregory KJ, Copolov D, et al. Binding of SEP-363856 within TAAR1 and the 5HT 1 A receptor: implications for the design of novel antipsychotic drugs. Mol Psychiatry. 2022;27:88-94.

[0952] Agren R, Betari N, Saarinen M, Zeberg H, Svenningsson P, Sahlholm K. In Vitro Comparison of Ulotaront (SEP-363856) and Ralmitaront (RO6889450): Two TAAR1 Agonist Candidate Antipsychotics. Int J Neuropsychopharmacol. 2023 Sep 25;26(9):599-606. doi: 10.1093 / ijnp / pyad049.

[0953] Saarinen, M., Mantas, I., Flais, I. et al. TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1 / 5-HT1A receptor agonist SEP-363856. Neuropsychopharmacol. 47, 2319-2329 (2022).

[0954] Wang et al. Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment. Frontiers in Pharmacology. 14, 1663-9812 (2023).

Claims

Claims1. A compound of Formula (I):Formula (I) whereinR1is H, C1-4 alkyl, CH2F, CHF2, or CF3;R3is H, C1-4 alkyl or cyclopropyl;R2is phenyl substituted with one or more independently selected R4, or a 5- or 6-membered heteroaryl selected from the group consisting of• furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl,1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol- 4-yl, pyrazol-3-yl, pyrazol-1-yl, pyrimidin-2-yl each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• thiazol-2-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and• oxazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; andR4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, provided that the compound is not selected from the group consisting of:3-(3,4-dimethoxyphenyl)-1 ,2,5,6-tetrahydropyridine;3-(3-methoxyphenyl)-1 ,2,5,6-tetrahydropyridine;1-methyl-3-[4-(2-methyl-1,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine; and3-[4-(2-methyl-1 ,3-thiazol)-yl]-1 ,2,5,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or alleviation of a trace amine-associated receptor 1 (TAAR1)- associated disorder.isothiazol-5-yl,1 ,2,4-thiadiazol-5-yl, 1,2,5- thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol-4-yl, pyrazol-1-yl,pyrazol-3-yl, pyrimidin-2-yl, or oxazol-4-yl.

3. The compound for use according to claim 1 , whereinR1is H, C1-4 alkyl, CH2F, CHF2, or CF3;R3is H, Me or cyclopropyl;R2is a 5- or 6-membered heteroaryl selected from the group consisting of• furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, or pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• thiazol-2-yl or thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• thiazol-4-yl which is optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2.3alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and• pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

4. The compound for use according to claim 3, wherein R2is furan-2-yl, furan-3-yl,5. The compound for use according to claim 1 , wherein R2is phenyl substituted with one or more R4, and wherein R4is independently selected from the group consisting of C1-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN, with the proviso that said phenyl is not substituted with methoxy in the meta position.

6. The compound for use according to claim 5, wherein R2is 2-fluorophenyl, 2- chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, or 4-chlorophenyl.

7. The compound for use according to any one of the preceding claims, wherein R1is H or Me, and R3is H, Me, or Et.

8. The compound for use according any one of the preceding claims, wherein R3is H.

9. The compound for use according to any one of the preceding claims, wherein the compound is selected from the group consisting of: 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(furan-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;2-(5,6-dihydro-2H-1 l2-pyridin-3-yl)furan-3-carbonitrile;5-(furan-2-yl)-1-methyl-1 ,2,3,6-tetrahydropyridine; 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine;4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;2-(1,2,5,6-tetrahydropyridin-3-yl)thiazole;2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;2-methyl-4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine;2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine;5-phenyl-1,2,3,6-tetrahydropyridine;4.5-dimethyl-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;4.5-dimethyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;4-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;5-(1-methyl-1 H-pyrazol-3-yl)-1 ,2,3,6-tetrahydropyridine;4-methoxy-2-(4-methyl-1,2,5,6-tetrahydropyridin-3-yl)thiazole;5-methyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;3-methyl-5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;5-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;5-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;5-(1 H-pyrazol-1-yl)-1 ,2,3,6-tetrahydropyridine;3-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;5-methyl-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;4-cyclopropyl-2-(4-methyl-1,2,5,6-tetrahydropyridin-3-yl)thiazole;2-cyclopropyl-5-(4-methyl-1,2,5,6-tetrahydropyridin-3-yl)thiazole;5-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;3-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;5-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;2-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,3,4-thiadiazole;5-(2-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;5-(3-fluorophenyl)-1 ,2,3,6-tetrahydropyridine;5-(4-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;5-(3-chlorophenyl)-1 ,2,3,6-tetrahydropyridine;5-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyridine; and 5-(2-fluorophenyl)-1 ,2,3,6-tetrahydropyridine, or a pharmaceutically acceptable salt thereof.

10. The compound for use according to any one of the preceding claims, wherein the disease or disorder is selected from the group comprising a mental disease or disorder, a cognitive disease or disorder, a neurological disease or disorder, a psychiatric disease or disorder, a neurodegenerative disease or disorder, and a substance-related and / or addictive disorder.11 . The compound for use according to any one of the preceding claims, wherein the disease or disorder is a neurological disease or disorder and / or a psychiatric disease or disorder and / or a neurodegenerative disease or disorder.

12. The compound for use according to any one of the preceding claims, wherein the disease or disorder is selected from the group comprising: Schizophrenia, Psychosis, Psychosis in Schizophrenia, psychosis in neurodegenerative diseases, Psychosis in Dementia with Lewy Bodies, Psychosis in Alzheimer’s disease, Psychosis in Parkinson’s disease, Psychosis in frontotemporal dementia, Psychosis in vascular dementia, Psychosis in Huntington’s disease, Bipolar disorder, Major depressive disorder, anxiety, generalized anxiety disorder, stress-induced disorder, Attention deficit hyperactive disorder (ADHD), autism spectrum disorder, obsessive-compulsive disorder, L-dopa-induced dyskinesias in Parkinson’s disease, Chorea in Huntington’s disease, Nicotine abuse, Cocaine abuse, Amphetamine abuse, Opioid abuse, Alcohol abuse, Sleep disorders, Excessive daytime sleepiness, narcolepsy, cataplexy, idiopathic hypersomnia, shift work sleep disorder, Fatigue, REM sleep behavioural disorder (RBD).

13. A pharmaceutical composition comprising a compound of Formula (I):Formula (I) whereinR1is H, Ci-4alkyl, CH2F, CHF2, or CF3;R3is H, Me or cyclopropyl; andR2is a 5- or 6-membered heteroaryl selected from the group consisting of• furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,3,4-thiadiazol-2-yl, pyrazol- 4-yl, pyrazol-3-yl, pyrazol-1-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and• pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 13, whereinR1is H, C1-4 alkyl, CH2F, CHF2, or CF3;R3is H, Me or cyclopropyl; andR2is a 5- or 6-membered heteroaryl selected from the group consisting of• furanyl, thienyl, isothiazol-3-yl, isothiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, or pyrazol-4-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN;• oxazol-4-yl optionally substituted with one or more substituents each independently selected from the group consisting of C2-3 alkyl, cyclopropyl, C1-3 alkoxy, CH2F, CHF2, CF3, F, Cl, Br, and CN; and• pyrimidin-2-yl optionally substituted with one or more substituents each independently selected from the group consisting of C1-3 alkyl, and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 14, wherein R2is furan-2-yl,16. The pharmaceutical composition according to any one of claims 13 to 15, wherein R1is H or Me, and R3is H or Me.

17. The pharmaceutical composition according to claim 13, wherein the compound is selected from the group consisting of: 5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(furan-2-yl)-4-methyl-1,2,3,6-tetrahydropyridine; 2-(5,6-dihydro-2H-1 l2-pyridin-3-yl)furan-3-carbonitrile;5-(furan-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine; 1-ethyl-5-(furan-2-yl)-1 ,2,3,6-tetrahydropyridine; 5-(furan-3-yl)-1 ,2,3,6-tetrahydropyridine; 4-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)oxazole;5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(4-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiophene-3-carbonitrile;5-(5-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(3-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(5-bromothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(3-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(3-chlorothiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(thiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(4-fluorothiophen-2-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(5-methylthiophen-2-yl)-1 ,2,3,6-tetrahydropyridine;5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;5-(2-chlorothiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(thiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(2-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;5-(2-chlorothiophen-3-yl)-4-methyl-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(5-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;4-methyl-5-(4-methylthiophen-3-yl)-1 ,2,3,6-tetrahydropyridine;2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;4-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;5-methyl-3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;4-methyl-5-(1 H-pyrazol-4-yl)-1 ,2,3,6-tetrahydropyridine;2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyrimidine;3-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;4-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;5-(1-methyl-1 H-pyrazol-3-yl)-1 ,2,3,6-tetrahydropyridine;4-methoxy-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;3-methyl-5-(1 ,2,5,6-tetrahydropyridin-3-yl)isothiazole;5-chloro-2-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;5-chloro-2-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; 5-(1 H-pyrazol-1-yl)-1 ,2,3,6-tetrahydropyridine;3-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,5-thiadiazole;4-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole;3-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole;5-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,2,4-thiadiazole; 3-(1 ,2,5,6-tetrahydropyridin- 3-yl)isothiazole;5-(1 ,2,5,6-tetrahydropyridin-3-yl)thiazole; and2-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 ,3,4-thiadiazole, or a pharmaceutically acceptable salt thereof.

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