neurodegenerative diseases Technical Field

The present invention belongs to the field of pharmaceutical industry and relates to novel inhibitors of monoamine oxidase B (MAO-B) for the treatment of acute and chronic diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, to the preparation of these compounds and pharmaceutical products that contain these compounds. The characteristic of these compounds is that they bind into the active site through specific noncovalent (polar and hydrophobic interactions) and/or covalent interactions.

Technical Problem

There is a need for novel drugs for the treatment of neurodegenerative diseases due to the lack of efficacy and safety reasons of the current therapy. One of the validated and promising targets for the development of new drugs for the aforementioned therapeutic indications represents the enzyme monoamine oxidase B (MAO-B). The field of present invention is the discovery of new drugs with azetidine, pyrrolidine, piperidine and azepane scaffold that are active as selective reversible or irreversible inhibitors of MAO-B.

Background Art

Amine oxidases are the enzymes, which catalyze the oxidative deamination of numerous biologically important amines to aldehyde, hydrogen peroxide and ammonia (Mondovi B and Finazzi A, 1985). According to the nature of the prosthetic group, which takes part in the catalytic cycle, we subdivide them into flavine- dependent and copper-dependent amine oxidases. To the flavine-dependent amine oxidases, which possess covalenty bound flavin adenine dinucleotide (FAD), belong monoamine oxidases (MAO, EC 1 .4.3.4) that are located in the outer mitochondrial membrane (Mondovi B and Finazzi A, 1985). MAO belong to the family of oxidoreductases and have an important role in regulation and metabolism of neurotransmitters that contain amine group (serotonin, noradrenaline, dopamine, histamine) in peripheral tissues and the central nervous system. Two isoforms of MAO are present in humans (MAO-A and MAO-B), which differs in amino acid sequences, three-dimensional structures, distributions in tissue and organs, inhibitor sensitivities and substrate specificity (Cai Z, Mol Med Rep, 2014, 9, 1533-1541 ). Both isozymes are found in and outside of the central nervous system (CNS). MAO-A preferentially catalyzes the oxidative deamination of serotonin, adrenaline, and noradrenaline, whereas MAO-B deaminates preferentially β-phenethylamine and benzylamine (Carradori S, J Med Chem, 2015, 58, 6717- 6732). The unique location of MAO in CNS and peripheral tissues enables modulation of the functions of different neurotransmitters in association with various conditions, including mood disorders, anxiety and depression, schizophrenia, attention deficit hyperactivity disorder, migraine, sexual maturation and neurodegenerative diseases (Cai Z, Mol Med Rep, 2014, 9, 1533-1541 ).

MAO-B comprises about 80% of the total MAO activity in the human brain and is the predominant isozyme in the striatum (Riederer P, NeuroToxicology, 2004, 25, 271- 277). In contrast to MAO-A, which is in CNS the most abundant in catecholaminergic neurons, MAO-B is predominantly found in serotonergic and histaminergic neurons and glial cells (Shih JC, Annu Rev Neurosci 1999, 22, 197-217), and in trombocytes in peripheral tissues. The activity of MAO-B in human body increases with aging, which might be related to the proliferation of glia cells (Shih JC, Annu Rev Neurosci 1999, 22, 197-217). The active site consists of two separate cavities, an entrance and a substrate cavity, that are separated by the side chain of lle-199; however, in the presence of larger ligands, the lle-199 adopts an alternate conformation, which enables the fusion of both cavities (Singh R, Chem Biol Lett, 2014, 1 , 33-39). MAO- B preferentially oxidizes phenethylamine, and also uses dopamine and tyramine as substrates irrespective of their concentration. Several studies have shown the connection between MAO-B enzyme and neuropsychiatric/neurodegenerative disorders, personality traits, type II alcoholism, borderline personality disorders, aggressiveness and violence, obsessive-compulsive disorder, depression, suicides, schizophrenia, anorexia, migraine, dementia, Alzheimer's disease and Parkinson's disease, therefore, MAO-B represents an attractive target for the treatment of numerous diseases. (Carradori S, J Med Chem, 2015, 58, 6717-6732). Selegiline and rasagiline are selective and irreversible inhibitors of MAO-B. Moreover, the enzymatic activity is also inhibited by several other compounds - chalcones, pyrazole derivatives, chromones, coumarins, xanthines, thiazolidindiones, isatines, (thiazol-2- yl)hydrazones and their analogs, hydrazones, hydrazothiazoles, phthalimides, and derivatives of 8-phenoxymethylcaffeine (Carradori S, J Med Chem, 2015, 58, 6717- 6732; Kumar B, RSC Adv, 2016, 6, 42660^12683). Among reversible inhibitors it is worth to mention lazabemide as antiparkinsonic, and safinamide for the treatment of CNS disorders, particularly Parkinson's disease, epilepsy, Alzheimer's disease, depression, restless legs syndrome and migraine (Asthon A, Pain: New Insights for the Healthcare Professional, 2013). The main therapeutic indications of MAO-B inhibitors from the literature are: Parkinson's disease (Riederer Z, Exp Neurobiol, 201 1 , 20, 1-17), Alzheimer's disease (Cai Z, Mol Med Rep. 2014, 9, 1533-1541 ), Huntington's disease (Ooi J, Mol Neurobiol, 2015, 52, 1850-1861 ), and amyotrophic lateral sclerosis.

The main structural feature of irreversible MAO-B inhibitors is /V-propargylamine group, which is present in therapeutic drugs and potential drugs in clinical studies, namely rasagiline, selegiline, ladostigil, pargyline (Kumar B et al. RSC Adv., 2016, 6, 42660-42683).

Solution to Problem

The present invention relates to compound of Formula (I)

(I) wherein: n: 1-5 m: 0, 1 , or 2 z: 0 or 1

L: -CH2CH2-, -CH ₂ -, =CH ₂ -, =CH ₂ CH ₂ -, ^trans

A: is saturated 3 to 8-membered ring optionally comprising one or more heteroatoms selected from N, O, S, and P; the ring being optionally substituted with one or more substituents independently selected from R ¹ , wherein:

R ¹ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , SR ² , OR ² , NR ² R ³

R ² : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ³ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu, is phenyl, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, pyridine, indole, quinoline, isoquinoline, 2,3.dihydrobenzo[i ][1 ,4]dioxine, benzo[c/][1 ,3]dioxole, indazole, bezimidazole, quinazoline, naphthalene,

R ¹ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ² : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ³ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷ R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁴ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷ R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁵ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu, R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu.

According to certain embodiments, n is 1 -5. According to certain embodiments, n is 1 -4. According to certain embodiments n is 1 -3. According to certain embodiments n is 1 or 2. According to certain embodiments, n is 1 . According to certain embdoments, n is 2. According to certain embodiments, n is 3. According to certain embodiments, n is 4. According to certain embodiments, n is 5.

According to certain embodiments, m is 0. According to certain embodiments, m is 1 . According to certain embodiments, m is 2.

According to certain embodiments z is 0. According to certain embodiments z is 1 .

According to certain embodiments, m is 1 and z is 1 . According to certain embodiments, n is 1 , m is 1 and z is 1 . According to certain embodiments, n is 2, m is 1 and z is 1 .

According to certain embodiments, L is -CH ₂ CH ₂ - or ^trans . According to certain embodiments, L is -CH ₂ CH ₂ -. According to certain embodiments, L is -CH ₂ -. According to certain embodiments, L is =CH ₂ -. According to certain embodiments, L is =CH ₂ CH ₂ -. According to certain embodiments, L is ^trans According to certain embodiments, A is saturated 3 to 8-membered ring optionally comprising one or more heteroatoms selected from N, O, S, and P; the ring being optionally substituted with one or more substituents independently selected from R ¹ , wherein:

R ¹ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , SR ² , OR ² , NR ² R ³ R ² : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu, R ³ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu.

According to certain embodiments, R ¹ is Me, i-Pr, CN, F, CI, Br or CF ₃ . According to some embodiments, R ¹ is Me. According to some embodiments, R ¹ is Et. According to some embodiments, R ¹ is i-Pr. According to some embodiments, R ¹ is t-Bu.

According to some embodiments, R ¹ is CN, F, CI, Br or CF ₃ . According to some embodiments, R ¹ is F, CI, Br or CF ₃ . According to some embodiments, R ¹ is F or CF ₃ .

According to some embodiments, R ¹ is F, CI or Br. According to some embodiments, R ¹ is F. According to some embodiments, R ¹ is CI.According to some embodiments,

R ¹ is Br. According to some embodiments, R ¹ is CF ₃ .

According to some embodiments, R ¹ is SR ² , wherein R ² is H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu.

According to some embodiments, R ¹ is OR ² , wherein R ² is H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu.

According to some embodiments, R ¹ is NR ² R ³ , wherein R ² is H, Me, Et, n-Pr, i-Pr, t- Bu or i-Bu, and R ³ is H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu.

According to certain embodiments, A is phenyl. According to certain embodiments, A is furan. According to certain embodiments, A is thiophene. According to certain embodiments, A is pyrrole. According to certain embodiments, A is pyrazole. According to certain embodiments, A is imidazole. According to certain embodiments, A is thiazole. According to certain embodiments, A is oxazole. According to certain embodiments, A is pyridine. According to certain embodiments, A is indole. According to certain embodiments A is quinoline. According to certain embodiments, A is isoquinoline. According to certain embodiments, A is 2,3.dihydrobenzo[i ][1 ,4]dioxine. According to certain embodiments, A is benzo[c/][1 ,3]dioxole. According to certain embodiments, A is indazole. According to certain embodiments, A is bezimidazole. According to certain embodiments, A is quinazoline. According to certain embodiments, A is naphthalene.

A compound according to the present invention may be a compound selected from the group consisting of:

According to certain embodiments, the compound of the present invention is a compound selected is from the group consisting of:

According to one embodiment, the compound of the present invention is (has the following structure

According to one embodiment, the compound of the present invention is (has the following structure)

According to one embodiment, the compound of the present invention is (has the following structure)≡—* ^

According to one embodiment, the compound of the present invention is has the

following structure

According to one embodiment, the compound of the present invention is has the following structure) According to a particular aspect, the present invention provides a compound of general Formula (I)

(I)

wherein:

n: 1-5;

m: 0, 1 , or 2;

z: 0 or 1 :

L: -CH2CH2-, -CH2-, =CH ₂ -, =CH ₂ CH ₂ - or ^trans ; and

, wherein

R ¹ : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ or NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu;

R ² : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ or NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu; R ³ : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ or NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu;

R ⁴ : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ or NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, or i-Bu; and

R ⁵ : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ or NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu or i-Bu.

According to certain embodiments, A is

According to certain embodiments, A is

According to certain embodiments, A is

R ¹ : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl or OCH _2;

R ² : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl or OCH _2; R ³ : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl or OCH _2;

R ⁴ : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl or OCH _2; and R ⁵ : H, OH, Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , CONH ₂ , cyclopropyl, cyclobutyl, cyclopentyl or OCH ₂ .

According to some embodiments, R ¹ is H. According to some embodiments, R ¹ is OH.

According to some embodiments, R ¹ is Me. According to some embodiments, R ¹ is Et. According to some embodiments, R ¹ is i-Pr. According to some embodiments, R ¹ is t-Bu. According to some embodiments, R ¹ is i-Bu. According to some embodiments, R ¹ is CN. According to some embodiments, R ¹ is F. According to some embodiments, R ¹ is CI. According to some embodiments, R ¹ is Br. According to some embodiments, R ¹ is CF3. According to some embodiments, R ¹ is CH ₂ CF ₂ . According to some embodiments, R ¹ is CONH ₂ . According to some embodiments, R ¹ is cyclopropyl. According to some embodiments, R ¹ is cyclobutyl. According to some embodiments, R ¹ is cyclopentyl. According to some embodiments, R ¹ is OCH ₂ .

According to some embodiments, R ² is H. According to some embodiments, R ² is OH. According to some embodiments, R ² is Me. According to some embodiments, R ² is Et. According to some embodiments, R ² is i-Pr. According to some embodiments, R ² is t-Bu. According to some embodiments, R ² is i-Bu. According to some embodiments, R ² is CN. According to some embodiments, R ² is F. According to some embodiments, R ² is CI. According to some embodiments, R ² is Br. According to some embodiments, R ² is CF3. According to some embodiments, R ² is CH ₂ CF ₂ . According to some embodiments, R ² is CON H ₂ . According to some embodiments, R ² is cyclopropyl. According to some embodiments, R ² is cyclobutyl. According to some embodiments, R ² is cyclopentyl. According to some embodiments, R ² is OCH ₂ .

According to some embodiments, R ³ is H. According to some embodiments, R ³ is OH. According to some embodiments, R ³ is Me. According to some embodiments, R ³ is Et. According to some embodiments, R ³ is i-Pr. According to some embodiments, R ³ is t-Bu. According to some embodiments, R ³ is i-Bu. According to some embodiments, R ³ is CN. According to some embodiments, R ³ is F. According to some embodiments, R ³ is CI. According to some embodiments, R ³ is Br. According to some embodiments, R ³ is CF ₃ . According to some embodiments, R ³ is CH ₂ CF ₂ . According to some embodiments, R ³ is CON H ₂ . According to some embodiments, R ³ is cyclopropyl. According to some embodiments, R ³ is cyclobutyl. According to some embodiments, R ³ is cyclopentyl. According to some embodiments, R ³ is OCH ₂ .

According to some embodiments, R ⁴ is H. According to some embodiments, R ⁴ is OH. According to some embodiments, R ⁴ is Me. According to some embodiments, R ⁴ is Et. According to some embodiments, R ⁴ is i-Pr. According to some embodiments, R ⁴ is t-Bu. According to some embodiments, R ⁴ is i-Bu. According to some embodiments, R ⁴ is CN. According to some embodiments, R ⁴ is F. According to some embodiments, R ⁴ is CI. According to some embodiments, R ⁴ is Br. According to some embodiments, R ⁴ is CF3. According to some embodiments, R ⁴ is CH ₂ CF ₂ . According to some embodiments, R ⁴ is CONH ₂ . According to some embodiments, R ⁴ is cyclopropyl. According to some embodiments, R ⁴ is cyclobutyl. According to some embodiments, R ⁴ is cyclopentyl. According to some embodiments, R ⁴ is OCH ₂ .

According to some embodiments, R ⁵ is H. According to some embodiments, R ⁵ is OH. According to some embodiments, R ⁵ is Me. According to some embodiments, R ⁵ is Et. According to some embodiments, R ⁵ is i-Pr. According to some embodiments, R ⁵ is t-Bu. According to some embodiments, R ⁵ is i-Bu. According to some embodiments, R ⁵ is CN. According to some embodiments, R ⁵ is F. According to some embodiments, R ⁵ is CI. According to some embodiments, R ⁵ is Br. According to some embodiments, R ⁵ is CF ₃ . According to some embodiments, R ⁵ is CH ₂ CF ₂ . According to some embodiments, R ⁵ is CONH ₂ . According to some embodiments, R ⁵ is cyclopropyl. According to some embodiments, R ⁵ is cyclobutyl. According to some embodiments, R ⁵ is cyclopentyl. According to some embodiments, R ⁵ is OCH ₂ .

According to certain embodiments, A is mono-substituted, such as at position R ² or R ³ (the remaining positions are each H).

According to certain embodiments, A is di-subsituted, such as at positions R ¹ and R ³ (the remaining positions are each H). According to certain embodiments, A is tri-subsituted, such as at positions R ¹ ,R ³ and R ⁴ (the remaining positions are each H).

According to some embodiments, R ¹ , R ² , R ⁴ and R ⁵ are each H, and R ³ is Me, Et, i- Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , cyclopropyl, cyclobutyl, cyclopentyl or OCH ₂ . According to some embodiments, R ¹ , R ² , R ⁴ and R ⁵ are each H, and R ³ is Me, i-Pr, CN, F, CI, Br, CF ₃ or cyclopropyl.

According to some embodiments, n is 1 -5. According to some embodiments, n is 1 -4. According to some embodiments n is 1 -3. According to some embodiments n is 1 or 2. According to some embodiments, n is 1 . According to some embdoments, n is 2. According to some embodiments, n is 3. According to some embodiments, n is 4. According to some embodiments, n is 5.

According to some embodiments, m is 0. According to some embodiments, m is 1 . According to some embodiments, m is 2.

According to some embodiments z is 0. According to some embodiments z is 1 . According to some embodiments, m is 1 and z is 1 .According to some embodiments, n is 1 , m is 1 and z is 1 . According to some embodiments, n is 2, m is 1 and z is 1 .

According to some embodiments, L is -CH ₂ CH ₂ - or ^trans . According to some embodiments, L is -CH ₂ CH ₂ -.According to some embodiments, L is -CH ₂ -. According to some embodiments, L is =CH ₂ -. According to some embodiments, L is =CH ₂ CH ₂ -. According to some embodiments, L is

Some compounds from this invention possess stereogenic center with an absolute configuration of R or S, where the compounds can appear in a racemic form, in a form of conglomerate or in a form of pure enantiomers.

The invention further relates to the pharmaceutically acceptable salts, hydrates and solvates of the compounds with the general Formula (I). The invention further relates to the use of the compounds with the general Formula (I) as active pharmaceutical ingredients for the preparation of medicaments. Compounds with the general Formula (I) are inhibitors of MAO-B enzyme and are used for the diagnostics, prevention, alleviation of symptoms and treatment of acute and chronic neurological disorders, cognitive and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease and dementia.

The invention is related to parenteral, oral, or other pharmaceutically acceptable forms containing the compounds with the general Formula (I). Beside active pharmaceutical ingredient, the pharmaceutical composition can contain excipients suitable for the intended route of administration. Pharmaceutical compositions are prepared using standard procedures. Pharmaceutical compositions can be prepared in the way that ensures the sustained and prolonged release of the active pharmaceutical ingredient. The dose, frequency, and way of use depend on several factors, which further depend on the active pharmaceutical ingredient used, its pharmacokinetic and pharmacodynamic properties and the condition of the patient.

According to certain embodiments, a compound of the present invention is used in the preparation of a medicament.

According to certain embodiments, a compound of the present invention is for use as a medicament.

According to some embodiments, a compound of the present invention is for use in the prevention, alleviation of symptoms or treatment of a medical condition selected from the group consisting of acute and chronic neurological disorders, cognitive and neurodegenerative diseases. According to some embodiments, a compound of the present invention is for use in the prevention, alleviation of symptoms or treatment of a neurodegenerative disease, such as Parkinson's disease, Alzheimer's disease, Huntington's disease or dementia.

According to some embodiments, a compound of the present invention is for use in the prevention, alleviation of symptoms or treatment of Parkinson's disease, Alzheimer's disease, Huntington's disease or dementia. According to some embodiments, a compound of the present invention is for use in the prevention, alleviation of symptoms or treatment of Parkinson's disease.

According to some embodiments, a compound of the present invention is for use in the prevention, alleviation of symptoms or treatment of Alzheimer's disease According to some embodiments, a compound of the present invention is for use in the prevention, alleviation of symptoms or treatment of Huntington's disease.

According to some embodiments, a compound of the present invention is for use in the prevention, alleviation of symptoms or treatment of dementia.

The present invention further encompasses methods for preventing, alleviating of symptoms of or treating a medical condition disclosed herein, comprising the step of administering a therapeutically effective amount of at least one compound of the invention or a pharmaceutical composition comprising same to a patient in need thereof.

Compounds with the general Formula (I) are prepared using the procedures, described in the section Synthesis of the compounds with the general Formula (I).

Examples

The present invention is further exemplified, but not limited by, the following examples that illustrate the preparation of compounds of Formula (I).

Synthesis of the compounds with the general Formula (I)

Reaction scheme 1 : Synthesis of (E) vinyl/alkenyl and reduced derivatives

H ₂ , Pd/C

General synthetic procedures

General procedure A: Synthesis of Wittig reagents

Appropriate benzyl or phenethyl halide (25.0 mmol, 1 .0 equiv.) was dissolved in MeCN (25 mL), and triphenylphosphine (6.56 g, 25.0 mmol, 1 .0 equiv.) was added at room temperature. The reaction mixture was stirred at 85 °C for 16-24 h. The solvent was evaporated and CH2CI2 (10 mL) and Et ₂ O (50 mL) were added to the residue. The precipitated solid was filtered off, washed with Et ₂ O (20 mL), and dried overnight at room temperature. The crude product was used in the following reaction step without further purification.

General procedure B: Wittig reaction

Appropriate Witting reagent synthesized according to the general procedure A (1 .1 equiv.) was dissolved in anhydrous THF (30 mL) under argon atmosphere. Sodium bis(trimethylsilyl)amide-NaHMDS (2N solution in THF, 1 .2 equiv.) was added to the resulting suspension at room temperature. The orange-red colored reaction mixture was then stirred for 30 min under argon, followed by a drop-wise addition of /V-Boc protected 4- formylpiperidine (1 .0 equiv.) solution in anhydrous THF (10 mL). The reaction mixture was stirred at room temperature overnight (16-24 h), and then quenched by adding saturated aqueous NaHCO3 solution (10-15 mL). The solvent was evaporated and the white residue was resuspended in EtOAc (50 mL) and saturated aqueous NaHCO3 solution (50 mL), and transferred into a separating funnel. The phases were separated and the aqueous phase was additionally extracted with EtOAc (2 ^χ 50 mL). Combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield pure trans (Z) isomer and a mixture of both isomers that was used for reduction of the double bond. General procedure C: reduction of the double bond

Alkene derivative (Wittig reaction product-mixture of cis and trans isomer, 1 .0 equiv.) was dissolved in EtOH or MeOH (20-50 mL) and purged under a stream of argon for 10 min. Catalytic amount of Pd/C (10% load on carbon, 10-20% [w/w] calculated to the starting material) was added, and the resulting suspension mixture was stirred under H ₂ (g) atmosphere at room temperature for 16-24 h. The catalyst was removed by filtration through a pad of Celite® and evaporated to obtain crude product that was used in the next reaction step.

General procedure D: Boc protection removal with HCI or TFA

To the solution of Boc protected derivative (1 .0 equiv.) in EtOH or 1 ,4-dioxane (30- 50 mL), or CH ₂ CI ₂ , concentrated HCI (10.0 equiv., method with HCI) or TFA (40.0 equiv., method with TFA) was added drop-wise. After stirring for 1-2 h at 85 °C (method with HCI) or 4-20 h at room temperature (method with TFA), the reaction mixture was evaporated. The crude material was used in the next reaction step without further purification.

General procedure E: /V-alkylation Intermediate in the form of the salt with HCI from the previous reaction step (procedure D) was dissolved in MeCN (20-30 mL) or DMF (5-10 mL) at 0 °C under argon atmosphere. K2CO3 or CS2CO3 (3.0 equiv.) was added, followed by a drop- wise addition of propargyl bromide (80 % solution in toluene, 1 .2 equiv.). The resulting suspension was stirred at room temperature (unless specified otherwise) for 16-72 h. The solvent was evaporated, the residue dissolved in a mixture of CH2CI2 (50 mL) and saturated aqueous NaHCO3 solution (50 mL), and transferred into a separating funnel. The organic phase was further washed with saturated brine solution (50 mL), dried over anhydrous Na2SO ₄ , and evaporated under reduced pressure. The crude product was purified by flash column chromatography. Procedure F1 : Synthesis of ferf-butyl 4-formylpiperidine-1 -carboxylate

Terf-butyl 4-formylpiperidine-1 -carboxylate was synthesized following the published procedure (Caroon JM, PCT Int. Appl. 9943657, Sep 02, 1999) starting from ferf- butyl 4-(methoxy(methyl)carmaboyl)piperidine-1 -carboxylate. The crude product was used in the Wittig reaction without further purification.

Procedure F2: Synthesis of ferf-butyl 4-formylpyrrolidine-1 -carboxylate

Terf-butyl 4-formylpyrrolidine-1 -carboxylate was synthesized following the published procedure (Caroon JM, PCT Int. Appl. 9943657, Sep 02, 1999) starting from tert- butyl 4-(methoxy(methyl)carmaboyl)pyrrolidine-1 -carboxylate. The crude product was used in the Wittig reaction without further purification.

Procedure G: Synthesis of ferf-butyl 4-oxoazepane-1-carboxylate

Terf-butyl 4-oxoazepane-1 -carboxylate was synthesized following the published procedure (Huang YS, Ind End Chem Res, 2010, 49, 12164-12167) starting from glycine ethyl ester (salt with HCI) and A/-Boc-4-piperidone (9,19 g, 46,12 mmol, 1 ,0 ekviv.).The crude product was used in the Wittig reaction without further purification. Rt = 0.39 (EtOAc/n-hex = 1/1 , v/v); colorles oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .42 (s, 9H), 1 .72-1 .78 (m, 2H), 2.60-2.63 (m, 4H), 3.53-3.58 (m, 4H). Procedure H: Synthesis of activated alcohols with mesyl chloride

The primary alcohol (1 .0 equiv.) was dissolved in CH2CI2 (20 ml_), solution purged under a stream of argon for 10 min, and cooled to 0 °C. Et ₃ N (1 .05 equiv.) and methansulfonyl chloride (1 .05 equiv.) were added consecutively. The reaction mixture was stirred at room temperature for 3 h. The resulting suspension was transferred into a separating funnel and washed with H ₂ O (2 ^χ 20 ml_), saturated brine solution (30 ml_), dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure. Crude intermediate (mesylate) was used in the next reaction step without purification.

EXAMPLE 1 Synthesis of (£)-4-(4-fluorostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(4-fluorostyryl)piperidine-1 -carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (2.00 g, 9.38 mmol, 1 .0 equiv.) and 4-fluorobenzyltriphenylphosphonium bromide (4.66 g, 10.32 mmol, 1 .1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Mass: 155 mg; R _f = 0.79 (EtOAc/n-hex = 1/2, v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .30-1 .42 (m, 2H), 1 .46 (s, 9H), 1 .51-1 .57 (m, 1 H), 1 .71-1 .77 (m, 2H), 2.77 (dt, J = 13.2, 2.7 Hz, 2H), 4.13 (d, J = 13.0 Hz, 2H), 6.05 (dd, J = 15.9, 6.9 Hz, 1 H), 6.34 (d, J = 16.2 Hz, 1 H), 6.95-7.01 (m, 2H), 7.27-7.32 (m, 2H). Step 2: (£)-4-(4-Fluorostyryl)-1 -(prop-2-yn-1-yl)piperidine

Synthesized from terf-butyl (E)-4-(4-fluorostyryl)piperidine-1-carboxylate (157 mg, 0.514 mmol, 1.0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 26% (33 mg); R _f = 0.17 (EtOAc/n-hex = 1/1, v/v); yellow oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.57 (dt, J = 12.3, 3.4 Hz, 1H), 1.60 (dt, J = 12.0, 3.7 Hz, 1H), 1.77-1.83 (m, 2H), 2.08-2.18 (m, 1H), 2.27 (t, J = 2.4 Hz, 1H), 2.30 (dd, J = 11.7, 2.0 Hz, 2H), 2.95 (td, J = 11.1, 2.8 Hz, 2H), 3.34 (d, J = 2.4 Hz, 2H), 6.07 (dd, J= 16.0, 7.0 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 6.95-7.00 (m, 2H), 7.28-7.33 (m, 2H); ¹³ C NMR (100 MHz, CDCIs): δ 31.88, 38.70, 47.19, 52.18, 73.26, 78.74, 115.32 (d, J _C, F = 21.4 Hz), 127.15, 127.41 (d, J _C, F=7.7 HZ), 133.71 (d, J _C, F = 3.3 Hz), 134.50, 161.95 (d, J _C, F = 245.9 Hz); HRMS (ESI+): m/z calcd forCi ₆ Hi ₉ FN [M+H] ⁺ 244.1502; found 244.1508; HPLC purity, 96.2%.

EXAMPLE 2 Synthesis of 4-(4-fluorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(4-fluorophenethyl)piperidine-1-carboxylate

Synthesized from terf-butyl (E/Z)-4-(4-fluorostyryl)piperidine-1-carboxylate (0.152 g, 0.50 mmol, 1.0 equiv.) via general procedure C. The product was used without further purification. Yield: quantitative (0.155 g); Rf = 0.86 (EtOAc/n-hex = 1/2, v/v); yellow transparent oil; 1H NMR (400 MHz, CDCI ₃ ): δ 1.11 (dt, J = 12.4, 4.2 Hz, 1H), 1.14 (dt, J = 12.5, 4.2 Hz, 1H), 1.35-1.44 (m, 1H), 1.45 (s, 9H), 1.51-1.56 (m, 2H), 1.60-1.62 (m, 1H), 1.65-1.72 (m, 2H), 2.57-2.62 (m, 1H), 2.66 (t, J = 11.5 Hz, 2H), 4.07 (bs, 2H), 6.93-6.99 (m, 2H), 7.09-7.14 (m, 2H); HRMS (ESI+): m/z calcd for Ci ₈ H ₂ 6FNO ₂ Na [M+Na] ⁺ 330.1845; found 330.1848.

Step 2: 4-(4-Fluorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(4-fluorophenethyl)piperidine-1-carboxylate (0.152 g, 0.45 mmol, 1.0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 85% (88 mg); R _f = 0.17 (EtOAc/n-hex = 1/1, v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.21-1.40 (m, 3H), 1.52-1.57 (m, 2H), 1.74-1.78 (m, 2H), 2.18-2.23 (m, 2H), 2.25 (t, J = 2.4 Hz, 1H), 2.57-2.61 (m, 2H), 2.89-2.94 (m, 2H), 3.33 (d, J = 2.4 Hz, 2H), 6.82-6.98 (m, 2H), 7.09-7.14 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 32.07, 32.21, 34.60, 38.35, 47.15, 52.47, 73.09, 78.90, 114.99 (d, J _C ,F = 21.1 Hz), 129.54 (d, J _C ,F = 7.9 Hz), 138.16 (d, J _C ,F = 3.1 Hz), 161 .1 1 (d, J _C ,F = 243.2 Hz); HRMS (ESI+): m/z calcd for Ci ₆ H ₂ iFN [M+H] ⁺ 246.1658; found 246.1657; HPLC purity, 97.5%.

EXAMPLE 3

Synthesis of (£)-4-(2,4,5-trifluorostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(2,4,5-trifluorostyryl)piperidine-1 -carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (0.575 g, 2.70 mmol, 1 .0 equiv.) and 2,4,5-trifluorobenzyltriphenylphosphonium bromide (1 .59 g, 3.25 mmol, 1 .1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Mass: 135 mg; R _f = 0.78 (EtOAc/n-hex = 1/2, v/v); pale yellow amorphous solid, mp 60-63 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .36 (dt, J = 12.4, 4.2 Hz, 1 H), 1 .39 (dt, J = 12.3, 4.3 Hz, 1 H), 1 .47 (s, 9H), 1 .71-1 .79 (m, 2H), 2.25-2.36 (m, 1 H), 2.78 (t, J = 12.0 Hz, 2H), 4.14 (bs, 2H), 6.13 (dd, J = 16.1 , 6.9 Hz, 1 H), 6.44 (d, J = 16.1 Hz, 1 H), 6.88 (dt, J = 9.9, 6.6 Hz, 1 H), 7.01 (ddd, J = 1 1 .1 , 8.8, 7.0 Hz, 1 H); HRMS (ESI+): m/z calcd for Ci ₈ H ₂₂ F3NO ₂ Na [M+Na] ⁺ 364.1500; found 364.1497. Step 2: (£)-4-(2,4,5-Trifluorostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(2,4,5-trifluorostyryl)piperidine-1-carboxylate (135 mg, 0.395 mmol, 1.0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 74% (82 mg); R _f = 0.26 (EtOAc/n-hex = 1/1, v/v); yellow oil; ¹ H NMR (400 MHz, CDCIs): δ 1.56 (dt, J = 12.4, 3.4 Hz, 1H), 1.59 (dt, J = 12.0, 3.7 Hz, 1H), 1.79-1.84 (m, 2H), 2.11-2.20 (m, 1 H), 2.26 (t, J = 2.4 Hz, 1 H), 2.30 (dt, J = 11.7, 2.3 Hz, 2H), 2.95 (dt, J = 11.6, 2.8 Hz, 2H), 3.34 (d, J = 2.4 Hz, 2H), 6.13 (dd, J = 16.1, 7.0 Hz, 1H), 6.43 (d, J = 16.1 Hz, 1H), 6.87 (dt, J= 9.9, 6.7 Hz, 1H), 7.23 (ddd, J = 11.1 , 8.8, 7.0 Hz, 1 H); ¹³ C NMR (100 MHz, CDCI3): δ 31.69, 39.02, 47.17, 52.07, 73.23, 78.73, 105.51 (dd, JC _, F= 28.5, 20.9 Hz), 114.06 (dd, J _C, F= 19.6, 5.2 Hz), 118.96-119.03 (m), 121.95 (ddd, J _C, F= 14.8, 5.8, 4.4 Hz), 138.10-138.17 (m), 146.93 (ddd, J _C, F= 243.5, 12.9, 3.4 Hz), 148.76 (ddd, J _C, F= 251.1, 14.9, 12.6 Hz); 154.73 (ddd, J _C, F= 247.4, 9.1, 2.3 Hz); HRMS (ESI+): m/z calcd for Ci ₆ Hi ₇ F ₃ N [M+H] ⁺ 280,1313; found 280,1318; HPLC purity, 100%.

EXAMPLE 4

Synthesis of 4-(2,4,5-trifluorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(2,4,5-trifluorophenethyl)piperidine-1 -carboxylate

Synthesized from terf-butyl (E/Z)-4-(2,4,5-thfluorostyryl)pipehdine-1 -carboxylate (0.152 g, 0.45 mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Yield: quantitative (0.155 g); R _f = 0.86 (EtOAc/n-hex = 1/2, v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .1 1 (dt, J = 12.4, 4.3 Hz, 1 H), 1 .14 (dt, J = 12.7, 4.2 Hz, 1 H), 1 .35-1 .44 (m, 1 H), 1 .45 (s, 9H), 1 .49-1 .54 (m, 2H), 1 .66-1 .73 (m, 2H), 2.59 (t, J = 8.0 Hz, 2H), 2.66 (dt, J = 13.2, 2.5 Hz, 2H), 4.09 (d, J = 13.2 Hz, 2H), 6.87 (ddd, J = 10.0, 9.4, 6.7 Hz, 1 H), 6.97 (ddd, J = 10.6, 8.8, 7.1 Hz, 1 H); HRMS (ESI+): m/z ca led for Ci8H ₂₄ F ₃ NO ₂ Na [M+Na] ⁺ 366.1657; found 366.1652.

Step 2: 4-(2,4,5-Trifluorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(2,4,5-trifluorophenethyl)piperidine-1 -carboxylate (0.175 g, 0.509 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 32% (45 mg); R _f = 0.16 (EtOAc/n-hex = 1/1 , v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .22-1 .39 (m, 3H), 1 .49-1 .55 (m, 2H), 1 .72-1 .78 (m, 2H), 2.16-2.22 (m, 2H), 2.23-2.25 (m, 1 H), 2.59 (t, J = 7.8 Hz, 2H), 2.88-2.93 (m, 2H), 3.30-3.32 (m, 2H), 6.86 (ddd, J = 10.0, 9.5, 6.7 Hz, 1H), 6.97 (ddd, J= 10.7, 8.8, 6.5 Hz, 1 H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 25.55, 31.94, 34.68, 36.55, 47.13, 52.40, 73.16, 78.81, 105.18 (dd, J _C ,F= 28.7, 20.6 Hz), 117.66 (dd, J _C ,F= 19.1, 6.5 Hz), 125.50-125.82 (m), 146.57 (ddd, J _C, F= 243.6, 12.6, 3.2 Hz), 148.09 (ddd, J _C, F = 249.2, 13.4, 11.5 Hz); 155.72 (ddd, J _C, F= 243.4, 9.3, 2.7 Hz); HRMS (ESI+): m/z calcd forCi ₆ Hi ₉ F ₃ N [M+H] ⁺ 282.1470; found 282.1471; HPLC purity, 100%.

EXAMPLE 5

Synthesis of (£)-4-(3-fluorostyryl)-1-(prop-2-yn-1-yl)piperidine

Step 1: Terf-butyl (£)-4-(3-fluorostyryl)piperidine-1-carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1-carboxylate (2.00 g, 9.38 mmol, 1.0 equiv.) and 3-fluorobenzyltriphenylphosphonium chloride (4.20 g, 10.32 mmol, 1.1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Mass: 355 mg; R _f = 0.67 (EtOAc/n-hex = 1/2, v/v); white solid, mp 45-46 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.31-1.44 (m, 2H), 1.47 (s, 9H), 1.71-1.78 (m, 2H), 2.23-2.33 (m, 1H), 2.78 (t, J = 12.2 Hz, 2H), 4.13 (bs, 2H), 6.15 (dd, J = 16.0, 6.8 Hz, 1H), 6.35 (d, J = 16.0 Hz, 1H), 6.89 (ddt, J = 8.4, 2.6, 0.9 Hz, 1H), 7.02-7.06 (m, 1 H), 7.07-7.1 1 (m, 1 H), 7.25 (td, J = 8.0, 5.8 Hz, 1 H); MS (ESI+): m/z [M+Na] ⁺ 328.17; found 328.40.

Step 2: (£)-4-(3-Fluorostyryl)-1 -(prop-2-yn-1-yl)piperidine

Synthesized from terf-butyl (E)-4-(3-fluorostyryl)piperidine-1 -carboxylate (300 mg, 0.982 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 38% (91 mg); R _f = 0.27 (EtOAc/n-hex = 1/2, v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .57 (dt, J = 12.0, 3.9 Hz, 1 H), 1 .60 (dt, J = 1 1 .9, 3.9 Hz, 1 H), 1 .78- 1 .85 (m, 2H), 2.09-2.19 (m, 1 H), 2.27 (t, J = 2.5 Hz, 1 H), 2.31 (dt, J = 1 1 .7, 2.5 Hz, 2H), 2.92-2.98 (m, 2H), 3.35 (d, J = 2.5 Hz, 2H), 6.17 (dd, J = 16.0, 6.9 Hz, 1 H), 6.34 (d, J = 16.0 Hz, 1 H), 6.88 (ddt, J = 8.4, 2.6, 0.9 Hz, 1 H), 7.02-7.06 (m, 1 H), 7.07-7.1 1 (m, 1 H), 7.21-7.27 (m, 1 H); ¹³ C NMR (100 MHz, CDCI3): 5 31 .71 , 38.64, 47.14, 52.09, 73.32, 78.63, 1 12.39 (d, J _C, F = 22.0 Hz), 1 13.73 (d, J _C, F = 21 .3 Hz), 121 .87 (d, JC,F = 2.9 Hz), 127.33 (d, J _C ,F = 2.9 Hz), 129.85 (d, J _C ,F = 8.7 Hz), 136.1 1 , 139.95 (d, JC _, F = 7.3 Hz), 163.07 (d, J _C, F = 244.9 Hz); HRMS (ESI+): m/z calcd for Ci ₆ Hi ₉ FN [M+H] ⁺ 244.1502; found 244.1504; HPLC purity, 99.6%.

EXAMPLE 6

Synthesis of 4-(3-fluorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(3-fluorophenethyl)piperidine-1 -carboxylate

Synthesized from terf-butyl (E/Z)-4-(3-fluorostyryl)piperidine-1 -carboxylate (0.452 g, 1 .48 mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Yield: 95% (0.432 g); R _f = 0.65 (EtOAc/n-hex = 1/2, v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .1 1 (dt, J = 12.3, 4.1 Hz, 1 H), 1 .14 (dt, J = 12.5, 4.2 Hz, 1 H), 1 .35-1 .44 (m, 1 H), 1 .45 (s, 9H), 1 .50-1 .59 (m, 2H), 1 .65-1 .72 (m, 2H), 2.59-2.72 (m, 4H), 4.08 (bs, 2H), 6.84-6.89 (m, 2H), 6.91-6.95 (m, 1 H), 7.22 (ddd, J = 8.9, 7.6, 6.1 Hz, 1 H); MS (ESI+): m/z [M+Na] ⁺ 330.18; found 330.42.

Step 2: 4-(3-Fluorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(3-fluorophenethyl)piperidine-1 -carboxylate (0.32 g, 1 .04 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 18% (46 mg); R _f = 0.18 (EtOAc/n-hex = 1/2, v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .23-1 .37 (m, 3H), 1 .53-1 .59 (m, 2H), 1 .72-1 .78 (m, 2H), 2.14-2.21 (m, 2H), 2.24 (t, J = 2.4 Hz, 1 H), 2.59-2.64 (m, 2H), 2.85-2.90 (m, 2H), 3.30 (d, J = 2.4 Hz, 2H), 6.83-6.89 (m, 2H), 6.92-6.95 (m, 1 H), 7.19-7.25 (m, 1 H); ¹³ C NMR (100 MHz, CDCI3): 5 32.09, 32.77, 34.64, 37.89, 47.14, 52.44, 72.92, 79.04, 1 12.46 (d, JC,F = 21 .9 Hz), 1 15.04 (d, J _C ,F = 20.5 Hz), 123.90 (d, J _C ,F = 2.2 Hz), 129.61 (d, JC,F = 8.7 Hz), 145.19 (d, J _C ,F = 7.2 Hz), 162.84 (d, J _C ,F = 245.0 Hz); HRMS (ESI+): m/z calcd forCi ₆ H ₂ iFN [M+H] ⁺ 246.1658; found 246.1659; HPLC purity, 97.6%.

EXAMPLE 7

Synthesis of (£)-4-(2-fluorostyryl)-1-(prop-2-yn-1-yl)piperidine

Step 1: Terf-butyl (£)-4-(2-fluorostyryl)piperidine-1-carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1-carboxylate (1.50 g, 7.04 mmol, 1.0 equiv.) and (2-fluorobenzyl)triphenylphosphonium bromide (3.49 g, 7.74 mmol, 1.1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Mass: 194 mg; f? _f = 0.14 (petroleum ether/Et ₂ O = 10/1, v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.36 (dt, J = 12.3, 4.2 Hz, 1H), 1.39 (dt, J = 12.3, 4.2 Hz, 1 H), 1.46 (s, 9H), 1.70-1.77 (m, 2H), 2.23-2.33 (m, 1 H), 2.76 (t, J = 11.0 Hz, 2H), 4.12 (bs, 2H), 6.20 (dd, J = 16.1, 7.0 Hz, 1H), 6.53 (d, J = 16.1 Hz, 1H), 6.99 (ddd, J = 10.8, 8.1, 1.2 Hz, 1H), 7.05 (dt, J = 7.6, 1.2 Hz, 1H), 7.12-7.18 (m, 1H), 7.41 (dt, J =7.7, 1.8 Hz, 1H); MS (ESI+): m/z [M+Na] ⁺ 328.17; found 328.42.

Step 2: (£)-4-(2-Fluorostyryl)-1-(prop-2-yn-1-yl)piperidine

Synthesized from terf-butyl (E)-4-(2-fluorostyryl)piperidine-1 -carboxylate (180 mg, 0.589 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 58% (83 mg); R _f = 0.20 (EtOAc/n-hex = 1/2, v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .56 (dt, J = 12.0, 3.9 Hz, 1 H), 1 .59 (dt, J = 12.0, 3.9 Hz, 1 H), 1 .80- 1 .86 (m, 2H), 2.12-2.22 (m, 1 H), 2.26 (t, J = 2.4 Hz, 1 H), 2.28 (dt, J = 1 1 .7, 2.5 Hz, 2H), 2.91-2.96 (m, 2H), 3.33 (d, J = 2.4 Hz, 2H), 6.23 (dd, J = 16.1 , 7.1 Hz, 1 H), 6.55 (d, J = 16.1 Hz, 1 H), 7.00 (ddd, J = 10.8, 8.1 , 1 .2 Hz, 1 H), 7.07 (dt, J = 7.4, 1 .0 Hz, 1 H), 7.14-7.19 (m, 1 H), 7.44 (dt, J = 7.7, 1 .7 Hz, 1 H); ¹³ C NMR (100 MHz, CDCI3): δ 31 .93, 39.21 , 47.24, 52.21 , 72.97, 79.06, 1 15.58 (d, J _C, F = 22.3 Hz), 120.60 (d, JC,F = 3.8 Hz), 123.96 (d, J _C ,F = 3.6 Hz), 125.32 (d, J _C ,F = 12.3 Hz), 126.88 (d, JC,F = 12.3 Hz), 128.15 (d, J _C ,F = 8.5 Hz), 137.41 (d, J _C ,F = 4.2 Hz), 159.95 (d, J _C ,F = 248.4 Hz); HRMS (ESI+): m/z calcd for Ci ₆ Hi ₉ FN [M+H] ⁺ 244.1502; found 244.1500; HPLC purity, 99.5%.

EXAMPLE 8

Synthesis of 4-(2-fluorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(2-fluorophenethyl)piperidine-1 -carboxylate

Synthesized from terf-butyl (E/Z)-4-(2-fluorostyryl)piperidine-1-carboxylate (0.252 g, 0.83 mmol, 1.0 equiv.) via general procedure C. The product was used without further purification. Yield: 95% (0.242 g); R _f = 0.70 (EtOAc/n-hex = 1/2, v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.12 (dt, J = 12.4, 4.1 Hz, 1H), 1.15 (dt, J = 12.4, 4.2 Hz, 1H), 1.37-1.44 (m, 1H), 1.46 (s, 9H), 1.52-1.59 (m, 2H), 1.69-1.76 (m, 2H), 2.58-2.72 (m, 4H), 4.08 (bs, 2H), 6.97-7.02 (m, 1H), 7.03-7.04 (m, 1 H), 7.13-7.19 (m, 2H); MS (ESI+): m/z [M+Na] ⁺ 330.18; found 330.41.

Step 2: 4-(2-Fluorophenethyl)-1-(prop-2-yn-1-yl)piperidine

Synthesized from terf-butyl 4-(2-fluorophenethyl)piperidine-1-carboxylate (0.22 g, 0.716 mmol, 1.0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 8% (14 mg); R _f = 0.21 (EtOAc/n-hex = 1/1, v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.23-1.37 (m, 3H), 1.53-1.59 (m, 2H), 1.74-1.80 (m, 2H), 2.14-2.21 (m, 2H), 2.23 (t, J = 2.4 Hz, 1H), 2.63-2.68 (m, 2H), 2.86-2.91 (m, 2H), 3.30 (d, J = 2.4 Hz, 2H), 6.97-7.02 (m, 1H), 7.03-7.07 (m, 1H), 7.12-7.20 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 26.16, 32.12, 34.85, 36.88, 47.19, 52.52, 72.89, 79.15, 115.15 (d, JC,F= 22.5 Hz), 123.88 (d, J _C ,F= 3.4 Hz), 127.32 (d, J _C ,F= 8.0 Hz), 129.41 (d, JC,F = 16.1 Hz), 130.41 (d, J _C ,F = 5.3 Hz), 161.09 (d, J _C ,F = 244.5 Hz); HRMS (ESI+): m/z calcd for Ci ₆ H ₂ iFN [M+H] ⁺ 246.1658; found 246.1657; HPLC purity, 95.1 %.

EXAMPLE 9

Synthesis of (£)-1 -(Prop-2-yn-1 -yl)-4-styrylpiperidine

Step 1: Terc-butyl (£)-4-styrylpiperidine-1 -carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (1 .50 g, 7.04 mmol, 1 .0 equiv.) and benzyltriphenylphosphonium bromide (3.49 g, 7.74 mmol, 1 .1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 9/1 (v/v) as eluent. Mass: 285 mg; f? _f = 0.28 (petroleum ether/Et ₂ O = 9/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .36 (ddd, J = 16.6, 12.6, 4.5 Hz, 2H), 1 .47 (s, 9H), 1 .73- 1 .76 (m, 2H), 2.22-2.31 (m, 1 H), 2.77 (t, J = 1 1 .5 Hz, 2H), 4.12 (bs, 2H), 6.13 (dd, J = 17.0, 6.9 Hz, 1 H), 6.38 (d, J = 16.0 Hz, 1 H), 7.17-7.21 (m, 1 H), 7.27-7.35 (m, 4H); MS (ESI+): m/z [M+Na] ⁺ 310.18; found 310.12.

Step 2: (£)-1 -(Prop-2-yn-1 -yl)-4-styrylpiperidine

Synthesized from terf-butyl (E)-4-styrylpiperidine-1 -carboxylate (196 mg, 0.682 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 89% (137 mg); R _f = 0.41 (EtOAc/n-hex = 1/1 , v/v); white crystals, mp 44-46 °C; ¹ H NMR (400 MHz, CDCIs): δ 1 .56 (dd, J = 1 1 .9, 3.9 Hz, 1 H), 1 .59 (dd, J = 1 1 .9, 3.9 Hz, 1 H), 1 .79- 1 .84 (m, 2H), 2.09-2.18 (m, 1 H), 2.24-2.31 (m, 3H), 2.94 (td, J = 1 1 .1 , 2.4 Hz, 2H), 3.33 (d, J = 2.5 Hz, 2H), 6.18 (dd, J = 16.0, 7.0 Hz, 1 H), 6.39 (d, J = 16.5 Hz, 1 H), 7.18-7.22 (m, 1 H), 7.27-7.32 (m, 2H), 7.35-7.37 (m, 2H); ¹³ C NMR (100 MHz, CDCI3): 5 31 .90, 38.70, 47.13, 52.13, 72.90, 78.98, 125.87, 126.85, 128.10, 128.36, 134.77, 137.48; HRMS (ESI+): m/z calcd for Ci ₆ H ₂₀ N [M+H] ⁺ 226.1596; found 226.1594; HPLC purity, 99.2%.

EXAMPLE 10

Synthesis of 4-phenethyl-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-phenethylpiperidine-1-carboxylate

Synthesized from terf-butyl 4-phenethylpiperidine-1 -carboxylate (1 .139 g, 4.84 mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Yield: quantitative (1 .39 g); f? _f = 0.44 (petroleum ether/Et ₂ O = 3/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .21 (ddd, J = 16.5, 12.5, 4.3 Hz, 2H), 1 .35-1 .43 (m, 1 H), 1 .45 (s, 9H), 1 .53-1 .59 (m, 2H), 1 .68-1 .71 (m, 2H), 2.60-2.69 (m, 4H), 4.07 (bs, 2H), 7.15-7.19 (m, 3H), 7.24-7.29 (m, 2H); MS (ESI+): m/z [M+Na] ⁺ 312.19; found 31 1 .91 .

Step 2: 4-Phenethyl-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-phenethylpiperidine-1 -carboxylate (1 .04 g, 3.593 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 56% (202 mg); R _f = 0.36 (EtOAc/n-hex = 1/1 , v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .20-1 .35 (m, 3H), 1 .52-1 .58 (m, 2H), 1 .73-1 .76 (m, 2H), 2.12-2.18 (m, 2H), 2.21 (t, J = 2.5 Hz, 1 H), 2.58-2.63 (m, 2H), 2.84-2.87 (m, 2H), 3.26 (d, J = 2.5 Hz, 2H), 7.13-7.17 (m, 3H), 7.23-7.28 (m, 2H); ¹³ C NMR (100 MHz, CDCI3): δ 32.04, 32.89, 34.57, 38.14, 47.03, 52.34, 72.74, 79.02, 125.45, 128.10 (4xC), 142.44; HRMS (ESI+): m/z calcd for Ci ₆ H ₂₂ N [M+H] ⁺ 228.1752; found 228.1755; HPLC purity, 99.0%.

EXAMPLE 1 1 Synthesis of (£)-4-(4-chlorostyryl)-1-(prop-2-yn-1-yl)piperidine

Step 1: Terf-butyl (£)-4-(4-chlorostyryl)piperidine-1-carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1-carboxylate (2.00 g, 9.38 mmol, 1.0 equiv.) and 4-chlorobenzyltriphenylphosphonium chloride (4.37 g, 10.32 mmol, 1.1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Mass: 221 mg; f? _f = 0.10 (petroleum ether/Et ₂ O = 10/1, v/v); white solid, mp 60-62 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.35 (dd, J = 12.4, 4.1 Hz, 1H), 1.38 (dd, J= 12.2, 4.1 Hz, 1H), 1.46 (s, 9H), 1.71-1.77 (m, 2H), 2.22-2.31 (m, 1H), 2.77 (t, J= 11.5 Hz, 2H), 4.14 (bs, 2H), 6.11 (dd, J= 16.0, 6.9 Hz, 1H), 6.32 (dd, J = 16.0, 1.2 Hz, 1 H), 7.52 (s, 4H); MS (ESI+): m/z [M+Na] ⁺ 344.14; found 344.48. Step 2: (£)-4-(4-Chlorostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(4-chlorostyryl)piperidine-1 -carboxylate (165 mg, 0.513 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 45% (87 mg); R _f = 0.30 (EtOAc/n-hex = 1/1 , v/v); white crystals, mp 83-85 °C; ¹ H NMR (400 MHz, CDCIs): δ 1 .49-1 .59 (m, 2H), 1 .76-1 .81 (m, 2H), 2.03-2.16 (m, 1 H), 2.23-2.29 (m, 2H), 2.25 (t, J = 2.4 Hz, 1 H), 2.92 (td, J = 1 1 .1 , 2.4 Hz, 2H), 3.31 (d, J = 2.5 Hz, 2H), 6.13 (dd, J = 16.0, 7.0 Hz, 1 H), 6.31 (dd, J = 16.0, 1 .1 Hz, 1 H), 7.22- 7.27 (m, 4H); ¹³ C NMR (100 MHz, CDCI3): δ 31 .88, 38.77, 47.18, 52.15, 72.94, 79.00, 127.00, 127.14, 128.52, 132.40, 135.55, 136.05; HRMS (ESI+): m/z calcd for Ci ₆ Hi ₉ CIN [M+H] ⁺ 260.1206; found 260.1207; HPLC purity, 99.6%.

EXAMPLE 12

Synthesis of 4-(4-chlorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(4-chlorophenethyl)piperidine-1 -carboxylate

Synthesized from terf-butyl (E/Z)-4-(4-chlorostyryl)piperidine-1 -carboxylate (0.850 g, 2.64 mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Yield: 86% (0.736 g); R _f = 0.37 (petroleum ether/Et ₂ O = 3/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .08 (dd, J = 12.3, 4.2 Hz, 1 H), 1 .1 1 (dd, J = 12.8, 3.9 Hz, 1 H), 1 .33-1 .40 (m, 1 H), 1 .44 (s, 9H), 1 .48-1 .53 (m, 2H), 1 .63-1 .68 (m, 2H), 2.55-2.59 (m, 2H), 2.64 (t, J = 1 1 .6 Hz, 2H), 4.07 (bs, 2H), 7.05-7.08 (m, 2H), 7.18-7.22 (m, 2H); MS (ESI+): m/z [M+Na] ⁺ 346.15; found 346.55.

Step 2: 4-(4-Chlorophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(4-chlorophenethyl)piperidine-1 -carboxylate (0.195 g, 0.602 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 62% (85 mg); R _f = 0.27 (EtOAc/n-hex = 1/1 , v/v); white solid, mp 37-39 °C; ¹ H NMR (400 MHz, CDCI ₃ ): 5 1 .18-1 .35 (m, 3H), 1 .49-1 .55 (m, 2H), 1 .72-1 .75 (m, 2H), 2.12-2.18 (m, 2H), 2.22 (t, J = 2.5 Hz, 1 H), 2.55-2.59 (m, 2H), 2.84-2.88 (m, 2H), 3.27 (d, J = 2.5 Hz, 2H), 7.06-7.10 (m, 2H), 7.20-7.24 (m, 2H); ¹³ C NMR (100 MHz, CDCIs): δ 32.1 1 , 32.32, 34.59, 38.08, 47.13, 52.42, 72.82, 79.10, 128.29, 129.56, 131 .21 , 140.98; HRMS (ESI+): m/z calcd for Ci ₆ H ₂ iCIN [M+H] ⁺ 262.1363; found 262.1362; HPLC purity, 100%.

EXAMPLE 13

Synthesis of (£)-4-(4-bromostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(4-bromostyryl)piperidine-1 -carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (2.00 g, 9.38 mmol, 1 .0 equiv.) and 4-bromobenzyltriphenylphosphonium bromide (5.28 g, 10.31 mmol, 1 .1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Mass: 325 mg; R _f = 0.40 (EtOAc/n-hex = 1/2, v/v); white amorphous solid, mp 65-67 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .36 (dt, J = 12.4, 4.2 Hz, 1 H), 1 .39 (dt, J = 12.4, 4.5 Hz, 1 H), 1 .47 (s, 9H), 1 .71-1 .78 (m, 2H), 2.22-2.32 (m, 1 H), 2.74-2.81 (m, 2H), 4.12 (bs, 2H), 6.13 (dd, J = 16.0, 6.8 Hz, 1 H), 6.32 (d, J = 16.0 Hz, 1 H); 7.19- 7.22 (m, 2H), 7.39-7.43 (m, 2H).

Step 2: (£)-4-(4-Bromostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(4-bromostyryl)piperidine-1 -carboxylate (360 mg, 0.98 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 34% (102 mg); R _f = 0.34 (EtOAc/n-hex = 1/2, v/v); white crystals, mp 103-106 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .54 (dt, J = 12.2, 3.4 Hz, 1 H), 1 .57 (dt, J = 12.3, 3.6 Hz, 1 H), 1 .77-1 .83 (m, 2H), 2.08-2.17 (m, 1 H), 2.19-2.30 (m, 3H), 2.91-2.96 (m, 2H), 3.32 (d, J = 2.2 Hz, 2H), 6.15 (dd, J = 16.0, 6.9 Hz, 1 H), 6.31 (d, J = 16.2 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 31 .92, 38.85, 47.24, 52.21 , 72.98, 79.04, 127.13, 127.56, 130.12, 131 .53, 135.77, 136.57; HRMS (ESI+): m/z calcd for Ci ₆ Hi ₉ NBr [M+H] ⁺ 304.0701 ; found 304.0706; HPLC purity, 100%.

EXAMPLE 14

Synthesis of 4-(4-bromophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(4-bromophenethyl)piperidine-1 -carboxylate

Synthesized from terf-butyl (E/Z)-4-(4-bromostyryl)piperidine-1 -carboxylate (0.200 g, 0.55 mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Mass: 0.20 g; f? _f = 0.62 (EtOAc/n-hex = 1/2, v/v); pale brown transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .07-1 .19 (m, 2H), 1 .36-1 .48 (m, 1 H), 1 .45 (s, 9H), 1 .53-1 .60 (m, 2H), 1 .65-1 .73 (m, 2H), 2.60-2.73 (m, 4H), 4.09 (bs, 2H), 7.15-7.19 (m, 2H), 7.25-7.29 (m, 2H).

Step 2: 4-(4-Bromophenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(4-bromophenethyl)piperidine-1 -carboxylate (0.200 g, 0.54 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 32% (54 mg); f? _f = 0.34 (EtOAc/n-hex = 1/2, v/v); yellow amorphous solid, mp 139— 140 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .26-1 .37 (m, 3H), 1 .55-1 .60 (m, 2H), 1 .76- 1 .79 (m, 2H), 2.14-2.21 (m, 2H), 2.23 (t, J = 2.4 Hz, 1 H), 2.61-2.65 (m, 2H), 2.86- 2.91 (m, 2H), 3.29 (d, J = 2.5 Hz, 2H), 7.16-7.20 (m, 3H), 7.28-7.30 (m, 1 H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 32.20, 33.04, 34.73, 38.29, 47.19, 52.53, 72.82, 79.19, 125.61 , 128.27, 128.28, 142.67; HPLC purity, 95.0%.

EXAMPLE 15 Synthesis of (£)-4-(4-methylstyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(4-methylstyryl)piperidine-1 -carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (1 .49 g, 7.00 mmol, 1 .0 equiv.) and 4-methylbenzyltriphenylphosphonium bromide (3.13 g, 7.00 mmol, 1 .0 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/5 (v/v) as eluent. Mass: 155 mg; R _f = 0.72 (EtOAc/n-hex = 1/5, v/v); colorless oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .36 (dt, J = 12.2, 4.2 Hz, 1 H), 1 .39 (dt, J = 12.4, 4.3 Hz, 1 H), 1 .47 (s, 9H), 1 .71-1 .78 (m, 2H), 2.22-2.31 (m, 1 H), 2.32 (s, 3H), 2.77 (t, J = 12,6 Hz, 2H), 4.12 (bs, 2H), 6.09 (dd, J = 16.0, 6.9 Hz, 1 H), 6.35 (d, J = 15.8 Hz, 1 H), 7.09-7.12 (m, 2H), 7.22-7.25 (m, 2H); MS (ESI+): m/z [M+H] ⁺ 302.21 ; found 302.60.

Step 2: (£)-4-(4-Methylstyryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(4-methylstyryl)piperidine-1 -carboxylate (420 mg, 1 .39 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1 /3 (v/v) as eluent. Yield: 36% (121 mg); R _f = 0.25 (EtOAc/n-hex = 1 /3, v/v); orange amorphous solid, mp 65-67 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .65 (dt, J = 12.0, 3.9 Hz, 1 H), 1 .68 (dt, J = 12.0, 3.9 Hz, 1 H), 1 .88-1 .95 (m, 2H), 2.18-2.28 (m, 1 H), 2.35-2.41 (m, 3H), 2.43 (s, 3H), 3.02-3.07 (m, 2H), 3.43 (d, J = 2.5 Hz, 2H), 6.22 (dd, J = 16.0, 7.0 Hz, 1 H) , 6.46 (d, J = 15.9 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H); ¹³ C NMR (100 MHz, CDCIs): δ 21 .09, 32.01 , 38.77, 47.21 , 52.25, 72.92, 79.07, 125.83, 127.93, 129.13, 133.84, 134.78, 136.62; HRMS (ESI+): m/z calcd for Ci ₇ H ₂₂ N [M+H] ⁺ 240.1752; found 240.1756; HPLC purity, 97.7%.

EXAMPLE 16

Synthesis of 4-(4-methylphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(4-methylphenethyl)piperidine-1 -carboxylate

Synthesized from terf-butyl (E/Z)-4-(4-methylstyryl)piperidine-1 -carboxylate (0.280 g, 0.93mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Mass: quantitative (200 mg); f? _f = 0.63 (EtOAc/n-hex = 1 /2, v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCIs): 5 1 .1 1 (dt, J = 12.3, 4.1 Hz, 1 H), 1 .14 (dt, J = 12.4, 4.1 Hz, 1 H), 1 .36-1 .44 (m, 1 H), 1 .45 (s, 9H), 1 .51 -1 .57 (m, 2H), 1 .65-1 .73 (m, 2H), 2.32 (s, 3H), 2.56-2.61 (m, 2H), 2.63-2.70 (m, 2H), 4.07 (bs, 2H), 7.04- 7.10 (m, 4H); MS (ESI+): m/z [M+Na] ⁺ 326.21 ; found 326.73.

Step 2: 4-(4-Methylphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(4-methylphenethyl)piperidine-1 -carboxylate (0.280 g, 0.92 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1 /3 (v/v) as eluent. Yield: 36% (79 mg); R _f = 0.26 (EtOAc/n-hex = 1 /3, v/v); yellow amorphous solid; ¹ H NMR (400 MHz, CDCI3): δ 1 .21 -1 .36 (m, 3H), 1 .52-1 .57 (m, 2H), 1 .74-1 .79 (m, 2H), 2.13-2.20 (m, 2H), 2.23 (t, J = 2.4 Hz, 1 H), 2.31 (s, 3H), 2.56-2.60 (m, 2H), 2.86-2.90 (m, 2H), 3.29 (d, J = 2.4 Hz, 2H), 7.05-7.10 (m, 4H); ¹³ C NMR (100 MHz, CDCI3): δ 20.97, 32.21 , 32.57, 34.68, 38.43, 47.21 , 52.55, 72.83, 79.06, 128.17, 128.97, 135.05, 139.58; HRMS (ESI+): m/z calcd for Ci ₇ H ₂₄ N [M+H] ⁺ 242.1909; found 242.1904; HPLC purity, 97.4%. EXAMPLE 17

Synthesis of (£)-4-(4-cyclopropylstyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(4-cyclopropylstyryl)piperidine-1 -carboxylate

To the solution of terf-butyl (£/Z)-4-(4-bromostyryl)piperidine-1 -carboxylate (0.733 g, 2.0 mmol, 1 .0 equiv.), cyclopropylboronic acid (0.224 g, 2.60 mmol, 1 .3 equiv.), K ₃ PO ₄ (1 .48 g, 7.00 mmol, 3.5 equiv.) and t cyclohexylphosphine (20% solution in toluene, 0.316 mL, 0.20 mmol, 0.1 equiv.) in toluene (10 mL) and water (0.4 mL), Pd(OAc)2 (23 mg, 0.1 mmol, 0.05 equiv.) was added under argon atmosphere. The reaction mixture was stirred at 100 °C for 3 h, and then allowed to cool down to room temperature. Water (20 mL) was added to the mixture that was then transferred into a separating funnel, and extracted with EtOAc (2 ^χ 50 mL). Combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO ₄ , and evaporated under reduced pressure. Crude product was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Mass: 210 mg; R _f = 0.22 (petroleum ether/Et ₂ O = 10/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 0.66-0.70 (m, 2H), 0.92-0.97 (m, 2H), 1 .36 (dt, J = 12.7, 4.4 Hz, 1 H), 1 .39 (dt, J = 12.3, 4.1 Hz, 1 H), 1 .48 (s, 9H), 1 .70-1 .78 (m, 2H), 1 .83-1 .90 (m, 1 H), 2.21 -2.31 (m, 1 H), 2.78 (t, J = 1 1 .6 Hz, 2H), 4.13 (bs, 2H), 6.08 (dd, J = 16.0, 6.9 Hz, 1 H), 6.34 (d, J = 16.0 Hz, 1 H), 6.98-7.02 (m, 2H), 7.22-7.25 (m, 2H).

Step 2: (£)-4-(4-Cyclopropylstyryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(4-cyclopropylstyryl)piperidine-1 -carboxylate (200 mg, 0.61 1 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1 /2 (v/v) as eluent. Yield: 40% (65 mg); R _f = 0.28 (EtOAc/n-hex = 1 /2, v/v); pale yellow crystals, mp 66- 68 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 0.68-0.72 (m, 2H), 0.95-0.99 (m, 2H), 1 .57 (dt, J = 12.0, 3.9 Hz, 1 H), 1 .60 (dt, J = 1 1 .9, 3.9 Hz, 1 H), 1 .79-1 .85 (m, 2H), 1 .86-1 .93 (m, 1 H), 2.09-2.20 (m, 1 H), 2.28 (t, J = 2.4 Hz, 1 H), 2.30 (dt, J = 1 1 .7, 2.5 Hz, 2H), 2.92-2.98 (m, 2H), 3.35 (d, J = 2.4 Hz, 2H), 6.13 (dd, J = 15.9, 7.0 Hz, 1 H), 6.37 (d, J = 15.9 Hz, 1 H), 7.00-7.04 (m, 2H), 7.25-7.29 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 9.16, 15.12, 32.03, 38.75, 47.20, 52.23, 72.91 , 79.06, 125.67, 125.84, 127.90, 133.78, 134.82, 142.79; HRMS (ESI+): m/z calcd for Ci ₉ H ₂₆ N [M+H] ⁺ 266.1909; found 266.1908; HPLC purity, 98.1 %.

EXAMPLE 18

Synthesis of 4-(4-cyclopropylphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(4-cyclopropylphenethyl)piperidine-1-carboxylate

Synthesized from terf-butyl (E/Z)-4-(4-cyclopropylstyryl)piperidine-1-carboxylate (0.216 g, 0.66 mmol, 1.0 equiv.) via general procedure C. The product was used without further purification. Mass: 0.200 g; R _f = 0.67 (EtOAc/n-hex = 1/2, v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 0.95 (t, J = 7.4 Hz, 2H), 1.11 (dt, J = 12.4, 4.1 Hz, 1H), 1.14 (dt, J= 12.4, 4.2 Hz, 1H), 1.37-1.47 (m, 1H), 1.45 (s, 9H), 1.52- 1.58 (m, 2H), 1.59-1.65 (m, 3H), 1.16-1.73 (m, 2H), 2.52-2.70 (m, 4H), 4.07 (bs, 2H), 7.06-7.11 (m,4H).

Step 2: 4-(4-Cyclopropylphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(4-cyclopropylphenethyl)piperidine-1 -carboxylate (0.185 g, 0.561 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 45% (68 mg); R _f = 0.32 (EtOAc/n-hex = 1/2, v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 0.95 (t, J = 7.4 Hz, 2H), 1 .26-1 .37 (m, 2H), 1 .53-1 .59 (m, 2H), 1 .60-1 .68 (m, 2H), 1 .74-1 .79 (m, 1 H), 2.14-2.21 (m, 2H), 2.23 (t, J = 2.4 Hz, 1 H), 2.53-2.62 (m, 4H), 2.86-2.91 (m, 3H), 3.30 (d, J = 2.4 Hz, 2H), 7.07-7.1 1 (m, 4H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 13.86, 24.59, 32.20, 32.60, 34.75, 37.63, 38.37, 47.19, 52.28, 72.80, 79.20, 128.08, 128.33, 132.38, 139.89; HPLC purity, 97.1 %.

EXAMPLE 19

Synthesis of (£)-4-(4-isopropylstyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(4-isopropylstyryl)piperidine-1-carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1-carboxylate (1.30 g, 6.10 mmol, 1.0 equiv.) and 4-isopropylbenzyltriphenylphosphonium bromide (3.19 g, 6.71 mmol, 1.1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 9/1 (v/v) as eluent. Mass: 235 mg; f? _f = 0.24 (petroleum ether/Et ₂ O = 10/1, v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.25 (d, J = 7.0 Hz, 6H), 1.37 (dd, J = 12.8, 4.1 Hz, 1H), 1.40 (dd, J = 12.1 , 3.9 Hz, 1H), 1.49 (s, 9H), 1.71-1.79 (m, 2H), 2.22-2.30 (m, 1H), 2.78 (t, J= 11.4 Hz, 2H), 2.89 (sept, J = 7.0 Hz, 1H), 4.14 (bs, 2H), 6.11 (dd, J = 16.0, 6.9 Hz, 1H), 6.38 (d, J = 15.9 Hz, 1H), 7.16-7.18 (m, 2H), 7.28-7.30 (m, 2H); MS (ESI+): m/z [M+Na] ⁺ 352.22; found 352.01.

Step 2: (£)-4-(4-lsopropylstyryl)-1-(prop-2-yn-1-yl)piperidine

Synthesized from terf-butyl (E)-4-(4-isopropylstyryl)piperidine-1-carboxylate (0.207 g, 0.628 mmol, 1.0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 45% (76 mg); R _f = 0.43 (EtOAc/n-hex = 1/1, v/v); pale yellow solid, mp 60- 64 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.24 (d, J = 6.9 Hz, 6H), 1.52-1.61 (m, 2H), 1.79-1.83 (m, 2H), 2.06-2.19 (m, 1H), 2.24-2.31 (m, 2H), 2.26 (t, J = 2.5 Hz, 1H), 2.83-2.95 (m, 3H), 3.32 (d, J = 2.5 Hz, 2H), 6.13 (dd, J = 16.0, 7.0 Hz, 1H), 6.37 (d, J= 16.6 Hz, 1H), 7.15-7.18 (m, 2H), 7.27-7.31 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 23.93, 32.05, 33.76, 38.75, 47.22, 52.25, 72.90, 79.08, 125.90, 126.50, 127.96, 134.01, 135.21, 147.74; HRMS (ESI+): m/z calcd for Ci ₉ H ₂₆ N [M+H] ⁺ 268.2065; found 268.2062; HPLC purity, 98.5%.

EXAMPLE 20

Synthesis of 4-(4-isopropylphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(4-isopropylphenethyl)piperidine-1-carboxylate

Synthesized from terf-butyl (E/Z)-4-(4-isopropylstyryl)piperidine-1-carboxylate (0.87 g, 2.64 mmol, 1.0 equiv.) via general procedure C. The product was used without further purification. Mass: 0.727 g; f? _f = 0.44 (petroleum ether/Et ₂ O = 3/1, v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.16 (ddd, J = 16.9, 12.9, 5.5 Hz, 2H), 1.27 (d, J= 7.0 Hz, 6H), 1.40-1.47 (m, 1H), 1.49 (s, 9H), 1.54-1.61 (m, 2H), 1.70- 1.76 (m, 2H), 2.61-2.64 (m, 2H), 2.70 (t, J = 11.5 Hz, 2H), 2.91 (sept. J = 6.9 Hz, 1 H), 4.10 (bs, 2H), 7.1 1-7.13 (m, 2H), 7.16-7.18 (m, 2H MS (ESI+): m/z [M+Na] ⁺ 354.24; found 354.05.

Step 2: 4-(4-lsopropylphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(4-isopropylphenethyl)piperidine-1 -carboxylate (0.290 g, 0.875 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1 /2 (v/v) as eluent. Yield: 55% (1 12 mg); R _f = 0.35 (EtOAc/n-hex = 1 /1 , v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .26 (d, J = 7.0 Hz, 6H), 1 .29-1 .39 (m, 3H), 1 .55-1 .61 (m, 2H), 1 .75-1 .81 (m, 2H), 2.16-2.22 (m, 2H), 2.24 (t, J = 2.4 Hz, 1 H), 2.59-2.63 (m, 2H), 2.86-2.93 (m, 3H), 3.31 (d, J = 2.5 Hz, 2H), 7.1 1 -7.13 (m, 2H), 7.15-7.17 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 24.01 , 32.18, 32.56, 33.59, 34.75, 38.34, 47.16, 52.50, 72.78, 79.17, 126.24, 128.1 1 , 139.91 , 146.03; HRMS (ESI+): m/z ca led for Ci ₉ H ₂₈ N [M+H] ⁺ 270.2222; found 270.2226; HPLC purity, 99.8%. EXAMPLE 21

Synthesis of (£)-4-(4-methoxystyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£/Z)-4-(4-methoxystyryl)piperidine-1 -carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (1 .87 g, 8.77 mmol, 1 .0 equiv.) and 4-methoxybenzyltriphenylphosphonium chloride (4.04 g, 9.65 mmol, 1 .1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/9 (v/v) as eluent. Mass: 1 120 mg (mixture of cis/trans isomers (ratio 20/80, estimated from ¹ H NMR)); R _f = 0.13 (EtOAc/n-hex = 1/9, v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .31-1 .41 (m, 2.6H, cis + trans), 1 .46-1 .47 (m, 1 1 .5H, cis + trans), 1 .63-1 .75 (m, 2.6H, cis + trans), 2.20-2.29 (m, 1 H, trans), 2.69-2.82 (m, 2.6H, cis + trans), 3.78 (s, 3H, trans), 3.78 (s, 0.7H, cis), 4.12 (bs, 2.6H, cis + trans), 5.36 (dd, J = 1 1 .6, 10.0 Hz, 0.2H, cis), 5.99 (dd, J = 16.0, 6.9 Hz, 1 H, trans), 6.30-6.34 (m, 1 .2H, cis + trans), 6.81-6.85 (m, 2H, trans), 6.85-6.89 (m, 0.5H, cis), 7.16-7.19 (m, 0.5H, cis), 7.24- 7.29 (m, 2H, trans); MS (ESI+): m/z [M+Na] ⁺ 340.19; found 340.04. Step 2: (£)-4-(4-Methoxystyryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E Z)-4-(4-methoxystyryl)piperidine-1 -carboxylate (0.810 g, 2.552 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Only trans derivative was isolated. Yield: 32% (192 mg); R _f = 0.29 (EtOAc/n-hex = 1/1 , v/v); white solid, mp 59-61 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .50-1 .60 (m, 2H), 1 .75-1 .82 (m, 2H), 2.06-2.15 (m, 1 H), 2.23-2.30 (m, 2H), 2.25 (t, J = 2.4 Hz, 1 H), 2.88-2.94 (m, 2H), 3.32 (d, J = 2.4 Hz, 2H), 3.79 (s, 3H), 6.02 (dd, J = 15.9, 7.0 Hz, 1 H), 6.32 (d, J = 15.9 Hz, 1 H), 6.81-6.85 (m, 2H), 7.26-7.30 (m, 2H); ¹³ C NMR (100 MHz, CDCIs): δ 32.13, 38.77, 47.23, 52.28, 55.23, 72.90, 79.1 1 , 1 13.85, 127.03, 127.49, 130.39, 132.78, 158.69; HRMS (ESI+): m/z calcd for Ci ₇ H ₂₂ NO [M+H] ⁺ 256.1701 ; found 256.1706; HPLC purity, 97.7%.

EXAMPLE 22

Synthesis of 4-(4-methoxyphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl 4-(4-methoxyphenethyl)piperidine-1-carboxylate

Synthesized from terf-butyl (E/Z)-4-(4-methoxystyryl)piperidine-1 -carboxylate (0.25 g, 0.79 mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Yield: 97 % (0.245 g); R _f = 0.75 (EtOAc/n-hex = 1/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCI3): δ 1 .12 (ddd, J = 16.3, 12.5, 4.3 Hz, 2H), 1 .35-1 .43 (m, 1 H), 1 .45 (s, 9H), 1 .50-1 .56 (m, 2H), 1 .64-1 .71 (m, 2H), 2.55-2.59 (m, 2H), 2.66 (t, J = 1 1 .8 Hz, 2H), 3.79 (s, 3H), 4.07 (bs, 2H), 6.81-6.84 (m, 2H), 7.07- 7.10 (m, 2H); MS (ESI+): m/z [M+Na] ⁺ 342.20; found 342.59. Step 2: 4-(4-Methoxyphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(4-methoxyphenethyl)piperidine-1 -carboxylate (0.230 g, 0.720 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1 /1 (v/v) as eluent. Yield: 57% (103 mg); R _f = 0.26 (EtOAc/n-hex = 1 /1 , v/v); white solid, mp 31 -32 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .22-1 .36 (m, 3H), 1 .50-1 .56 (m, 2H), 1 .72-1 .77 (m, 2H), 2.13-2.19 (m, 2H), 2.23 (t, J = 2.5 Hz, 1 H), 2.54-2.58 (m, 2H), 2.85-2.89 (m, 2H), 3.28 (d, J = 2.5 Hz, 2H), 3.77 (s, 3H), 6.80-6.84 (m, 2H), 7.07-7.10 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 32.00, 32.14, 34.57, 38.45, 47.12, 52.46, 55.10, 72.77, 79.15, 1 13.60, 129.04, 134.60, 157.51 ; HRMS (ESI+): m/z calcd for Ci ₇ H ₂₄ NO [M+H] ⁺ 258.1858; found 258.1857; HPLC purity, 100%.

EXAMPLE 23

Synthesis of 4-(4-hydroxyphenethyl)-1 -(prop-2-yn-1 -yl)piperidine

The methoxy substituted starting compound (50 mg, 0.194 mmol, 1 .0 equiv.) was dissolved in anhydrous toluene (6 ml_), purged under a stream of argon for 15 min, and cooled to -20 °C. BBr ₃ (1 M solution in CH ₂ CI ₂ , 582 μΙ_, 0.582 mmol, 3.0 equiv.) was added drop-wise and the reaction mixture was stirred for another hour at -20 °C. The mixture was allowed to warm-up to room temperature (1 h). Saturated aqueous NaHCO3 (10 mL) was added, and the resulting emulsion was stirred vigorously for 15 min before EtOAc (30 mL) was added. The phases were separated, and the organic layer was washed with saturated brine (50 mL), dried over anhydrous Na2SO ₄ , and evaporated under reduced pressure. The crude product was purified by flash column chromatography using CH ₂ CI ₂ /MeOH = 20/1 (v/v) as eluent. Yield: 57% (27 mg); Rf = 0.19 (CH ₂ CI ₂ /MeOH = 20/1 , v/v); white solid, mp 104-106 °C; ¹ H NMR (400 MHz, CDCI3): δ 1 .22-1 .39 (m, 3H), 1 .48-1 .54 (m, 2H), 1 .72-1 .78 (m, 2H), 2.21 -2.27 (m, 2H), 2.25 (t, J = 2.4 Hz, 1 H), 2.51 -2.55 (m, 2H), 2.89-2.95 (m, 2H), 3.32 (d, J = 2.5 Hz, 2H), 6.71 -6.74 (m, 2H), 6.99-7.02 (m, 2H), resonance for OH missing; ¹³ C NMR (100 MHz, CDCI3): δ 31 .89, 32.09, 34.55, 38.41 , 47.07, 52.41 , 73.33, 78.68, 1 15.29, 129.27, 134.35, 153.92; HRMS (ESI+): m/z calcd for Ci ₆ H ₂₂ NO [M+H]+ 244.1701 ; found 244.1697; HPLC purity, 96.1 %. EXAMPLE 24

Synthesis of (£)-4-(4-cyanostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(4-cyanostyryl)piperidine-1 -carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (2.35 g, 1 1 .02 mmol, 1 .0 equiv.) and 4-cyanobenzyltriphenylphosphonium bromide (5.56 g, 12.12 mmol, 1 .1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 3/1 (v/v) as eluent. Yield: 9,3 % (320 mg); R _f = 0.14 (petroleum ether/Et ₂ O = 3/1 , v/v); white crystals, mp 88-90 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .30-1 .40 (m, 2H), 1 .43 (s, 9H), 1 .70-1 .75 (m, 2H), 2.25-2.34 (m, 1 H), 2.75 (t, J = 10.7 Hz, 2H), 4.1 1 (bs, 2H), 6.26 (dd, J = 16.0, 6.6 Hz, 1 H), 6.36 (d, J = 16.0 Hz, 1 H), 7.37-7.39 (m, 2H), 7.52-7.55 (m, 2H); MS (ESI+): m/z [M-H] ^" 31 1 .17; found 31 1 .37.

Step 2: (£)-4-(4-Cyanostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(4-cyanostyryl)piperidine-1 -carboxylate (0.300 g, 0.96 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using CH ₂ Cl ₂ /MeOH = 50/1 (v/v) as eluent. Yield: 54% (130 mg); R _f = 0.16 (CH ₂ CI ₂ /MeOH = 50/1 , v/v); white solid, mp 59-62 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .47-1 .58 (m, 2H), 1 .76-1 .79 (m, 2H), 2.10-2.17 (m, 1 H), 2.21-2.27 (m, 2H), 2.23 (t, J = 2.4 Hz, 1 H), 2.88-2.91 (m, 2H), 3.28 (d, J = 2.5 Hz, 2H), 6.27 (dd, J = 16.0, 6.5 Hz, 1 H), 6.35 (d, J = 16.1 Hz, 1 H), 7.36-7.39 (m, 2H), 7.51-7.54 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 31 .58, 38.78, 47.06, 51 .94, 72.96, 78.83, 109.94, 1 18.93, 126.35, 126.77, 132.16, 138.94, 142.00; HRMS (ESI+): m/z calcd for Ci ₇ Hi ₉ N ₂ [M+H] ⁺ 251 .1548; found 251 .1549; HPLC purity, 99.3%.

EXAMPLE 25 Synthesis of 4-(2-(1 -(prop-2-yn-1 -yl)piperidine-4-yl)ethyl)benzonitrile

Step 1: Terf-butyl 4-(4-cyanophenethyl)piperidine-1 -carboxylate

Synthesized from terf-butyl (E/Z)-4-(4-cyanostyryl)piperidine-1 -carboxylate (0.658 g, 2.1 1 mmol, 1 .0 equiv.) via general procedure C. The crude product was purified by flash column chromatography using petroleum ether/Et ₂ O = 3/1 (v/v) as eluent. Yield: 95% (0.632 g); R _f = 0.15 (petroleum ether/Et ₂ O = 3/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .09 (dd, J = 12.4, 4.2 Hz, 1 H), 1 .12 (dd, J = 12.5, 4.3 Hz, 1 H), 1 .34-1 .40 (m, 1 H), 1 .42 (s, 9H), 1 .51-1 .58 (m, 2H), 1 .63-1 .68 (m, 2H), 2.61-2.68 (m, 4H), 4.06 (bs, 2H), 7.23-7.25 (m, 2H), 7.51-7.54 (m, 2H); MS (ESI+): m/z [M+Na] ⁺ 337.19; found 337.07.

Step 2: 4-(2-(1 -(Prop-2-yn-1 -yl)piperidine-4-yl)ethyl)benzonitrile

Synthesized from terf-butyl 4-(4-cyanophenethyl)piperidine-1 -carboxylate (0.075 g, 0.239 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 59% (106 mg); R _f = 0.14 (EtOAc/n-hex = 1/1 , v/v); white solid, mp 40-42 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .21-1 .36 (m, 3H), 1 .53-1 .58 (m, 2H), 1 .72-1 .77 (m, 2H), 2.13-2.19 (m, 2H), 2.22 (t, J = 2.4 Hz, 1 H), 2.65-2.69 (m, 2H), 2.86-2.89 (m, 2H), 3.28 (d, J = 2.5 Hz, 2H), 7.25-7.28 (m, 2H), 7.54-7.57 (m, 2H); ¹³ C NMR (100 MHz, CDCIs): δ 31 .99, 33.13, 34.62, 37.60, 47.03, 52.28, 72.82, 78.97, 109.39, 1 18.96, 128.96, 132.01 , 148.23; HRMS (ESI+): m/z calcd for Ci ₇ H ₂ iN ₂ [M+H] ⁺ 253.1705; found 253.1706; HPLC purity, 96.0%.

EXAMPLE 26

Synthesis of (£)-4-(2-(1 -(Prop-2-yn-1 -yl)piperidine-4-yl)vinyl)benzamide

The starting (E)-4-(2-(1 -(prop-2-yn-1 -yl)piperidin-4-yl)vinyl)benzonitrile (0.080 g, 0.320 mmol, 1 .0 equiv.) was dissolved in terf-butanol (40 mL), followed by the addition of powdered KOH (0.054 g, 0.960 mmol, 3.0 equiv.). The resulting suspension was stirred at 90 °C for 12 h, and then the solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of CH2CI2 (70 mL) and saturated aqueous NaHCO3 (50 mL), and transferred into a separating funnel. Water layer was additionally extracted with CH2CI2 (30 mL). Combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure. The crude product was purified by flash column chromatography using CH ₂ CI ₂ /MeOH = 20/1 (v/v) as eluent. Yield: 63% (54 mg); Rf = 0.08 (CH ₂ CI ₂ /MeOH = 20/1 , v/v); white crystals, mp 181-184; 1 H NMR (400 MHz, DMSO-c/e): δ 1 .42 (dq, J = 12.7, 3.9 Hz, 2H), 1 .71-1 .75 (m, 2H), 2.06-2.12 (m, 1 H), 2.17 (td, J = 1 1 .5, 2.2 Hz, 2H), 2.79-2.83 (m, 2H), 3.14 (t, J = 2.4 Hz, 1 H), 3.26 (d, J = 2.4 Hz, 2H), 6.36-6.46 (m, 2H), 7.30 (bs, 1 H), 7.44-7.47 (m, 2H), 7.79-7.82 (m, 2H), 7.93 (bs, 1 H); 13C NMR (100 MHz, DMSO-c/ ₆ ): δ 31 .34, 38.32, 46.38, 51 .42, 75.53, 79.53, 125.53, 126.97, 127.76, 132.41 , 137.05, 140.00, 167.45; HRMS (ESI+): m/z calcd for Ci ₇ H ₂ iN ₂ O [M+H] ⁺ 269.1654; found 269.1656; HPLC purity, 99.4%. EXAMPLE 27

Synthesis of 4-(2-(1 -(Prop-2-yn-1 -yl)piperidine-4-yl)ethyl)benzamide

The starting 4-(2-(1 -(prop-2-yn-1 -yl)piperidin-4-yl)ethyl)benzonitrile (0.075 g, 0.297 mmol, 1 .0 equiv.) was dissolved in terf-butanol (20 mL), followed by the addition of powdered KOH (0.050 g, 0.892 mmol, 3.0 equiv.). The resulting suspension was stirred at 90 °C for 12 h, and then the solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of CH2CI2 (50 mL) and saturated aqueous NaHCO3 (50 mL), and transferred into a separating funnel. Water layer was additionally extracted with CH2CI2 (30 mL). Combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure. The crude product was purified by flash column chromatography using CH ₂ CI ₂ /MeOH = 9/1 (v/v) as eluent. Yield: 42% (34 mg); R _f = 0.25 (CH ₂ CI ₂ /MeOH = 9/1 , v/v); white solid, mp 155-158 °C; ¹ H NMR (400 MHz, MeOD): δ 1 .28-1 .34 (m, 3H), 1 .57-1 .63 (m, 2H), 1 .80-1 .83 (m, 2H), 2.21 (t, J = 1 1 .3 Hz, 2H), 2.69 (t, J = 2.5 Hz, 1 H), 2.70-2.74 (m, 2H), 2.94-2.98 (m, 2H), 3.29 (d, J = 2.5 Hz, 2H), 7.29-7.32 (m, 2H), 7.79-7.82 (m, 2H), resonance for CONH ₂ missing; ¹³ C NMR (100 MHz, MeOD): δ 32.79, 33.93, 35.97, 39.16, 47.69, 53.60, 75.15, 79.24, 128.88, 129.55, 132.45, 148.46, 172.44; HRMS (ESI+): m/z calcd for Ci ₇ H ₂₃ N ₂ O [M+H] ⁺ 269.1810; found 269.1816; HPLC purity, 99.6%. EXAMPLE 28

Synthesis of (£)-4-(4-(trifluoromethyl)styryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(4-(trifluoromethyl)styryl)piperidine-1-carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (2.00 g, 9.38 mmol, 1 .0 equiv.) and 4-(trifluoromethyl)benzyltriphenylphosphonium bromide (5.56 g, 10.32 mmol, 1 .0 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 9/1 (v/v) as eluent. Yield: 23 % (780 mg); R _f = 0.18 (petroleum ether/Et ₂ O = 9/1, v/v); white crystals, mp 46-48 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.35 (dd, J = 12.2, 4.1 Hz, 1H), 1.39 (dd, J = 12.5, 4.1 Hz, 1H), 1.46 (s, 9H), 1.71-1.77 (m, 2H), 2.24- 2.33 (m, 1H), 2.76 (t, J= 11.4 Hz, 2H), 4.14 (bs, 2H), 6.22 (dd, J= 16.0, 6.8 Hz, 1H), 6.38 (d, J = 16.1 Hz, 1H), 7.40 (d, J= 8.4 Hz, 2H), 7.51 (d, J= 8.2 Hz, 2H).

Step 2: (£)-4-(4-(Trifluoromethyl)styryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(4-(trifluoromethyl)styryl)piperidine-1-carboxylate (580 mg, 1.632 mmol, 1.0 ekviv.) via general procedures D and E. For the alkylation (procedure E) 440 mg of (E)-4-(4-(trifluoromethyl)styryl)piperidinium chloride was used. The compound was purified by flash column chromatography using EtOAc/n- hex = 2/1 (v/v) as eluent. Yield: 85% (376 mg); R _f = 0.50 (EtOAc/n-hex = 2/1, v/v); white solid, mp 72-74 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.52-1.62 (m, 2H), 1.80- 1.84 (m, 2H), 2.12-2.19 (m, 1H), 2.26 (t, J = 2.4 Hz, 1H), 2.25-2.32 (m, 2H), 2.92- 2.96 (m, 2H), 3.33 (d, J = 2.5 Hz, 2H), 6.27 (dd, J = 16.0, 6.9 Hz, 1H), 6.41 (d, J = 16.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H); ¹³ C NMR (100 MHz, CDCIs): δ 31.78, 38.84, 47.17, 52.10, 72.97, 78.95, 121.50 (d, J _C, F = 271.6 Hz), 125.35 (q, J _C, F = 3.7 Hz), 126.07, 127.03, 128.69 (q, J _C, F = 32.4 Hz), 137.62, 140.07 (q, JC _, F = 1.3 Hz); HRMS (ESI+): m/z calcd for C17H19F3N [M+H] ⁺ 294.1470; found 294.1464; HPLC purity, 99.9%.

EXAMPLE 29

Synthesis of 1 -(prop-2-yn-1 -yl)-4-(4-(trifluoromethyl)phenethyl)piperidine

Step 1: Terf-butyl 4-(4-(trifluoromethyl)phenethyl)piperidine-1-carboxylate

Synthesized from terf-butyl (EZ)-4-(4-(trifluoromethyl)styryl)piperidine-1-carboxylate (0.24 g, 0.68 mmol, 1.0 equiv.) via general procedure C. The product was used without further purification. Yield: quantitative (241 mg); f? _f = 0.56 (EtOAc/n-hex = 1/2, v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.12 (dt, J = 12.4, 4.2 Hz, 1H), 1.15 (dt, J= 12.3, 4.3 Hz, 1H), 1.36-1.44 (m, 1H), 1.45 (s, 9H), 1.53-1.61 (m, 2H), 1.65-1.73 (m, 2H), 2.60-2.70 (m, 4H), 4.08 (bs, 2H), 7.25-7.28 (m, 2H), 7.50- 7.53 (m, 2H).

Step 2: 4-(4-(Trifluoromethyl)phenethyl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl 4-(4-(trifluoromethyl)phenethyl)piperidine-1 -carboxylate (0.230 g, 0.64 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 7% (14 mg); R _f = 0.12 (EtOAc/n-hex = 1/2, v/v); brown amorphous solid, mp 31-33 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .23-1 .37 (m, 3H), 1 .54-1 .60 (m, 2H), 1 .74-1 .78 (m, 2H), 2.14-2.20 (m, 2H), 2.23 (t, J = 2.4 Hz, 1 H), 2.65-2.70 (m, 2H), 2.86-2.90 (m, 2H), 3.29 (d, J = 2.4 Hz, 2H) , 7.26-7.29 (m, 2H), 7.50-7.53 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 32.14, 32.91 , 34.71 , 37.97, 47.17, 52.45, 72.89, 79.1 1 , 124.35 (q, J _C ,F = 271 .9 Hz), 125.20 (q, J _C ,F = 7.9 Hz), 128.02 (q, J _C , _F = 32,3 Hz) 128.56, 146.76; HRMS (ESI+): m/z calcd for Ci ₇ H ₂ iF ₃ N [M+H] ⁺ 296.1626; found 296.1625 HPLC purity, 100%.

EXAMPLE 30

Synthesis of (£)-4-(3-(trifluoromethyl)styryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(3-(trifluoromethyl)styryl)piperidine-1-carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (1 .49 g, 7.00 mmol, 1 .0 equiv.) and 3-(trifluoromethyl)benzyltriphenylphosphonium bromide (3.51 g, 7.00 mmol, 1 .0 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 9/1 (v/v) as eluent. Mass: 404 mg; R _f = 0.16 (petroleum ether/Et ₂ O = 8/1 , v/v); colorless transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .37 (dt, J = 12.4, 4.3 Hz, 1 H), 1 .40 (dt, J =12.2, 4.1 Hz, 1 H), 1 .47 (s, 9H), 1 .73-1 .80 (m, 2H), 2.26-2.36 (m, 1 H), 2.78 (t, J = 12.0 Hz, 2H), 4.14 (bs, 2H), 6.22 (dd, J = 16.0, 6.9 Hz, 1 H), 6.41 (d, J = 16.0 Hz, 1 H), 7.38-7.46 (m, 2H), 7.48-7.51 (m, 1 H), 7.57-7.59 (m, 1 H); MS (ESI+): m/z [M+Na] ⁺ 378.17; found 378.69.

Step 2: (£)-4-(3-(Trifluoromethyl)styryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(3-(trifluoromethyl)styryl)piperidine-1 -carboxylate (190 mg, 0.53 mmol, 1 .0 ekviv.) via general procedures D and E.. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/3 (v/v) as eluent. Yield: 70% (109 mg); R _f = 0.18 (EtOAc/n-hex = 1/3, v/v); green oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .56 (dt, J = 12.1 , 3.7 Hz, 1 H), 1 .59 (dt, J = 12.1 , 3.7 Hz, 1 H), 1 .79-1 .85 (m, 2H), 2.1 1-2.20 (m, 1 H), 2.26 (t, J = 2.4 Hz, 1 H), 2.29 (dt, J = 1 1 .8, 2.3 Hz, 2H), 2.92-2.97 (m, 2H), 3.33 (d, J = 2.4 Hz, 2H), 6.24 (dd, J = 16.0, 6.9 Hz, 1 H), 6.41 (d, J = 16.0 Hz, 1 H), 7.38-7.45 (m, 2H), 7.51 (d, J = 7.5 Hz, 1 H), 7.58 (s, 1 H); ¹³ C NMR (100 MHz, CDCI3): δ 31 .87, 38.86, 47.24, 52.19, 73.01 , 79.02, 122.64 (q, JC,F = 3.9 Hz), 123.49 (q, J _C ,F = 3.9 Hz), 124.16 (q, J _C ,F = 272.3 Hz), 127.03, 128.88, 129.18, 130.85 (q, J _C, F = 32.1 Hz), 136.90, 138.38; HRMS (ESI+): m/z calcd for C17H 19NF3 [M+H] ⁺ 294.1470; found 294.1465; HPLC purity, 99.8%.

EXAMPLE 31

Synthesis of 1 -(prop-2-yn-1 -yl)-4-(3-(trifluoromethyl)phenethyl)piperidine

Step 1: Terf-butyl 4-(3-(trifluoromethyl)phenethyl)piperidine-1 -carboxylate

Synthesized from terf-butyl (E Z)-4-(3-(trifluoromethyl)styryl)piperidine-1 -carboxylate (0.27 g, 0.77 mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Yield: quantitative (274 mg); f? _f = 0.58 (EtOAc/n-hex = 1/2, v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .13 (dt, J = 12.2, 4.2 Hz, 1 H), 1 .16 (dt, J = 12.4, 4.2 Hz, 1 H), 1 .37-1 .45 (m, 1 H), 1 .46 (s, 9H), 1 .55-1 .61 (m, 2H), 1 .67- 1 .74 (m, 2H), 2.63-2.72 (m, 4H), 4.09 (bs, 2H), 7.34-7.45 (m, 4H); MS (ESI+): m/z [M+Na] ⁺ 380.18; found 380.

Step 2: 1 -(Prop-2-yn-1 -yl)-4-(3-(trifluoromethyl)phenethyl)piperidine

Synthesized from terf-butyl 4-(3-(trifluoromethyl)phenethyl)piperidine-1 -carboxylate (0.270 g, 0.76 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/3 (v/v) as eluent. Yield: 29% (65 mg); R _f = 0.20 (EtOAc/n-hex = 1/3, v/v); yellow-orange transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .21-1 .26 (m, 2H), 1 .34 (dt, J = 1 1 .1 , 3.7 Hz, 1 H), 1 .54-1 .60 (m, 2H), 1 .73-1 .80 (m, 2H), 2.14-2.21 (m, 2H), 2.22 (t, J = 2.4 Hz, 1 H), 2.66-2.70 (m, 2H), 2.86-2.91 (m, 2H), 3.28 (d, J = 2.46 Hz, 2H), 7.33- 7.44 (m, 4H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 32.10, 32.89, 34.82, 38.03, 47.13, 52.43, 72.86, 79.07, 122.51 (q, J _C ,F = 3.8 Hz), 124.21 (q, J _C , _F = 272.2 Hz), 124.88 (q, J _C ,F = 3.7 Hz), 128.63, 130.51 (q, J _C ,F = 31 .8 Hz), 131 .64, 143.48; HRMS (ESI+): m/z calcd for C17H21 NF3 [M+H] ⁺ 296.1626; found 296.1629; HPLC purity, 98.7%. EXAMPLE 32

Synthesis of (£)-4-(2-chloro-4-fluorostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Step 1: Terf-butyl (£)-4-(2-chloro-4-fluorostyryl)piperidine-1 -carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (1 .50 g, 7.03 mmol, 1 .0 equiv.) and 2-chloro-4-fluorobenzyltriphenylphosphonium bromide (3.76 g, 7.74 mmol, 1 .1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Mass: 285 mg; R _f = 0.68 (EtOAc/n-hex = 1/2, v/v); white solid, mp 90-92 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .36 (dt, J = 12.4, 4.1 Hz, 1 H), 1 .39 (dt, J = 12.3, 4.2 Hz, 1 H), 1 .46 (s, 9H), 1 .72-1 .79 (m, 2H), 2.27-2.36 (m, 1 H), 2.77 (t, J = 1 1 .4 Hz, 2H), 4.13 (bs, 2H), 6.04 (dd, J = 15.9, 6.9 Hz, 1 H), 6.67 (d, J = 15.9 Hz, 1 H), 6.92 (dt, J = 8.4, 2.6 Hz, 1 H), 7.07 (dd, J = 8.5, 2.6 Hz, 1 H), 7.44 (dd, J = 8.8, 6.1 Hz, 1 H); MS (ESI+): m/z [M+Na] ⁺ 362.13; found 362.40.

Step 2: (£)-4-(2-chloro-4-fluorostyryl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(2-chloro-4-fluorostyryl)piperidine-1 -carboxylate (263 mg, 0.774 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 58% (125 mg); R _f = 0.18 (EtOAc/n-hex = 1/2, v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .56 (dt, J = 12.0, 3.9 Hz, 1 H), 1 .59 (dt, J = 1 1 .9, 3.9 Hz, 1 H), 1 .76-1 .85 (m, 2H), 2.12-2.23 (m, 1 H), 2.25 (t, J = 2.4 Hz, 1 H), 2.28 (dt, J = 1 1 .7, 2.5 Hz, 2H), 2.90-2.96 (m, 2H), 3.32 (d, J = 2.4 Hz, 2H), 6.07 (dd, J = 15.9, 7.1 Hz, 1 H), 6.68 (d, J = 15.9 Hz, 1 H), 6.90-6.95 (m, 1 H), 7.08 (dd, J = 8.5, 2.6 Hz, 1 H), 7.47 (dt, J = 8.8, 6.1 Hz, 1 H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 31 .87, 38.93, 47.18, 52.10, 72.95, 78.99, 1 14.1 1 (d, J _C, F = 21 .3 Hz), 1 16.57 (d, J _C, F = 24.7 Hz), 123.61 , 127.49 (d, J _C ,F = 8.8 Hz), 131 .98 (d, J _C ,F = 3.7 Hz), 133.00 (d, J _C ,F = 10.2 Hz), 137.51 (d, J _C, F = 1 .7 Hz), 161 .33 (d, J _C, F = 249.4 Hz); HRMS (ESI+): m/z calcd for Ci ₆ Hi ₈ FCIN [M+H] ⁺ 278.1 1 12; found 278.1 120; HPLC purity, 100%.

EXAMPLE 33

Synthesis of (£)-2-(2-(1 -(prop-2-yn-1 -yl)piperidine-4-yl)vinyl)pyridine

Step 1: Terf-butyl (£)-4-(2-(pyridine-2-yl)vinyl)piperidine-1-carboxylate

Synthesized from terf-butyl 4-formylpiperidine-1 -carboxylate (0.46 g, 2.16 mmol, 1 .0 equiv.) and triphenyl(pyridine-2-ilmethyl)phosphonium bromide (0.94 g, 2.16 mmol, 1 .0 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 26% (0.16 g); R _f = 0.19 (EtOAc/n-hex = 1/2, v/v); brown oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .36 (dt, J = 12.3, 4.1 Hz, 1 H), 1 .40-1 .44 (m, 1 H), 1 .44 (s, 9H), 1 .73-1 .80 (m, 2H), 2.27-2.36 (m, 1 H), 2.76 (t, J = 1 1 .5 Hz, 2H), 4.10 (bs, 2H), 6.45 (dd, J = 15.8, 1 .2 Hz, 1 H), 6.66 (dd, J = 15.8, 6.8 Hz, 1 H), 7.08 (ddd, J = 7.5, 4.8, 1 .1 Hz, 1 H), 7.21 (td, J = 7.9, 0.9 Hz, 1 H), 7.58 (dt, J = 7.7, 1 .8 Hz, 1 H), 8.50 (ddd, J = 4.8, 1 .7, 0.8 Hz, 1 H); MS (ESI+): m/z [M+Na] ⁺ 31 1 .17; found 31 1 .55.

Step 2: (£)-2-(2-(1-(Prop-2-yn-1 -yl)piperidine-4-yl)vinyl)pyridine

Synthesized from terf-butyl (E)-4-(2-(pyridine-2-yl)vinyl)piperidine-1 -carboxylate (30 mg, 0.10 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 10/0 (v/v) as eluent. Yield: 48% (1 1 mg); R _f = 0.07 (EtOAc/n-hex = 2/1 , v/v); brown oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .56-1 .66 (m, 2H), 1 .80-1 .88 (m, 2H), 2.15-2.24 (m, 1 H), 2.25 (t, J = 2.4 Hz, 1 H), 2.29 (dt, J = 1 1 .8, 2.6 Hz, 2H), 2.92-2.96 (m, 2H), 3.33 (d, J = 2.4 Hz, 2H), 6.48 (dd, J = 15.8, 1 .2 Hz, 1 H), 6.70 (dd, J = 15.8, 7.0 Hz, 1 H), 7.10 (ddd, J = 7.5, 4.8, 1 .1 Hz, 1 H), 7.25 (td, J = 7.9, 1 .0 Hz, 1 H), 7.60 (dt, J = 7.7, 1 .8 Hz, 1 H), 8.53 (ddd, J = 4.8, 1 .8, 0.9 Hz, 1 H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 31 .69, 38.69, 47.24, 52.22, 73.02, 79.01 , 121 .27, 121 .72, 128.33, 136.45, 139.45, 149.42, 155.90; HRMS (ESI+): m/z calcd for Ci ₅ Hi ₉ N ₂ [M+H] ⁺ 227.1548; found 227.1543; HPLC purity, 95.4%.

EXAMPLE 34

Synthesis of 4-(4-fluorobenzylidene)-1-(prop-2-yn-1 -yl)-piperidine

Step 1: Terf-butyl 4-(4-fluorobenzylidene)piperidine-1 -carboxylate

Synthesized from terf-butyl 4-oxopiperidine-1 -carboxylate (1 .00 g, 5.02 mmol, 1 .0 equiv.) and 4-(fluorobenzyltriphenyl)phosphonium chloride (0.94 g, 5.02 mmol, 1 .0 equiv., prepared via general procedure A) via general procedure B (potassium tert- butoxide was used instead of NaHMDS). The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Yield: 39% (0.57 g); R _f = 0.12 (petroleum ether/Et ₂ O = 10/1 , v/v); white amorphous solid, mp 50-52 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .47 (s, 9H), 2.32 (t, J = 5.6 Hz, 2H), 2.41 (t, J = 5.6 Hz, 2H), 3.40 (t, J = 5.8 Hz, 2H), 3.50 (t, J = 5.6 Hz, 2H), 6.31 (s, 1 H), 6.97-7.03 (m, 2H), 7.12-7.17 (m, 2H). Step 2: (4-(4-Fluorobenzylidene)-1 -(prop-2-yn-1 -yl)-piperidine

Synthesized from terf-butyl 4-(4-fluorobenzylidene)piperidine-1 -carboxylate (380 mg, 1 .30 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 5% (14 mg); f? _f = 0.12 (EtOAc/n-hex = 1/2, v/v); yellow-orange transparent oil; ¹ H NMR (400 MHz, CDCIs): δ 2.23 (t, J = 2.4 Hz, 1 H), 2.40-2.43 (m, 2H), 2.49-2.56 (m, 4H), 2.63-2.66 (m, 2H), 3.33 (d, J = 2.4 Hz, 2H), 6.25 (s, 1 H), 6.96-7.02 (m, 2H), 7.13- 7.16 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 28.83, 36.17, 46.93, 53.07, 53.80, 73.05, 78.86, 1 14.91 (d, J _C, F = 21 .2 Hz), 122.51 , 130.37 (d, J _C, F = 7.4 Hz), 133.56, 138.62, 161 .23 (d, JC _, F = 245.2 Hz); HRMS (ESI+): m/z ca led for C15H17FN [M+H] ⁺ 230.1345; found 230.1343; HPLC purity, 99.4%.

EXAMPLE 35

Synthesis of 4-(4-fluorobenzyl)-1 -(prop-2-yn-1 -yl)-piperidine

Synthesized from terf-butyl 4-(4-fluorobenzyl)piperidinium chloride (380 mg, 1 .30 mmol, 1 .0 ekviv.) via general procedure E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 4% (10 mg); R _f = 0.10 (EtOAc/n-hex = 1/2, v/v); brown oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.28 (dt, J = 11.8, 3.8 Hz, 1H), 1.31 (dt, J= 12.3, 3.8 Hz, 1H), 1.41-1.52 (m, 1H), 1.61-1.65 (m, 2H), 2.13 (dt, J = 11.6, 2.6 Hz, 2H), 2.20 (t, J = 2.4 Hz, 1H), 2.49 (d, J = 7.1 Hz, 2H), 2.82-2.87 (m, 2H), 3.26 (d, J = 2.5 Hz, 2H), 6.91-6.96 (m, 2H), 7.04-7.09 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 31.90, 37.36, 42.14, 47.07, 52.37, 72.82, 79.04, 114.80 (d, JC,F= 21.220.5 Hz), 130.27 (d, J _C ,F= 8.1 Hz), 136.05 (d, J _C ,F= 3,6 Hz), 161.18 (d, JC,F= 243.6 Hz); HRMS (ESI+): m/z ca led for C1 ₅ H19NF [M+H] ⁺ 232.1502; found 232.1506; HPLC purity, 97.5%. EXAMPLE 36

Synthesis of (£)-4-(3-(4-f luorophenyl)prop-1 -en-1 -yl)-1 -(prop-2-yn-1 - yl)piperidine

Synthesized from terf-butyl 4-formylpiperidine-1-carboxylate (0.50 g, 2.34 mmol, 1.0 equiv.) and (4-fluorophenethyl)triphenylphosphonium bromide (1.31 g, 2.81 mmol, 1.1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 10/1 (v/v) as eluent. Yield: 47% (0.35 g); R _f = 0.18 (petroleum ether/Et ₂ O = 10/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .29 (dt, J= 12.3, 4.1 Hz, 1 H), 1 .32 (dt, J= 12.3, 4.2 Hz, 1 H), 1 .44 (s, 9H), 1 .55-1 .62 (m, 2H), 2.44-2.54 (m, 1 H), 2.73 (t, J = 1 1 .7 Hz, 2H), 3.35 (d, J = 7.5 Hz, 2H), 4.07 (bs, 2H), 5.31 (tdd, J = 10.8, 9.3, 1 .5 Hz, 1 H), 5.45 (dtd, J = 10.8, 7.4, 0.9 Hz, 1 H), 6.89-6.95 (m, 2H), 7.06-7.1 1 (m, 2H).

Step 2: (£)-4-(3-(4-f luorophenyl)prop-1 -en-1 -yl)-1 -(prop-2-yn-1 -yl)piperidine

Synthesized from terf-butyl (E)-4-(3-(4-fluorophenyl)prop-1 -en-1 -yl)piperidine-1 - carboxylate (220 mg, 0.69 mmol, 1 .0 ekviv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/2 (v/v) as eluent. Yield: 38% (68 mg); R _f = 0.21 (EtOAc/n-hex = 1/2, v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .45-1 .55 (m, 2H), 1 .61-1 .70 (m, 2H), 2.22-2.30 (m, 3H), 2.32-2.42 (m, 1 H), 2.86-2.91 (m, 2H), 3.31 (d, J = 2.4 Hz, 2H), 3.38 (br d, J = 7.3 Hz, 2H), 5.34-5.40 (m, 1 H), 5.44-5.51 (m, 1 H), 6.94-7.00 (m, 2H), 7.09-7.15 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 32.28, 32.80, 33.82, 47.28, 52.09, 72.97, 79.02, 1 15.1 1 (d, J _C ,F = 21 .1 Hz), 127.05, 129.54 (d, J _C ,F= 7.3 Hz), 135.54, 136.47 (d, J _C ,F = 2.9 Hz), 161 .27 (d, J _C ,F = 243.6 Hz); HRMS (ESI+): m/z calcd for Ci ₇ H ₂ iFN [M+H] ⁺ 258.1658; found 258.1652;; HPLC purity, 95.2%.

EXAMPLE 37 Synthesis of (£)-3-(4-fluorostyryl)-1 -(prop-2-yn-1 -yl)pyrrolidine

Step 1: Terf-butyl (£)-3-(4-fluorostyryl)pyrrolidine-1-carboxylate

Synthesized from terf-butyl 4-formylpyrrolidine-1 -carboxylate (1 .58 g, 7.93 mmol, 1 .0 equiv.) and (4-fluorobenzyl)triphenylphosphonium bromide (3.94g, 8.72 mmol, 1 .1 equiv., prepared via general procedure A) via general procedure B. The compound was purified by flash column chromatography using petroleum ether/Et ₂ O = 9/1 (v/v) as eluent. Mass: 210 mg; R _f = 0.68 (EtOAc/n-hex = 1/2, v/v); white solid, mp 70- 72 °C; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .45 (s, 9H), 1 .67-1 .80 (m, 1 H), 2.04 (dtd, J = 9.6, 6.6, 3.2 Hz, 1 H), 2.84-2.96 (m, 1 H), 3.05-3.16 (m, 1 H), 3.25-3.36 (m, 1 H), 3.42-3.64 (m, 2H), 6.01 (dd, J = 15.9, 7.8 Hz, 1 H), 6.39 (d, J = 15.9 Hz, 1 H), 6.93- 6.99 (m, 2H), 7.25-7.30 (m, 2H); MS (ESI+): m/z [M+Na] ⁺ 314.15; found 314.37.

Step 2: (£)-3-(4-Fluorostyryl)-1 -(prop-2-yn-1-yl)pyrrolidine

Synthesized from terf-butyl ((E)-3-(4-fluorostyryl)pyrrolidine-1 -carboxylate (0.15 g, 0.515 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 2/1 (v/v) as eluent. Yield: 65% (77 mg); R _f = 0.18 (EtOAc/n-hex = 1/2, v/v); yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .66-1 .74 (m, 1 H), 2.1 1-2.19 (m, 1 H), 2.23 (t, J = 2.4 Hz, 1 H), 2.50 (dd, J = 8.6, 6.7 Hz, 1 H), 2.72 (dt, J = 8.8, 5.5 Hz, 1 H), 2.77-2.83 (m, 1 H), 2.92-3.02 (m, 2H), 3.44 (d, J = 2.4 Hz, 2H), 6.12 (dd, J = 15.8, 8.1 Hz, 1 H), 6.34 (d, J = 15.8 Hz, 1 H), 6.94-7.00 (m, 2H), 7.26-7.32 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): 5 31 .68, 41 .46, 42.79, 52.13, 58.40, 72.55, 79.21 , 1 15.32 (d, J _C, F = 21 .1 Hz), 127.44 (d, JC,F = 8.1 Hz), 128.02, 133.1 1 (d, J _C ,F = 2.2 Hz), 133.48, 161 .96 (d, J _C ,F = 245.7 Hz); HRMS (ESI+): m/z calcd for Ci ₅ Hi ₇ FN [M+H] ⁺ 230.1345; found 230.1340; HPLC purity, 95.3%.

EXAMPLE 38

Synthesis of (£)-4-(2-(4-fluorophenyl)ethylidene)-1-(prop-2-yn-1 -yl)azepane and (Z)-4-(2-(4-fluorophenyl)ethylidene)-1 -(prop-2-yn-1 -yl)azepane

Step 1: Terf-butyl (E/Z)-4-(2-(4-fluorophenyl)ethylidene)azepan-1 -carboxylate

The solution of (4-fluorophenethyl)thphenylphosphonium bromide (2.80 g, 6.00 mmol, 1 .0 equiv.) in anhydrous THF (15 mL) was purged under a stream of argon for 5 min and cooled to 0 °C. To the resulting solution t-BuO ^" K ⁺ (0.70 g, 6.30 mmol, 1 .05 equiv.) was added, and stirred for 30 min before the solution of terf-butyl 4- oxoazepane-1 -carboxylate (1 .28 g, 6.00 mmol, 1 .0 equiv.) in THF (10 mL) was added. The reaction mixture was stirred for 2 h at 0 °C, and then the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography using EtOAc/n-hex = 1/9 (v/v) as eluent to obtain a mixture of cis/trans (ratio ~ 1/1 , estimared from 1 H NMR) isomers. Overall yield (both isomers): 90% (1 .728 g). colorless oil; Rf = 0.24 (EtOAc/n-hex = 1/9, v/v); 1 H NMR (400 MHz, CDCIs): δ 1 .40 (s, 9H), 1 .41 (s, 9H), 1 .63 (bs, 4H, cis + trans), 2.19-2.22 (m, 2H, cis + trans), 2.24-2.28 (m, 2H, cis + trans), 2.35 (t, J = 6.2 Hz, 2H, cis + trans), 2.46 (bs, 2H, cis + trans), 3.25-3.29 (m, 4H, cis + trans), 3.30-3.41 (m, 8H, cis + trans), 5.27- 5.32 (m, 1 H, trans), 5.37 (t, J = 6.7 Hz, 1 H, cis), 6.87-6.93 (m, 4H, cis + trans), 7.04- 7.09 (m, 4H, cis + trans); MS (ESI+): m/z [M+H]+ 342.18; found 342.01 .

Step 2: (£)-4-(2-(4-Fluorophenyl)ethylidene)-1 -(prop-2-yn-1 -yl)azepane and (Z)- 4-(2-(4-fluorophenyl)ethylidene)-1 -(prop-2-yn-1 -yl)azepane

Synthesized from terf-butyl (E/Z)-4-(2-(4-fluorophenyl)ethylidene)azepan-1 - carboxylate (1 .20 g, 3.757 mmol, 1 .0 equiv.) via general procedures D and E. The compounds were purified by flash column chromatography using CH ₂ Cl ₂ /acetone = 20/1 (v/v) as eluent to obtain both isomers.

(Z)-4-(2-(4-Fluorophenyl)ethylidene)-1-(prop-2-yn-1-yl)az epane: 82 mg, R _f = 0.38 (CH ₂ CI ₂ /acetone = 9/1 , v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCI3): δ 1 .70-1 .76 (m, 2H), 2.22 (t, J = 2.4 Hz, 1 H), 2.31-2.34 (m, 2H), 2.48-2.51 (m, 2H), 2.67-2.69 (m, 2H), 2.73-2.76 (m, 2H), 3.29 (d, J = 7.2 Hz, 2H), 3.40 (d, J = 2.4 Hz, 2H), 5.35 (tt, J = 7.2, 1 .2 Hz, 1 H), 6.92-6.97 (m, 2H), 7.1 1-7.14 (m, 2H); ¹³ C NMR (100 MHz, CDCIs): δ 28.71 , 30.54, 32.96, 36.49, 48.10, 53.58, 56.38, 72.36, 79.59, 1 14.96 (d, JC,F = 21 .1 Hz), 123.73, 129.55 (d, J _C ,F = 7.9 Hz), 136.97 (d, J _C ,F= 3.3 Hz); 140.24, 161 .13 (d, J _C, F = 243.4 Hz); HRMS (ESI+): m/z calcd for C1 ₇ H21 FN [M+H] ⁺ 258.1658; found 258.1653; .HPLC purity, 95.5%.

(E)-4-(2-(4-Fluorophenyl)ethylidene)-1-(prop-2-yn-1-yl)az epane: 29 mg, f? _f = 0.32 (CH ₂ CI ₂ /acetone = 9/1 , v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCI3): δ 1 .78-1 .84 (m, 2H), 2.23 (t, J = 2.4 Hz, 1 H), 2.40-2.45 (m, 4H), 2.67-2.72 (m, 4H), 3.29 (d, J = 7.3 Hz, 2H), 3.39 (d, J = 2.4 Hz, 2H), 5.35 (tt, J = 7.2, 1 .4 Hz, 1 H), 6.92- 6.98 (m, 2H), 7.10-7.15 (m, 2H); ¹³ C NMR (100 MHz, CDCI3): δ 26.54, 29.26, 32.99, 38.03, 48.00, 56.17, 56.78, 72.62, 79.43, 1 15.00 (d, J _C, F = 21 .3 Hz), 124.05, 129.55 (d, JC,F = 7.4 Hz), 136.96 (d, J _C ,F = 2.9 Hz); 140.45, 161 .16 (d, J _C ,F = 243.5 Hz); HRMS (ESI+): m/z calcd for C1 ₇ H21 FN [M+H] ⁺ 258.1658; found 258.1651 ; HPLC purity, 97.4%. EXAMPLE 39

Synthesis of 4-(4-fluorophenethyl)-1 -(prop-2-yn-1 -yl)azepane

Step 1: Terf-butyl 4-(4-fluorophenethyl)azepane-1 -carboxylate

Synthesized from terf-butyl (E/Z)-4-(2-(4-fluorophenyl)ethylidene)azepan-1 - carboxylate (0.41 g, 1 .284 mmol, 1 .0 equiv.) via general procedure C. The product was used without further purification. Yield: quantitative (0.414 g); R _f = 0.82 (EtOAc/n-hex = 1/1 , v/v); colorless oil; ¹ H NMR (400 MHz, DMSO-c/ ₆ , 80 °C): δ 1 .16- 1 .35 (m, 3H), 1 .40 (s, 9H), 1 .44-1 .55 (m, 3H), 1 .68-1 .85 (m, 3H), 2.57-2.61 (m, 2H), 3.14-3.27 (m, 2H), 3.34-3.48 (m, 2H), 7.01-7.07 (m, 2H), 7.18-7.23 (m, 2H); MS (ESI+): m/z [M+H] ⁺ 344.20; found 344.05.

Step 2: 4-(4-Fluorophenethyl)-1 -(prop-2-yn-1 -yl)azepane

Synthesized from terf-butyl 4-(4-fluorophenethyl)azepane-1 -carboxylate (0.370 g, 1 .151 mmol, 1 .0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 32% (84 mg); R _f = 0.26 (EtOAc/n-hex = 1/1 , v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .30-1 .63 (m, 6H), 1 .75-1 .84 (m, 3H), 2.19 (t, J = 2.4 Hz, 1 H), 2.54-2.59 (m, 2H), 2.61 (dd, J = 9.6, 3.0 Hz, 1 H), 2.67-2.70 (m, 2H), 2.75 (ddd, J = 12.9, 6.9, 3.2 Hz, 1 H), 3.36 (t, J = 2.3 Hz, 2H), 6.91-6.97 (m, 2H), 7.07- 7.12 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 26.60, 32.74, 32.82, 34.36, 37.45, 39.79, 47.95, 53.13, 55.35, 72.08, 79.97, 1 14.90 (d, J _C ,F = 21 .3 Hz), 129.50 (d, J _C ,F = 8.0 Hz), 138.31 (d, JC _, F = 3.7 Hz); 161 .03 (d, J _C, F = 243.5 Hz); HRMS (ESI+): m/z ca led for C1 ₇ H23FN [M+H] ⁺ 260.1815; found 260.1809; HPLC purity, 98.2%.

EXAMPLE 40 Synthesis of (£)-4-(2-(4-fluorobenzylidene)-1 -(prop-2-yn-1 -yl)azepane and (Z)-4- (2-(4-f luorobenzylidene)-1 -(prop-2-yn-1 -yl)azepane

The solution of (4-fluorobenzyl)triphenylphosphoniunn chloride (2.71 g, 6.66 mmol, 1 .1 equiv.) in anhydrous THF (20 ml_) was purged under a stream of argon for 5 min before NaH (60% dispersion on mineral oil, 0.27 g, 6.66 mmol, 1 .1 equiv.) was added. The resulting suspension was stirred for 3 h at room temperature, and then the solution of terf-butyl 4-oxoazepane-1 -carboxylate (1 .29 g, 6.05 mmol, 1 .0 equiv.) in THF (15 ml_) was added. The reaction mixture was stirred under reflux for 16 h, and then allowed to cool down to room temperature. The precipitate formed was filtered off, and the mother liquor was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography using petroleum ether/Et ₂ O = 9/1 (v/v) as eluent to obtain a mixture of cis/trans isomers (ratio ~ 42/58, estimated from 1 H NMR). Overall yield (both isomers): 35% (649 mg), colorless oil; R _f = 0.12 (petroleum ether/Et ₂ O = 9/1 , v/v); ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .29 (s, 5H, cis), 1 .43 (s, 4H, cis), 1 .45 (s, 12.5H, trans), 1 .63 (bs, 4.8H, cis + trans), 2.34-2.37 (m, 4.8H, cis + trans), 2.50 (t, J = 6.1 Hz, 2.8H, trans), 2.58 (td, J = 6.3, 1 .3 Hz, 2H, cis), 3.40-3.48 (m, 9.8H, cis + trans), 6.28 (d, J = 6.9 Hz, 1 .4H, trans), 6.34 (bs, 1 H, cis), 6.96-7.01 (m, 4.8H, cis + trans), 7.13-7.16 (m, 4.8H, cis + trans); MS (ESI+): m/z [M+Na] ⁺ 328.17; found 327.77. Step 2: (£)-4-(2-(4-Fluorobenzylidene)-1 -(prop-2-yn-1 -yl)azepane and (Z)-4-(2-(4- f luorobenzylidene)-1 -(prop-2-yn-1 -yl)azepane

Synthesized from terf-butyl (E/Z)-4-(2-(4-fluorobenzylidene)azepan-1 -carboxylate (270 mg, 0.884 mmol, 1 .0 equiv.) via general procedures D and E. The compounds were purified by flash column chromatography using CH ₂ Cl ₂ /acetone = 20/1 (v/v) as eluent to obtain both isomers.

(Z)-4-(4-fluorobenzylidene)-1-(prop-2-yn-1-yl)azepane: 9 mg, f? _f = 0.52 (CH ₂ CI ₂ /acetone = 9/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .80-1 .86 (m, 2H), 2.23 (t, J = 2.4 Hz, 1 H), 2.47-2.50 (m, 2H), 2.63-2.66 (m, 2H), 2.74-2.76 (m, 2H), 2.78-2.80 (m, 2H), 3.41 (d, J = 2.4 Hz, 2H), 6.27 (s, 1 H), 6.96-7.02 (m, 2H), 7.14-7.19 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 28.24, 31 .65, 37.14, 48.07, 53.82, 56.67, 72.88, 79.09, 1 14.86 (d, J _C, F = 21 .2 Hz), 124.65, 130.18 (d, J _C, F = 7.9 Hz), 134.14 (d, JC _, F = 3.1 Hz); 142.44, 161 .10 (d, J _C, F = 245.0 Hz); HRMS (ESI+): m/z calcd for Ci ₆ Hi ₉ FN [M+H] ⁺ 244.1502; found 244.1507; HPLC purity, 97.7%.

(E)-4-(4-fluorobenzylidene)-1-(prop-2-yn-1-yl)azepane: 16 mg, f? _f = 0.35 (CH ₂ CI ₂ /acetone = 9/1 , v/v); pale yellow transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .82-1 .88 (m, 2H), 2.24 (t, J = 2.4 Hz, 1 H), 2.54-2.60 (m, 4H), 2.70-2.72 (m, 2H), 2.78-2.81 (m, 2H), 3.42 (d, J = 2.4 Hz, 2H), 6.25 (s, 1 H), 6.96-7.02 (m, 2H), 7.16- 7.21 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 26.70, 30.62, 38.68, 47.94, 55.81 , 56.45, 72.91 , 79.16, 1 14.85 (d, J _C ,F = 21 .2 Hz), 124.90, 130.16 (d, J _C ,F = 7.8 Hz), 134.18 (d, JC,F = 3.5 Hz); 142.68, 161.08 (d, J _C ,F = 245.5 Hz); HRMS (ESI+): m/z calcd for Ci ₆ Hi ₉ FN [M+H] ⁺ 244.1502; found 244.1505; HPLC purity, 96.9%.

EXAMPLE 41

Synthesis of 4-(4-fluorobenzyl)-1-(prop-2-yn-1-yl)azepane

Step 1: Terf-butyl 4-(4-fluorobenzyl)azepane-1-carboxylate

Synthesized from terf-butyl (E/Z)-4-(2-(4-fluorobenzylidene)azepan-1-carboxylate (0.315 g, 1.031 mmol, 1.0 equiv.) via general procedure C. The product was used without further purification. Yield: quantitative (0.317 g); f? _f = 0.74 (EtOAc/n-hex = 1/1 , v/v); colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1.10-1.20 (m, 1H), 1.25-1.34 (m, 1H), 1.45 (s, 9H), 1.47-1.56 (m, 1H), 1.62-1.85 (m, 4H), 2.50 (d, J = 7.3 Hz, 2H), 3.09 (ddd, J = 13.9, 10.2, 3.8 Hz, 1H), 3.30-3.43 (m, 2H), 3.56 (d, J = 13.6 Hz, 1H), 6.92-6.98 (m, 2H), 7.05-7.11 (m, 2H); MS (ESI+): m/z [M+Na] ⁺ 330.18; found 329.81.

Step 2: 4-(4-Fluorobenzyl)-1-(prop-2-yn-1-yl)azepane

Synthesized from terf-butyl 4-(4-fluorobenzyl)azepane-1-carboxylate (0.290 g, 0.943 mmol, 1.0 equiv.) via general procedures D and E. The compound was purified by flash column chromatography using EtOAc/n-hex = 1/1 (v/v) as eluent. Yield: 56% (110 mg); R _f = 0.27 (EtOAc/n-hex = 1/1, v/v); colorless oil; ¹ H NMR (400 MHz, CDCIs): δ 1.25-1.45 (m, 2H), 1.53-1.59 (m, 1H), 1.61-1.87 (m, 4H), 2.18 (t, J = 2.4 Hz, 1 H), 2.49 (d, J = 7.4 Hz, 2H), 2.57 (ddd, J = 12.9, 9.8, 3.1 Hz, 1 H), 2.67-2.70 (m, 2H), 2.72 (ddd, J = 12.9, 6.5, 3.4 Hz, 1H), 3.34 (dd, J = 3.8, 2.4 Hz, 2H), 6.90-6.96 (m, 2H), 7.05-7.10 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 26.55, 32.60, 34.05, 40.08, 43.15, 47.91, 52.94, 55.10, 72.10, 79.89, 114.78 (d, J _C, F= 20.8 Hz), 130.31 (d, JC,F = 8.0 Hz), 136.76 (d, J _C ,F = 3.0 Hz); 161.11 (d, J _C ,F = 243.4 Hz); HRMS (ESI+): m/z calcd for Ci ₆ H ₂ iFN [M+H] ⁺ 246.1658; found 246.1660; IR (ATR): 3303, 2917, 2848, 1601, 1509, 1468, 1449, 1326, 1221, 1157, 1102, 835, 761, 663, 636 cm ^"1 ; HPLC purity, 97.4%. EXAMPLE 42

Synthesis of (£)-1-(but-3-yn-1-yl)-4-(4-fluorostyryl)piperidine

Step 1: But-3-yn-1-yl methanesulfonate

The activated primary alcohol intermediate (but-3-yn-1 -yl methanesulfonate) was synthesized from but-3-yn-1 -ol (0.227 mL, 3.00 mmol, 1 .0 equiv.) via general procedure H. The product was used without further purification. Yield: 89% (395 mg); Rf = 0.15 (EtOAc/n-hex = 1/4, v/v); pale yellow transparent oil.

Step 2: (£)-1 -(But-3-yn-1 -yl)-4-(4-fluorostyryl)piperidine

The titled compound synthesized from (E)-4-(4-fluorostyryl)piperidine 2,2,2- trifluoroacetate (0.122 g, 0.382 mmol, 1 .0 equiv.; prepared as described under the general procedure E) via general procedure G using previously prepared but-3-yn-1 - yl methanesulfonate instead of propargyl bromide. The crude product was purified by flash column chromatography using EtOAc/n-hex = 2/1 (v/v) as eluent. Yield: 43% (42 mg); R _f = 0.34 (EtOAc/n-hex = 2/1 , v/v); pale orange solid, mp 44-46 °C; ¹ H NMR (400 MHz, CDCI3): δ 1 .52 (dt, J = 12.5, 3.2 Hz, 1 H), 1 .55 (dt, J = 12.0, 3.6 Hz, 1 H), 1 .74-1 .79 (m, 2H), 1 .99 (t, J = 2.7 Hz, 1 H), 2.06-2.15 (m, 3H), 2.39-2.43 (m, 2H), 2.60-2.64 (m, 2H), 2.97 (dt, J = 1 1 .6, 3.6 Hz, 2H), 6.06 (dd, J = 16.0, 7.0 Hz, 1 H), 6.33 (d, J = 16.0 Hz, 1 H), 6.94-7.00 (m, 2H), 7.27-7.32 (m, 2H); ¹³ C NMR (100 MHz, CDCI3): δ 16.77, 31 .92, 39.1 1 , 53.24, 57.35, 69.02, 82.81 , 1 15.30 (d, J _C, F = 21 .4 Hz), 127.09, 127.40 (d, J _C, F = 7.9 Hz), 133.79 (d, J _C, F = 3.2 Hz), 134.66, 161 .97 (d, JC _, F = 245.8 Hz); HRMS (ESI+): m/z calcd for Ci ₇ H ₂ iFN [M+H] ⁺ 258.1658; found 258.1654; HPLC purity, 98.9%.

EXAMPLE 43 Synthesis of (£)-1 -(but-3-yn-1 -yl)-4-(4-fluorophenethyl)piperidine

Step 1: But-3-yn-1 -yl methanesulfonate

The activated primary alcohol intermediate (but-3-yn-1 -yl methanesulfonate) was synthesized from but-3-yn-1 -ol (0.227 mL, 3.00 mmol, 1 .0 equiv.) via general procedure H. The product was used without further purification. Yield: 89% (395 mg); Rf = 0.15 (EtOAc/n-hex = 1/4, v/v); pale yellow transparent oil.

Step 2: (£)-1 -(but-3-yn-1 -yl)-4-(4-fluorostyryl)piperidine

The titled compound synthesized from 4-(4-fluorophenethyl)piperidine 2,2,2- trifluoroacetate (0.160 g, 0.498 mmol, 1 .0 equiv.; prepared as described under the general procedure E) via general procedure G using previously prepared but-3-yn-1 - yl methanesulfonate. The crude product was purified by flash column chromatography using EtOAc/n-hex = 1 /1 (v/v) as eluent. Yield: 33% (42 mg); R _f = 0.20 (EtOAc/n-hex = 1 /1 , v/v); orange transparent oil; ¹ H NMR (400 MHz, CDCI ₃ ): δ 1 .22-1 .34 (m, 3H), 1 .50-1 .55 (m, 2H), 1 .70-1 .73 (m, 2H), 1 .97 (t, J = 2.7 Hz, 1 H), 1 .95-2.01 (m, 2H), 2.36-2.41 (m, 2H), 2.56-2.61 (m, 4H), 2.90-2.93 (m, 2H), 6.91 - 6.97 (m, 2H), 7.08-7.13 (m, 2H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 16.67, 32.05, 32.18, 35.02, 38.38, 53.51 , 57.33, 68.96, 82.81 , 1 14.95 (d, J _C ,F = 20.6 Hz), 129.51 (d, J _C ,F = 8.1 Hz), 138.16 (d, J _C ,F = 3.6 Hz), 161 .08 (d, J _C ,F = 243.1 Hz); HRMS (ESI+): m/z calcd for Ci ₇ H ₂₃ FN [M+H] ⁺ 260.1815; found 260.1808; IR (ATR): 331 1 , 2928, 2849, 1509, 1448, 1309, 1219, 1 157, 1087, 892, 823, 640 cm ^"1 ; HPLC purity, 100%. EXAMPLE 44

Synthesis of (£)-1 -(pent-4-yn-1 -yl)-4-(4-fluorophenethyl)piperidine

Step 1: Pent-4-yn-1 -yl methanesulfonate The activated primary alcohol intermediate (pent-4-yn-1 -yl methanesulfonate) was synthesized from pent-4-yn-1 -ol (0.464 mL, 5.00 mmol, 1 .0 equiv.) via general procedure H. The product was used without further purification. Yield: 46% (376 mg); Rf = 0.17 (EtOAc/n-hex = 1/4, v/v); colorless oil.

Step 2: (£)-1 -(Pent-4-yn-1 -yl)-4-(4-fluorostyryl)piperidine

The titled compound synthesized from (E)-4-(4-fluorostyryl)piperidine 2,2,2- trifluoroacetate (0.150 g, 0.470 mmol, 1 .0 equiv.; prepared as described under the general procedure E) via general procedure G using previously prepared pent-4-yn- 1 -yl methanesulfonate instead of propargyl bromide. The crude product was purified by flash column chromatography using CH ₂ CI ₂ /MeOH = 20/1 (v/v) as eluent. Yield: 43% (55 mg); R _f = 0.20 (CH ₂ CI ₂ /MeOH = 20/1 , v/v); orange transparent oil; ¹ H NMR (400 MHz, CDCIs): δ 1 .47-1 .58 (m, 2H), 1 .70-1 .77 (m, 4H), 1 .95 (t, J = 2.7 Hz, 1 H), 2.01 (td, J = 1 1 .7, 2.4 Hz, 2H), 2.07-2.16 (m, 1 H), 2.23 (td, J = 7.1 , 2.7 Hz, 2H), 2.42-2.45 (m, 2H), 2.95 (dt, J = 1 1 .7, 2.6 Hz, 2H), 6.07 (dd, J = 16.0, 7.0 Hz, 1 H), 6.33 (d, J = 16.0 Hz, 1 H), 6.94-7.00 (m, 2H), 7.27-7.32 (m, 2H); ¹³ C NMR (100 MHz, CDCI3): δ 16.50, 25.83, 32.00, 39.30, 53.60, 57.73, 68.40, 84.17, 1 15.28 (d, J _C ,F = 21 .3 Hz), 126.92, 127.36 (d, J _C, F = 8.1 Hz), 133.80, 134.84 (d, J _C, F = 2.1 Hz), 161 .90 (d, JC _, F = 245.7 Hz); HRMS (ESI+): m/z calcd for Ci ₈ H ₂₃ FN [M+H] ⁺ 272.1815; found 272.1818; HPLC purity, 99.8%.

Biological procedures

Inhibition assay using human recombinant MAO-B

The effects of the compounds on hMAO-B (hMAO-B, Sigma Aldrich, M7441 ) were investigated using a previously described fluorimetric assay (Zhou M, Anal Biochem, 1997, 253, 169-174; Bautista-Aguilera OM, J Med Chem, 2014, 57, 10455-10463). The inhibitory activity of the compounds was evaluated by their effects on the production of hydrogen peroxide (H ₂ O ₂ ) from p-tyramine, a nonspecific substrate for both hMAO isoforms. The production of the H ₂ O ₂ was detected using Amplex Red reagent in the presence of horseradish peroxidase, where a highly sensitive fluorescent product, resorufin, is produced at stoichiometric amounts. Recombinant human microsomal hMAO enzymes expressed in baculovirus infected insect cells (BTI-TN-5B1 -4), horse-radish peroxidase (type II, lyophilized powder), and p- tyramine hydrochloride were purchased from Sigma Aldrich. 10-Acety 1-3,7- dihydroxyphenoxazine (Amplex Red reagent) was synthesized as described in the literature (von der Eltz H, USP Patent No. 4900822, Feb. 13, 1990).

Briefly, 100 μΙ_ 50 mM sodium phosphate buffer (pH 7.4, 0.05% [v/v] Triton X-1 14) containing the compounds or the reference inhibitors and hMAO-A or hMAO-B required to oxidize (in the control group) approximately 15 pmol of p-tyramine/min (hMAO-A, 0.25 g protein; hMAO-B, 1 .2 g protein) were incubated for 15 min at 37 °C in a flat-bottomed black 96-well microplate ( CLEAR® microplate; Greiner Bio One International GmbH, Germany), and placed in a dark microplate reader chamber. After the pre-incubation, the reaction was started by adding the final concentrations of 250 μΜ Amplex Red reagent, 4 U/mL horseradish peroxidase, and 1 mM p-tyramine (final volume, 200 μΙ_). The production of resorufin was quantified on the basis of the fluorescence generated (A _ex = 530 nm, A _em = 590 nm) at 37 °C over a period of 20 min, during which time the fluorescence increase linearly. For control experiments, DMSO was used instead of the appropriate dilutions of the compounds in DMSO. To determine the blank value (b), phosphate-buffered solution replaced the enzyme solution. The initial velocities were calculated from the trends obtained, with each measurement carried out in duplicate. The inhibitory potencies are expressed as the residual activities (RA = (v, - b) I (v ₀ - b), where v, is the velocity in the presence of the test compounds, and v ₀ the control velocity in the presence of DMSO. The IC ₅ o values were obtained by plotting residual enzyme activities against applied inhibitor concentration, with the experimental data fitted to a Hill four parameter equation (Equation (1 )) using in-house python script and Gnuplot software.

Y = Min + (Max - Min) / (1 +10 ^" ((LoglC ₅₀ - X) ^x Hill coefficient)) (1), where X represent logarithm of inhibitor concentration, and Y the residual activity. The capacity of the test compounds to react directly with Amplex Red was determined by adding these compounds to a solution containing all of the components except the MAO isoenzyme. No significant interference was detected for the test compounds.

Reversibility assay

For the reversibility assay, hMAO-B at 100-fold final concentration was incubated with the inhibitors at a concentration 10-fold the IC ₅ o at 37 °C (volume, 50 μΙ_). After 15 min, the mixture was diluted 100-fold into the reaction buffer containing Amplex Red reagent, horseradish peroxidase, and p-tyramine hydrochloride. The final concentrations of all of the reagents and MAO-B were the same as in the assay described above. The reaction was monitored for 30 min. Control experiments were carried out in the same manner, where the inhibitor solution was replaced by DMSO.

Results of biological assays

Table 1 : Inhibitor potencies of the compounds with general Formula (I)

J 67.0 ±11.4 17402.0 ±2039.1

hMAO-B: human monoamine oxidase B

RA: residual activity at 100 μΜ of the test compound expressed as percentage Table 2: Reversibility assay of inhibitors with general Formula (I)

Activity of the enzyme after 100-fold dilution

Structure

(in percentage ±SD)

21.47 ±2.35

6.20 ±0.71

94.91 ±2.52

74.01 ±2.76

5.55 ±0.25

Embodiments of the invention

[Item 1 ] Disubstituted azetidines, pyrrolidine, piperidines and azepanes with general Formula (I):

(I) wherein: n: 1-5 m: 0, 1 , or 2 z: 0 or 1

L: -CH2CH2-, -CH2-, =CH ₂ -, =CH ₂ CH ₂ -, ^trans

A: is saturated 3 to 8-membered ring optionally comprising one or more heteroatoms selected from N, O, S, and P; the ring being optionally substituted with one or more substituents independently selected from R ¹ , wherein:

R ¹ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , SR ² , OR ² , NR ² R ³ R ² : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu, R ³ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu, is phenyl, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, pyridine, indole, quinoline, isoquinoline, 2,3.dihydrobenzo[i ][1 ,4]dioxine, benzo[c/][1 ,3]dioxole, indazole, bezimidazo le, quinazoline, naphthalene,

R ¹ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ² : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ³ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁴ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁵ : Me, Et, i-Pr, t-Bu, i-Bu, CN, F, CI, Br, CF ₃ , CH ₂ CF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, SR ⁶ , OR ⁶ , NR ⁶ R ⁷

R ⁶ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu,

R ⁷ : H, Me, Et, n-Pr, i-Pr, t-Bu, i-Bu, or a pharmaceutically acceptable salt, hydrate or solvate thereof; in the form of a pure diastereoisomer or as a mixture of diastereomers, in the form of a pure enantiomer or as a mixture of enantiomers.

[Item 2] The use of compound with the general Formula (I) of iteml as a pharmaceutically active agent.

[Item 3] The use of compound with the general Formula (I) of item 1 as a medicament for diagnostics, prevention, alleviation of symptoms and treatment of acute and chronic neurological disorders, cognitive and neurodegenerative diseases.

[Item 4] The use of compound with the general Formula (I) of item 1 as a medicament for diagnostics, prevention, alleviation of symptoms and treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease and dementia.

[Item 5] A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 and a pharmaceutical acceptable excipient.

[Item 6] The use of compound with the general Formula (I) of item 1 in a combination with pharmaceutically acceptable excipients as a medicament for diagnostics, prevention, alleviation of symptoms and treatment of acute and chronic neurological disorders, cognitive and neurodegenerative diseases.

[Item 7] The use of compound with the general Formula (I) of item 1 for the manufacture of a medicament for diagnostics, prevention, alleviation of symptoms and treatment of acute and chronic neurological disorders, cognitive and neurodegenerative diseases.