AUTOPHAGY INDUCING COMPOUNDS AND USES THEREOF

Field of the invention

The present invention relates to compounds of formula (I) or a salt, stereoisomer, tautomer or N- oxide thereof. Furthermore, the present invention relates to compounds of formula (I), or a salt, stereoisomer, tautomer or N-oxide thereof, which are suitable for inducing and/or stimulating the process of autophagy, as well as the compounds of formula (I) for use in medicine and for use in the treatment of autophagy-related diseases or conditions.

Background of the invention

Autophagy is the cell’s method for degradation of unnecessary or damaged components such as proteins, organelles and invading pathogens. It utilises an orchestrated process resulting in lysosomal degradation resulting in recycling of cellular components and maintenance of cellular homeostasis.

The cell-autonomous antimicrobial defense functions of autophagy, demonstrated initially in the case of streptococci and Mycobacterium tuberculosis have been extended to a wide variety of microbes with a caveat that most highly adapted pathogens have evolved specific protective mechanisms against autophagic elimination of microbes. Other studies have uncovered orderly intersections between autophagy and innate and adaptive immunity, T cell development, differentiation and homeostasis, and inflammatory responses. Thus, autophagy plays a large role in various diseases such as cancer, inflammatory disease, degenerative neurological disease, and immune disease. Autophagy is a cell survival mechanism that is induced in stressed cells.

Towers and Thorburn (Therapeutic Targeting of Autophagy. EBioMedicine. 2016;14:15-23) disclose that autophagy is widely accepted as cytoprotective against neurodegenerative diseases and a variety of clinical interventions are moving forward to increase autophagy as a therapeutic intervention. Autophagy has both positive and negative roles in cancer and this has led to controversy over whether or how autophagy manipulation should be attempted in cancer therapy. Nevertheless, cancer is the disease where most current activity in trying to manipulate autophagy for therapy is taking place and dozens of clinical trials are using autophagy inhibition with Chloroquine or Hydroxychloroquine in combination with other drugs for the treatment of multiple neoplasms. They review recent literature implicating autophagy in neurodegenerative diseases and cancer and highlight some of the opportunities, controversies and potential pitfalls of therapeutically targeting autophagy.

Mulcahy Levy and Thorburn (Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ 27, 543-857 (2020)) disclose that autophagy allows for cellular material to be delivered to lysosomes for degradation resulting in basal or stress-induced turnover of cell components that provide energy and macromolecular precursors. These activities are thought to be particularly important in cancer where both tumorpromoting and tumor-inhibiting functions of autophagy have been described. Autophagy has also been intricately linked to apoptosis and programmed cell death, and understanding these interactions is becoming increasingly important in improving cancer therapy and patient outcomes. In the review, they consider how recent discoveries about how autophagy manipulation elicits its effects on cancer cell behavior can be leveraged to improve therapeutic responses.

Grainger et al. (1995, Nature Medicine 1 : 1067-1073) and Reckless et al. (1997, Circulation 95: 1542-1548) have demonstrated that tamoxifen, a potent inducer of autophagy, inhibited atherosclerosis in mice models by suppressing the diet-induced formation of lipid lesions in the aorta by lowering of low-density lipoprotein (LDL) cholesterol.

Dikic and Elazar (Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 2018 19(6):349-364) discuss that autophagy is deregulated in the context of various human pathologies, including cancer and neurodegeneration, and its modulation has considerable potential as a therapeutic approach.

Pierzynowska et al. (Metab Brain Dis 2018; 33(4):989-1008) focuses on ways by which autophagy can be stimulated and discusses that activation of autophagy by different factors or processes can be considered as a therapeutic strategy in metabolic neurodegenerative diseases.

The development of more selective autophagy inducers is needed for the treatment and/or prevention of diseases where autophagy plays a role. It is an object of the present invention to provide effective agents that can be used for the prevention and treatment of conditions and diseases that can be treated/prevented by inducing and/or stimulating autophagy, in particular cancer, age-related diseases, and infections. Objects and summary of the invention

It is therefore an object of the present invention to provide compounds, which induce and/or stimulate autophagy. It is another object of the present invention to provide compounds, which are suitable for use as a medicament. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of an autophagy-related disease or condition, in particular cancer, age-related diseases, and infections. It is yet another object of the present invention to provide compounds, which are suitable for use in the treatment of one or more autophagy-related diseases selected from the group consisting of neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, systemic lupus erythematosus, epilepsy, cancer, liver diseases (e.g. nonalcoholic fatty liver disease (NAFLD)), a1 antitrypsin deficiency, Charcot Marie Tooth syndrome, Rett Syndrome, Sickle Cell disease, Wilson Disease, amyloidosis, Gaucher’s diseases, lysosomal and glycogen storage disorders (e.g., Glycogen Storage Disease type 1A (GSD1A)), cystic fibrosis; viral infection and diseases human cytomegalovirus (HCMV) infection, hepatitis B, human immunodeficiency virus infection, Zika virus infection, coronavirus infection, HCoV-229E, HCoV-NL63, betacoronavirus infection, such as HCoV-OC43, SARS-CoV-1 , HCoV-HKLH , MERS-CoV or SARS-CoV-2, bacterial infections, metabolic disorders, diabetes, fibrosis, silicosis, diabetic retinopathy, glaucoma, cataracts, age- related macular degeneration, glomerulonephritis, glomerulosclerosis, wound healing disorders, Niemann-Pick type C (NPC) disease, fibrinogen storage disease (FSB), inclusion body disease (IBD), muscular dystrophy, Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, myopathy, myofibrillar myopathy, hereditary myopathy, diabetic cardiomyopathy, anti-inflammatory disorders, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, irritable bowel syndrome, Crohn’s disease, vascular disorders, stroke, coronary artery diseases, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, Behcet’s syndrome, giant cell arteritis, polymyalgia rheumatic, Wegener’s granulomatosis, Churg-Strauss syndrome, vasculitis, Henoch- Schonlein pruprua, Kawasaki disease, viral infection or replication, pox virus infection, herpes virus infection, asthma, allergic rhinitis, COPD, osteoporosis, organ transplant rejection, psoriasis, hypertrophic scarring (keloid formation), adhesion formations following general or gynecological surgery, lung fibrosis, liver fibrosis, kidney fibrosis, disorders caused by intracellular parasites, malaria, tuberculosis, neuropathic pain, post-operative phantom limb pain or postherpetic neuralgia, allergies, amyotrophic lateral sclerosis (ALS), antigen induced recall response, immune response suppression, muscle degeneration and atrophy, frailty in aging, spinal cord injury, and diseases and conditions involving misfolded and/or nonfolded proteins. It is yet a further object of the present invention to provide compounds suitable for use for stimulating autophagy in an in-vitro assay.

The above objects can be achieved by the compounds of formula (I) as defined herein as well as pharmaceutical compositions comprising the same, and by the medical uses thereof. The inventors of the present invention surprisingly found that the compounds of formula (I) as defined herein induce and/or stimulate autophagy. Accordingly, the compounds of formula (I) are for use in medicine, in particular for use in the treatment of an autophagy-related disease or condition, in particular cancer, age-related diseases, and infections.

In a first aspect, the present invention therefore relates to a compound according to formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof, wherein

R ¹ , R ² are independently of each other selected from H, CN, halogen, OR ^C , Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; or

R ¹ and R ² together with the atoms to which they are attached form a 5- or 6-membered partially or fully unsaturated or aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ³ is H, CN, halogen, OR ^C , Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or -O- Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ;

R ^N is H or Ci-C ₄ -alkyl;

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-Ci-C2- alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or R ^N and R ⁶ together with the atoms to which they are attached form a 4- to 6-membered saturated or partially unsaturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^x is Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^Y is halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , Ci-C4-alkyl-NR ^a R ^b , or two R ^Y form cyclopropyl;

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl;

R ^c is H, Ci-C4-alkyl, or phenyl; and m is 1 , 2 or 3.

In a preferred embodiment, the compound is not

In another preferred embodiment, the compound is not

In another preferred embodiment, the compound is not

In another preferred embodiment, the compound according to formula (I) is present in the form of a salt, preferably in the form of a hydrochloride salt.

In another preferred embodiment,

R ¹ , R ² are independently of each other selected from halogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x .

In another preferred embodiment,

R ¹ is Ci-C4-alkoxy, Ci-C4-haloalkoxy or -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; and

R ² is halogen, Ci-C4-alkoxy, or Ci-C4-haloalkoxy;

R ^x is phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In another preferred embodiment,

R ³ is H, or halogen; and m is 1 .

In another preferred embodiment,

R ⁴ , R ⁵ are H; and

R ⁶ is a 5- or 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In another preferred embodiment,

R ⁴ is H; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 6- membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In another preferred embodiment,

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; preferably R ⁶ is a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In another preferred embodiment, the compound of formula (I) is selected from N-(5-chloro-2- ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(5-chloro-2-propoxybenzyl)-1- (piperidin-4-yl)methanamine hydrochloride, 2-(4-chloro-2-(((piperidin-4- ylmethyl)amino)methyl)phenoxy)ethan-1-ol hydrochloride, N-(5-chloro-2-(2-methoxyethoxy)benzyl)- 1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5-fluorobenzyl)-1 -(piperidin-4- yl)methanamine hydrochloride, N-(5-chloro-2-isopropoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, (S)-N-(5-chloro-2-ethoxybenzyl)-1 -(pyrrolidin-3-yl)methanamine hydrochloride, (R)- N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanamine hydrochloride, (R)-N-(5-chloro-2- ethoxybenzyl)-1-methylpiperidin-3-amine, N-(5-chloro-2-ethoxybenzyl)-1-ethylpiperidin-4-amine, N ¹ -(5-chloro-2-ethoxybenzyl)ethane-1 ,2-diamine hydrochloride, (1r, 4/')-/V ¹ -(5-chloro-2- ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2-ethoxybenzyl)pentane-1 ,5- diamine, N-(5-chloro-2-ethoxybenzyl)-1-methylpiperidin-4-amine, A/-(5-chloro-2-ethoxybenzyl)-2- (piperazin-1-yl)ethan-1 -amine hydrochloride, (R)-N-(5-chloro-2-ethoxybenzyl)pyrrolidin-3-amine hydrochloride, (1 r,3r)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclobutane-1 ,3-diamine hydrochloride, (1S,3S)- N ¹ -(5-chloro-2-ethoxybenzyl)cyclopentane-1 ,3-diamine hydrochloride, (S)-N-(5-chloro-2- ethoxybenzyl)piperidin-3-amine hydrochloride, N-(5-chloro-2-ethoxybenzyl)azetidin-3-amine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1 -amine hydrochloride, 2-(2- aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine hydrochloride, N ¹ -(5-chloro-2- ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2-ethoxybenzyl)-2- methylpropane-1 ,2-diamine hydrochloride, N-(4-chloro-2-ethoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(4,5-dichloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamin e hydrochloride, N-(2-chloro-6-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(3- chloro-4-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- methoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (tnfluoromethoxy)benzyl)-1-(pipendin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5-

(trifluoromethyl) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2-

(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2-

(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 3-(4-chloro-2-

(((piperidin-4-ylmethyl)amino)methyl)phenoxy)propan-1-ol hydrochloride, N-(5-chloro-2-(3- methoxypropoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 1-(6- chlorobenzo[d][1 ,3]dioxol-4-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, 1-(7-chloro- 2,3-dihydrobenzo[b][1 ,4]dioxin-5-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, N-(2- ethoxy-5-(trifluoromethoxy)benzyl)-1-methylpiperidin-4-amine , N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-methylpiperidin-4-amine, N ¹ -(2-ethoxy-5-(trifluoromethoxy)benzyl) cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine hydrochloride, N-(2-(2-methoxyethoxy)-5- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (1 r, 4r)-N ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, (1s, 4s)-/V ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, N-(5-chloro-2-(2- methoxyethoxy)benzyl)-1-methylpiperidin-4-amine, N-(2-ethoxy-5-fluorobenzyl)-1-methylpiperidin- 4-amine, N-(5-chloro-2-propoxybenzyl)-1 -methylpiperidin-4-amine, N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1-methylpiperidin-4-amine, N-(5-fluoro-2-propoxybenzyl)-1-(piperidin- 4-yl)methanamine hydrochloride, N-(4-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, /V-(4-chloro-2-(2-methoxyethoxy)benzyl)-1-(piperidin-4-yl)me thanamine hydrochloride, N-(2-(cyclopropylmethoxy)-5-fluorobenzyl)-1-(piperidin-4-yl) methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-4-fluorobenzyl)-1-(piperidin-4-yl) methanamine hydrochloride, A/-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl )methanamine hydrochloride, (S)-N-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin- 3-yl)methanamine hydrochloride, N-(5-chloro-2-phenoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5- chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (R)-N-(5- chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin-3-yl)meth anamine hydrochloride, A/-(4-fluoro-2- propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(2-(cyclopropylmethoxy)-4,5- difluorobenzyl)-1 -(pi pe rid i n-4-y I) methanamine hydrochloride, (R)-N-(5-chloro-2-propoxybenzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, (R)-N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, N-(4-chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-1-(1-methylpiperidin-4- yl)methanamine, N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4-yl)me thanamine hydrochloride, N-(2-(benzyloxy)-5-chlorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, and N-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1-(piperidin-4-yl )methanamine hydrochloride.

In another preferred embodiment, the compound of formula (I) is selected from N-(5-chloro-2- ethoxybenzyl)-1 -(piperidin-4-yl)methanamine, A/-(5-chloro-2-propoxybenzyl)-1 -(piperidin-4- yl)methanamine, 2-(4-chloro-2-(((piperidin-4-ylmethyl)amino)methyl)phenoxy)e than-1-ol, N-(5- chloro-2-(2-methoxyethoxy)benzyl)-1-(piperidin-4-yl)methanam ine, N-(2-ethoxy-5-fluorobenzyl)-1- (piperidin-4-yl)methanamine, N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4-yl)methanamin e, (S)- N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanamine, (R)-N-(5-chloro-2-ethoxybenzyl)-1- (pyrrolidin-3-yl)methanamine, (R)-N-(5-chloro-2-ethoxybenzyl)-1-methylpiperidin-3-amine, N-(5- chloro-2-ethoxybenzyl)-1-ethylpiperidin-4-amine, N ¹ -(5-chloro-2-ethoxybenzyl)ethane-1 ,2-diamine, (1r, 4r)-/V ¹ -(5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine, N ¹ -(5-chloro-2- ethoxybenzyl)pentane-1 ,5-diamine, N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-4-amine, A/-(5- chloro-2-ethoxybenzyl)-2-(piperazin-1-yl)ethan-1 -amine, (R)-N-(5-chloro-2-ethoxybenzyl)pyrrolidin- 3-amine, (1 r,3r)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclobutane-1 ,3-diamine, (1 S,3S)-N ¹ -(5-chloro-2- ethoxybenzyl)cyclopentane-1 ,3-diamine, (S)-N-(5-chloro-2-ethoxybenzyl)piperidin-3-amine, N-(5- chloro-2-ethoxybenzyl)azetidin-3-amine, N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1- amine, 2-(2-aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine, N ¹ -(5-chloro-2- ethoxybenzyl)cyclohexane-1 ,4-diamine, N ¹ -(5-chloro-2-ethoxybenzyl)-2-methylpropane-1 ,2- diamine, N-(4-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(4,5-dichloro-2- ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(2-chloro-6-ethoxybenzyl)-1-(piperidin-4- yl)methanamine, N-(3-chloro-4-ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(2-ethoxy-5- methoxybenzyl)-1 -(piperidin-4-yl)methanamine, N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1 -

(piperidin-4-yl)methanamine, N-(2-ethoxy-5-(trifluoromethyl)benzyl)-1-(piperidin-4-yl)met hanamine, N-(5-chloro-2-(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)me thanamine, N-(5-chloro-2-

(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl)methanamine , 3-(4-chloro-2-(((piperidin-4- ylmethyl)amino)methyl)phenoxy)propan-1-ol, N-(5-chloro-2-(3-methoxypropoxy)benzyl)-1-

(piperidin-4-yl)methanamine, 1 -(6-chlorobenzo[d][1 , 3]d ioxol-4-y l)-N-(piperid in-4-yl methyl) methanamine, 1 -(7-chloro-2,3-dihydrobenzo[b][1 , 4]d ioxi n-5-y I)- N- (pi perid i n-4-y I methy I) methanamine, N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-methylpiperidin-4- amine, N-(2-(2- methoxyethoxy)-5-(trifluoromethoxy)benzyl)-1-methylpiperidin -4-amine, N ¹ -(2-ethoxy-5-

(trifluoromethoxy)benzyl) cyclohexane-1 ,4-diamine, N ¹ -(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine, (1 r, 4r)-N ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine, (1s, 4s)-/V ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine, N-(5-chloro-2-(2-methoxyethoxy)benzyl)-1- methylpiperidin-4-amine, N-(2-ethoxy-5-fluorobenzyl)-1 -methylpiperidin-4-amine, N-(5-chloro-2- propoxybenzyl)-1-methylpiperidin-4-amine, N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1- methylpiperidin-4-amine, N-(5-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(4-chloro- 2-propoxybenzyl)-1 -(piperidin-4-yl)methanamine, A/-(4-chloro-2-(2-methoxyethoxy)benzyl)-1 - (piperidin-4-yl)methanamine, N-(2-(cyclopropylmethoxy)-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine, N-(2-(cyclopropylmethoxy)-4-fluorobenzyl)-1-(piperidin-4-yl) methanamine, A/-(4- chloro-2-(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl)metha namine, (S)-N-(4-chloro-2-

(cyclopropylmethoxy)benzyl)-1 -(pyrrolidin-3-yl)methanamine, N-(5-chloro-2-phenoxybenzyl)-1 - (piperidin-4-yl)methanamine, N-(5-chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1 -(piperidin-4- yl)methanamine, (R)-N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin- 3-yl)methanamine, N- (4-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine, A/-(2-(cyclopropylmethoxy)-4,5- difluorobenzyl)-1 -(piperidin-4-yl) methanamine, (R)-N-(5-chloro-2-propoxybenzyl)-1-(pyrrolidin-3- yl)methanamine, (R)-N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-(pyrrolidin-3- yl)methanamine, N-(4- chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4-yl)methanamin e, N-(5-chloro-2-ethoxybenzyl)-1-(1- methylpiperidin-4-yl)methanamine, N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4- yl)methanamine, N-(2-(benzyloxy)-5-chlorobenzyl)-1-(piperidin-4-yl)methanami ne, and N-(5-chloro- 2-((4-fluorobenzyl)oxy)benzyl)-1-(piperidin-4-yl)methanamine .

In a further aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (I) as defined herein and optionally a pharmaceutically acceptable carrier, diluent or excipient.

In yet another aspect, the present invention relates to a compound of formula (I) as defined herein, or a pharmaceutical composition comprising the same as defined herein for use in medicine. In particular, the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein for inducing and/or stimulating autophagy.

In yet another aspect, the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein for use in a method of treating an autophagy-related disease or condition.

In one embodiment, the compound of the present invention or the pharmaceutical composition comprising the same is for use in the treatment of an autophagy-related disease or condition selected from the group consisting of neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, systemic lupus erythematosus, epilepsy, cancer, liver diseases (e.g. nonalcoholic fatty liver disease (NAFLD)), a1 antitrypsin deficiency, Charcot Marie Tooth syndrome, Rett Syndrome, Sickle Cell disease, Wilson Disease, amyloidosis, Gaucher’s disease, lysosomal and glycogen storage disorders (e.g., Glycogen Storage Disease type 1A (GSD1A)), cystic fibrosis; viral infection and diseases, human cytomegalovirus (HCMV) infection, hepatitis B, human immunodeficiency virus infection, Zika virus infection, coronavirus infection, HCoV-229E, HCoV-NL63, betacoronavirus infection, such as HCoV-OC43, SARS-CoV-1 , HCoV- HKU1 , MERS-CoV or SARS-CoV-2, bacterial infections, metabolic disorders, diabetes, fibrosis, silicosis, diabetic retinopathy, glaucoma, cataracts, age-related macular degeneration, glomerulonephritis, glomerulosclerosis, wound healing disorders, Niemann-Pick type C (NPC) disease, fibrinogen storage disease (FSB), inclusion body disease (IBD), muscular dystrophy, Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, myopathy, myofibrillar myopathy, hereditary myopathy, diabetic cardiomyopathy, anti-inflammatory disorders, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, irritable bowel syndrome, Crohn’s disease, vascular disorders, stroke, coronary artery diseases, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, Behcet’s syndrome, giant cell arteritis, polymyalgia rheumatic, Wegeners granulomatosis, Churg-Strauss syndrome, vasculitis, Henoch-Schonlein pruprua, Kawasaki disease, viral infection or replication, pox virus infection, herpes virus infection, asthma, allergic rhinitis, COPD, osteoporosis, organ transplant rejection, psoriasis, hypertrophic scarring (keloid formation), adhesion formations following general or gynecological surgery, lung fibrosis, liver fibrosis, kidney fibrosis, disorders caused by intracellular parasites, malaria, tuberculosis, neuropathic pain, post-operative phantom limb pain or postherpetic neuralgia, allergies, amyotrophic lateral sclerosis (ALS), antigen induced recall response, immune response suppression, muscle degeneration and atrophy, frailty in aging, spinal cord injury, and diseases and conditions involving misfolded and/or nonfolded proteins.

In another embodiment of the present invention, said treatment comprises a combination of at least one compound of formula (I) as defined herein with at least one additional pharmaceutically active substance for said autophagy-related disease or condition.

In another aspect, the present invention relates to the use of a compound of formula (I) as defined herein for stimulating autophagy in an in-vitro assay.

Detailed description

In the following, preferred embodiments of the substituents in the above compound of formula (I) are described in further detail. It is to be understood that each preferred embodiment is relevant on its own as well as in combination with other preferred embodiments. Furthermore, it is to be understood that the preferences in each case also apply to the salts, stereoisomers, tautomers and N-oxides of the compounds of formula (I) of the invention. The invention also includes pharmaceutically acceptable salts, solvates, stereoisomers, tautomers and N-oxides of the compound of formula (I).

As indicated above, in a first aspect the present invention relates to a compound of formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof, wherein

R ¹ , R ² are independently of each other selected from H, CN, halogen, OR ^C , Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; or R ¹ and R ² together with the atoms to which they are attached form a 5- or 6-membered partially or fully unsaturated or aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ³ is H, CN, halogen, OR ^C , Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or -O- Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ;

R ^N is H or Ci-C ₄ -alkyl;

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-Ci-C2- alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ^N and R ⁶ together with the atoms to which they are attached form a 4- to 6-membered saturated or partially unsaturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^x is Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^Y is halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , Ci-C4-alkyl-NR ^a R ^b , or two R ^Y form cyclopropyl;

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl;

R ^c is H, Ci-C4-alkyl, or phenyl; and m is 1 , 2 or 3.

In one embodiment of the present invention, the following substituent definitions with regard to the substituents R ¹ and R ² are preferred for the compound of formula (I). Thus, in one embodiment, the present invention relates to a compound according to formula (I) wherein

R ¹ , R ² are independently of each other selected from H, CN, halogen, OR ^C , Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; and

R ^x is Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In another embodiment, the present invention relates to a compound according to formula (I) wherein

R ¹ and R ² together with the atoms to which they are attached form a 5- or 6-membered partially or fully unsaturated or aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In connection with the above embodiment, it is to be understood that R ¹ and R ² are attached to neighboring C-atoms of the phenyl-ring in the core structure and form together with these C-atoms to which they are attached a fused 5- or 6-membered partially or fully unsaturated or aromatic heterocyclic ring.

In connection with the above embodiments, it is to be understood that R ³ , R ⁴ , R ⁵ , R ⁶ , R ^N , R ^Y , R ^c and m have the meanings as defined above or further below. Furthermore, in connection with the above embodiments it is to be understood that the compounds according to formula (I) may be present in the form of a salt, preferably the compounds according to formula (I) may be present in the form of the hydrochloride salt.

In a preferred embodiment of the present invention,

R ¹ , R ² are independently of each other selected from halogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; and

R ^x is phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In a more preferred embodiment of the present invention,

R ¹ is Ci-C4-alkoxy, Ci-C4-haloalkoxy or -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; and

R ² is halogen, Ci-C4-alkoxy, or Ci-C4-haloalkoxy; wherein

R ^x is phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In an even more preferred embodiment of the present invention,

R ¹ is Ci-Cs-alkoxy, Ci-C2-haloalkoxy, or -O-C2-C3-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; wherein

R ^x is phenyl, or a 3- to 5- membered saturated carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C4-alkyl, NR ^a R ^b , or Ci-C4-alkyl-NR ^a R ^b ; and

R ^c is H, Ci-C4-alkyl, or phenyl.

In a particularly preferred embodiment of the present invention,

R ¹ is -OCH ₃ , -OCH2CH3, -O(CH ₂ ) ₂ CH3, -OCF3, or -O-C ₂ -C ₃ -alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; wherein

R ^x is phenyl, or cyclopropyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^Y is halogen, preferably F or Cl, more preferably F;

R ^c is H, CH ₃ .

In another even more preferred embodiment of the present invention,

R ² is halogen, Ci-C4-alkoxy, or Ci-C4-haloalkoxy; preferably

R ² is F, Cl, CH ₃ , CH ₂ CH ₃ , or -OCF ₃ ; more preferably

R ² is F, Cl, or -OCF ₃ .

In connection with the above preferred embodiments it is to be understood that R ³ , R ⁴ , R ⁵ , R ⁶ , R ^N and m are as defined above or further below. Furthermore, in connection with the above preferred embodiments it is to be understood that the compounds according to formula (I) may be present in the form of a salt, preferably in the form of the hydrochloride salt.

In another embodiment of the present invention, the following substituent definitions with regard to the substituent R ³ are preferred for the compound of formula (I). Thus, in one embodiment, the present invention relates to a compound of formula (I) wherein

R ³ is H, CN, halogen, OR ^C , Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or -O- Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; wherein

R ^x is Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

In a preferred embodiment of the present invention,

R ³ is H, or halogen; preferably

R ³ is H, F, or CI; more preferably

R ³ is H or Cl; even more preferably

R ³ is H.

In connection with the above embodiments, it is to be understood that the remaining substituents R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^N , R ^Y , R ^c and m are as defined above or further below. Furthermore, in connection with the above embodiments it is to be understood that the compounds of formula (I) may be present in the form of a salt, preferably in the form of the hydrochloride salt.

In another embodiment of the present invention, the following substituent definitions with regard to the substituents R ⁴ , R ⁵ and R ⁶ are preferred for the compounds of formula (I). Thus, in one embodiment, the present invention relates to a compound of formula (I) wherein

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-Ci-C2- alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , Ci-C4-alkyl-NR ^a R ^b , or two R ^Y form cyclopropyl; and

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl.

In a preferred embodiment of the present invention,

R ⁴ , R ⁵ are H; and

R ⁶ is a 5- or 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C ₄ -alkyl, NR ^a R ^b , or Ci-C ₄ -alkyl-NR ^a R ^b ;

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl.

In a more preferred embodiment of the present invention,

R ⁴ , R ⁵ are H; and

R ⁶ is a 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C4-alkyl, preferably F, Cl, CH3 or CH2CH3.

In an even more preferred embodiment of the present invention,

R ⁴ , R ⁵ are H; and

R ⁶ is piperidinyl, wherein the piperidinyl-ring is either unsubstituted or substituted with one substituent R ^Y ; wherein

R ^Y is CH ₃ .

In a particularly preferred embodiment, R ⁴ , R ⁵ are H; and

R ⁶ is piperidinyl. In connection with the above preferred embodiments, it is to be understood that the remaining substituents R ¹ , R ² , R ³ , R ^N and m are as defined above or further below. Further, in connection with the above preferred embodiments it is to be understood that the compounds according to formula (I) may be present in the form of a salt, preferably in the form of the hydrochloride salt.

In another embodiment, the following substituent definitions with regard to R ⁴ , R ⁵ and R ⁶ are preferred with regard to the compounds of formula (I).

In a preferred embodiment of the present invention,

R ⁴ is H; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 6- membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; and wherein

R ^Y is halogen, Ci-C4-alkyl, NR ^a R ^b , or Ci-C4-alkyl-NR ^a R ^b ; and

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl.

In a more preferred embodiment of the present invention,

R ⁴ is H; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 6- membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one heteroatom selected from N, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; and wherein

R ^Y is F, Cl, Ci-C ₂ -alkyl, or NR ^a R ^b ; and

R ^a , R ^b are independently of each other selected from H, and Ci-C2-alkyl.

In a particularly preferred embodiment of the present invention,

R ⁴ is H; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 6- membered saturated carbocyclyl or piperidinyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; and wherein

R ^Y is CH ₃ , CH2CH3, or NH ₂ .

In connection with the above preferred embodiments, it is to be understood that the remaining substituents R ¹ , R ² , R ³ , R ^N and m are as defined above or further below. Further, in connection with the above preferred embodiments it is to be understood that the compounds according to formula (I) may be present in the form of a salt, preferably in the form of the hydrochloride salt.

In another embodiment, the present invention relates to a compound of formula (I) wherein

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; preferably R ⁶ is a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C ₄ -alkyl, NR ^a R ^b , or Ci-C ₄ -alkyl-NR ^a R ^b ; and

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl.

In a preferred embodiment of the present invention,

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; preferably R ⁶ is a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C4-alkyl, NR ^a R ^b , or Ci-C4-alkyl-NR ^a R ^b ; and

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl. In an even more preferred embodiment of the present invention,

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C ₄ -alkyl;

R ⁶ is a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C ₄ -alkyl, NR ^a R ^b , or Ci-C ₄ -alkyl-NR ^a R ^b ; and

R ^a , R ^b are independently of each other selected from H, and Ci-C ₄ -alkyl.

In another preferred embodiment of the present invention,

R ⁴ is selected from H, and Ci-C ₄ -alkyl; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C ₄ -alkyl, NR ^a R ^b , or Ci-C ₄ -alkyl-NR ^a R ^b ; and

R ^a , R ^b are independently of each other selected from H, and Ci-C ₄ -alkyl.

In connection with the above embodiments, it is to be understood that the remaining substituents R ¹ , R ² , R ³ , R ^N and m are as defined above or further below. Further, in connection with the above preferred embodiments it is to be understood that the compounds according to formula (I) may be present in the form of a salt, preferably in the form of the hydrochloride salt.

In another embodiment of the present invention, the following substituent definitions for R ^N and m are preferred with regard to the compounds of formula (I). Thus in one embodiment, the present invention relates to a compound of formula (I) wherein

R ^N is H or Ci-C ₄ -alkyl; and m is 1 , 2, or 3.

In a preferred embodiment of the present invention, R ^N is H or CH3; and m is 1 or 2. In a particularly preferred embodiment of the present invention,

R ^N is H, and m is 1 .

In connection with the above embodiments, it is to be understood that the remaining substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above or further below. Further, in connection with the above preferred embodiments it is to be understood that the compounds according to formula (I) may be present in the form of a salt, preferably in the form of the hydrochloride salt.

Thus, in a preferred embodiment, the present invention refers to a compound of formula (I) wherein R ^N is H, and m is 1 , corresponding to a compound according to the following formula (l)-A or (l)-B

With regard to the compounds according to formula (I), in particular with regard to the compounds according to formula (l)-A and (l)-B the following substituent definitions for R ¹ are preferred:

R ¹ is -OCH3, -OCH2CH3, -O(CH ₂ ) ₂ CH ₃ , -OCF3, or -O-C ₂ -C3-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; wherein

R ^x is phenyl, or cyclopropyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^c is H, CH3; and

R ^Y is halogen, preferably F or Cl, more preferably F;

With regard to the compounds according to formula (I), in particular with regard to the compounds according to formula (l)-A and (l)-B the following substituent definitions for R ² are preferred: R ² is F, Cl, or -OCF ₃ .

With regard to the compounds according to formula (I), in particular with regard to the compounds according to formula (l)-A and (l)-B the following substituent definitions for R ³ are preferred: R ³ is H or Cl.

With regard to the compounds according to formula (I), in particular with regard to the compounds according to formula (l)-A and (l)-B the following substituent definitions for R ⁴ , R ⁵ and R ⁶ are preferred: R ⁴ , R ⁵ are H; and

R ⁶ is piperidinyl, wherein the piperidinyl-ring is either unsubstituted or substituted with one substituent R ^Y ; wherein

R ^Y is CH ₃ ; or

R ⁴ is H; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 6- membered saturated carbocyclyl or piperidinyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; and wherein

R ^Y is CH ₃ , CH2CH3, or NH ₂ .

Further, with regard to the compounds according to formula (I), in particular with regard to the compounds according to formula (l)-A and (l)-B the following substituent definitions for R ⁴ , R ⁵ and R ⁶ are preferred:

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C4-alkyl, NR ^a R ^b , or Ci-C4-alkyl-NR ^a R ^b ; and

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl; or

R ⁴ is selected from H, and Ci-C4-alkyl; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; wherein

R ^Y is halogen, Ci-C4-alkyl, NR ^a R ^b , or Ci-C4-alkyl-NR ^a R ^b ; and

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl.

In connection with the regard to the above compounds of formula (I), particularly with regard to the above compounds of formula (l)-A and (l)-B, it is preferred that the compounds are present in the form of a salt, preferably in the form of the hydrochloride salt.

In connection with the compounds of formula (I), as well as in connection with the compounds of formula (l)-A and (l)-B it is preferred that the compound is not

Further, in connection with the compounds of formula (I), as well as in connection with the compounds of formula (l)-A and (l)-B it is preferred that the compound is not

Further, in connection with the compounds of formula (I), as well as in connection with the compounds of formula (l)-A and (l)-B it is preferred that the compound is not

In particular, in connection with the compounds of formula (I), preferably in connection with the compounds of formula (l)-A and (l)-B it is preferred that the compound is not

In particularly preferred embodiments, the compound of formula (I) is a compound selected from the group consisting of N-(5-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, /V-(5-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 2-(4-chloro-2- (((piperidin-4-ylmethyl)amino)methyl)phenoxy)ethan-1 -ol hydrochloride, N-(5-chloro-2-(2- methoxyethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5-fluorobenzyl)- 1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, (S)-N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanami ne hydrochloride, (R)-N-(5-chloro-2-ethoxybenzyl)-1 -(pyrrolidin-3-yl)methanamine hydrochloride, (R)- N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-3-amine, N-(5-chloro-2-ethoxybenzyl)-1 - ethylpiperidin-4-amine, N ¹ -(5-chloro-2-ethoxybenzyl)ethane-1 ,2-diamine hydrochloride, (1r, 4r)-A/ ¹ - (5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2- ethoxybenzyl)pentane-1 ,5-diamine, N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-4-amine, A/-(5- chloro-2-ethoxybenzyl)-2-(piperazin-1-yl)ethan-1 -amine hydrochloride, (R)-N-(5-chloro-2- ethoxybenzyl)pyrrolidin-3-amine hydrochloride, (1 r,3r)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclobutane-

1 .3-diamine hydrochloride, (1 S,3S)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclopentane-1 ,3-diamine hydrochloride, (S)-N-(5-chloro-2-ethoxybenzyl)piperidin-3-amine hydrochloride, N-(5-chloro-2- ethoxybenzyl)azetidin-3-amine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan- 1 -amine hydrochloride, 2-(2-aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine hydrochloride, N ¹ -(5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2- ethoxybenzyl)-2-methylpropane-1 ,2-diamine hydrochloride, N-(4-chloro-2-ethoxybenzyl)-1 - (piperidin-4-yl)methanamine hydrochloride, N-(4,5-dichloro-2-ethoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(2-chloro-6-ethoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(3-chloro-4-ethoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2- ethoxy-5-methoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (trifluoromethyl) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, 3-(4-chloro-2- (((piperidin-4-ylmethyl)amino)methyl)phenoxy)propan-1-ol hydrochloride, N-(5-chloro-2-(3- methoxypropoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 1 -(6- chlorobenzo[d][1 ,3]dioxol-4-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, 1-(7-chloro-

2.3-dihydrobenzo[b][1 ,4]dioxin-5-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, N-(2- ethoxy-5-(trifluoromethoxy)benzyl)-1 -methylpiperidin-4-amine, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-methylpiperidin-4-amine, N ¹ -(2-ethoxy-5-(trifluoromethoxy)benzyl) cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine hydrochloride, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (1 r, 4r)-N ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, (1s, 4s)-/V ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, N-(5-chloro-2-(2- methoxyethoxy)benzyl)-1-methylpiperidin-4-amine, N-(2-ethoxy-5-fluorobenzyl)-1-methylpiperidin- 4-amine, N-(5-chloro-2-propoxybenzyl)-1 -methylpiperidin-4-amine, N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1-methylpiperidin-4-amine, N-(5-fluoro-2-propoxybenzyl)-1-(piperidin- 4-yl) methanamine hydrochloride, N-(4-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(4-chloro-2-(2-methoxyethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-5-fluorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-4-fluorobenzyl)-1-(piperidin-4-yl) methanamine hydrochloride, A/-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl )methanamine hydrochloride, (SJ-N-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin- 3-yl)methanamine hydrochloride, N-(5-chloro-2-phenoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5- chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (R)-N-(5- chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin-3-yl)meth anamine hydrochloride, A/-(4-fluoro-2- propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(2-(cyclopropylmethoxy)-4,5- difluorobenzyl)-1 -(pi pe rid i n-4-y I) methanamine hydrochloride, (R)-N-(5-chloro-2-propoxybenzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, (R)-N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, N-(4-chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-1-(1-methylpiperidin-4- yl)methanamine, N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4-yl)me thanamine hydrochloride, N-(2-(benzyloxy)-5-chlorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, and N-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1-(piperidin-4-yl )methanamine hydrochloride.

In another preferred embodiment, the compound of formula (I) is selected from N-(5-chloro-2- ethoxybenzyl)-1 -(piperidin-4-yl)methanamine, A/-(5-chloro-2-propoxybenzyl)-1 -(piperidin-4- yl)methanamine, 2-(4-chloro-2-(((piperidin-4-ylmethyl)amino)methyl)phenoxy)e than-1-ol, N-(5- chloro-2-(2-methoxyethoxy)benzyl)-1-(piperidin-4-yl)methanam ine, N-(2-ethoxy-5-fluorobenzyl)-1- (piperidin-4-yl)methanamine, N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4-yl)methanamin e, (S)- N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanamine, (R)-N-(5-chloro-2-ethoxybenzyl)-1- (pyrrolidin-3-yl)methanamine, (R)-N-(5-chloro-2-ethoxybenzyl)-1-methylpiperidin-3-amine, N-(5- chloro-2-ethoxybenzyl)-1-ethylpiperidin-4-amine, N ¹ -(5-chloro-2-ethoxybenzyl)ethane-1 ,2-diamine, (1r, 4/')-/V ¹ -(5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine, N ¹ -(5-chloro-2- ethoxybenzyl)pentane-1 ,5-diamine, N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-4-amine, A/-(5- chloro-2-ethoxybenzyl)-2-(piperazin-1-yl)ethan-1 -amine, (R)-N-(5-chloro-2-ethoxybenzyl)pyrrolidin- 3-amine, (1 r,3r)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclobutane-1 ,3-diamine, (1 S,3S)-N ¹ -(5-chloro-2- ethoxybenzyl)cyclopentane-1 ,3-diamine, (S)-N-(5-chloro-2-ethoxybenzyl)piperidin-3-amine, N-(5- chloro-2-ethoxybenzyl)azetidin-3-amine, N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1- amine, 2-(2-aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine, N ¹ -(5-chloro-2- ethoxybenzyl)cyclohexane-1 ,4-diamine, N ¹ -(5-chloro-2-ethoxybenzyl)-2-methylpropane-1 ,2- diamine, N-(4-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(4,5-dichloro-2- ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(2-chloro-6-ethoxybenzyl)-1-(piperidin-4- yl)methanamine, N-(3-chloro-4-ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(2-ethoxy-5- methoxybenzyl)-1 -(piperidin-4-yl)methanamine, N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1 -

(piperidin-4-yl)methanamine, N-(2-ethoxy-5-(trifluoromethyl)benzyl)-1-(piperidin-4-yl)met hanamine, N-(5-chloro-2-(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)me thanamine, N-(5-chloro-2-

(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl)methanamine , 3-(4-chloro-2-(((piperidin-4- ylmethyl)amino)methyl)phenoxy)propan-1-ol, N-(5-chloro-2-(3-methoxypropoxy)benzyl)-1-

(piperidin-4-yl)methanamine, 1 -(6-chlorobenzo[d][1 ,3]dioxol-4-yl)-N-(piperidin-4-ylmethyl) methanamine, 1 -(7-chloro-2,3-dihydrobenzo[b][1 , 4]d ioxi n-5-y I)- N- (pi perid i n-4-y I methy I) methanamine, N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-methylpiperidin-4- amine, N-(2-(2- methoxyethoxy)-5-(trifluoromethoxy)benzyl)-1-methylpiperidin -4-amine, N ¹ -(2-ethoxy-5-

(trifluoromethoxy)benzyl) cyclohexane-1 ,4-diamine, N ¹ -(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine, (1 r, 4r)-N ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine, (1s, 4s)-/V ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine, N-(5-chloro-2-(2-methoxyethoxy)benzyl)-1- methylpiperidin-4-amine, N-(2-ethoxy-5-fluorobenzyl)-1 -methylpiperidin-4-amine, N-(5-chloro-2- propoxybenzyl)-1-methylpiperidin-4-amine, N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1- methylpiperidin-4-amine, N-(5-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(4-chloro- 2-propoxybenzyl)-1 -(piperidin-4-yl)methanamine, A/-(4-chloro-2-(2-methoxyethoxy)benzyl)-1 - (piperidin-4-yl)methanamine, N-(2-(cyclopropylmethoxy)-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine, N-(2-(cyclopropylmethoxy)-4-fluorobenzyl)-1-(piperidin-4-yl) methanamine, A/-(4- chloro-2-(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl)metha namine, (S)-N-(4-chloro-2-

(cyclopropylmethoxy)benzyl)-1 -(pyrrolidin-3-yl)methanamine, N-(5-chloro-2-phenoxybenzyl)-1 - (piperidin-4-yl)methanamine, N-(5-chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1 -(piperidin-4- yl)methanamine, (R)-N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin- 3-yl)methanamine, N- (4-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine, A/-(2-(cyclopropylmethoxy)-4,5- difluorobenzyl)-1 -(piperidin-4-yl) methanamine, (R)-N-(5-chloro-2-propoxybenzyl)-1-(pyrrolidin-3- yl)methanamine, (R)-N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-(pyrrolidin-3- yl)methanamine, N-(4- chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4-yl)methanamin e, N-(5-chloro-2-ethoxybenzyl)-1-(1- methylpiperidin-4-yl)methanamine, N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4- yl)methanamine, N-(2-(benzyloxy)-5-chlorobenzyl)-1-(piperidin-4-yl)methanami ne, and N-(5-chloro- 2-((4-fluorobenzyl)oxy)benzyl)-1-(piperidin-4-yl)methanamine .

Also provided herein is a compound as shown in Table 1. In one embodiment, the compound is not compound 66 or compound 67 as shown in Table 1 .

Definitions

The term “compound(s) of the present invention" is to be understood as equivalent to the term "compound(s) according to the invention", and also covers a salt, stereoisomer, tautomer or N- oxide thereof. Pharmaceutically acceptable salts, solvates, stereoisomers, tautomers or N-oxides are also covered. The compounds according to the invention may be amorphous or may exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activities. The present invention relates to amorphous and crystalline forms of the compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), as well as amorphous or crystalline salts thereof. Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA Orange Book database. They can be formed in a customary manner, e.g., by reacting the compound with an acid of the anion in question, if the compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the invention with a suitable base. This may include addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, palmoate and stearate. Exemplary salts also include oxalate, chloride, bromide, iodide, bisulphate, acid phosphate, isonicotinate, salicylate, acid citrate, oleate, tannate, pantothenate, bitartrate, ascorbate, gentisinate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, ethanesulfonate, and benzenesulfonate salts.

The compounds of the present invention can also be present in the form of the free base. The term “free base”, as used herein, refers to the neutral form of the compounds of the present invention, i.e., the compounds not in the form of a salt. The free base of the compounds of the present invention can be formed by common methods known to the person skilled in the art. For example, if the synthesis of the compounds according to the present invention provides the product compounds in the form of a salt, in particular a salt of an inorganic or organic acid (such as the hydrochloride salt), the free base can be obtained, e.g., by treating the salt of an inorganic or organic acid, such as the hydrochloride salt, with an alkaline aqueous solution (such as, e.g., sodium hydroxide or ammonia) and extracting said solution with an organic non-polar solvent (such as, e.g., diethyl ether or DCM). The organic solvent phase containing the free base can then be separated followed by evaporation of the organic solvent. For example, the free base of the compounds of the present invention can be obtained following the experimental procedure for salt breaking described below.

Depending on the substitution pattern, the compounds according to the invention may have one or more centres of chirality, including axial chirality. The invention provides both, pure enantiomers or pure diastereomers of the compounds according to the invention, and their mixtures, including racemic mixtures. Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis/trans isomers or E/Z isomers) and mixtures thereof. E/Z- isomers may be present with respect to, e.g., an alkene, carbon-nitrogen double-bond or amide group.

Tautomers may be formed, if a substituent is present at the compound of formula (I) of the present invention, which allows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers or the like.

The term "N-oxide" includes any compound of the present invention, which has at least one tertiary nitrogen atom that is oxidized to a N-oxide moiety. The term "substituted", as used herein, means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected.

The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.

When it is referred to certain atoms or moieties being substituted with “one or more” substituents, the term “one or more” is intended to cover at least one substituent, e.g. 1 , 2, 3, 4, or 5 substituents, preferably 1 , 2, or 3 substituents, more preferably 1 , or 2 substituents. When neither the term “unsubstituted” nor “substituted” is explicitly mentioned concerning a moiety, said moiety is to be considered as unsubstituted.

The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix C _n -C _m indicates in each case the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine, or bromine, preferably fluorine or chlorine.

The term "alkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n- butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, and 1 -ethylpropyl.

The term "haloalkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from Ci-C4-haloalkyl, more preferably from Ci-Cs-haloalkyl or Ci- C2-haloalkyl, in particular from Ci-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

The term "alkoxy" as used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 2 carbon atoms. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like. The term "haloalkoxy" as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C2-haloalkoxy, in particular C2 -fluoroalkoxy, such as trifluoroethoxy and the like.

The term “cycloalkyl” as used herein denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term “carbocyclic” or “carbocyclyl” includes, unless otherwise indicated, in general a 3- to 9- membered, preferably a 3- to 6-membered, more preferably a 5- or 6-membered monocyclic ring comprising 3 to 9, preferably 3 to 6, more preferably 5 or 6 carbon atoms. The carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hiickel rule for aromaticity is not fulfilled, whereas aromatic means that the Hiickel (4n + 2) rule is fulfilled. The term “carbocycle” or “carbocyclyl”, unless otherwise indicated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl. Preferably, the term “carbocycle” covers cycloalkyl and cycloalkenyl groups, for example cyclopropane, cyclobutane, cyclopentane and cyclohexane rings.

The term “heterocyclic” or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 9- membered, preferably a 3- to 6-membered, more preferably 5- or 6-membered monocyclic ring. The heterocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hiickel rule for aromaticity is not fulfilled, whereas aromatic means that the Hiickel (4n + 2) rule is fulfilled. The heterocycle typically comprises one or more, e.g. 1 , 2, or 3, preferably 1 , or 2 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The remaining ring members are carbon atoms. The saturated or partially or fully unsaturated heterocycles usually comprise 1 , 2, or 3, preferably 1 , or 2 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The skilled person is aware that llows:

Further, a skilled person is aware that resonance structures of the oxidized forms may be possible. Saturated heterocycles include, unless otherwise indicated, in general 3- to 9-membered, preferably 3- to 6-membered, more preferably 5- or 6-membered monocyclic rings comprising 3 to 9, preferably 3 to 6, more preferably 5 or 6 atoms comprising at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetra hydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.

As used herein, the terms “carbocyclylalkyl” and “heterocyclylalkyl” and the like refer to the corresponding groups, which are bonded to the remainder of the molecule via an alkyl, preferably via a Ci-C2-alkyl group. Preferred examples include benzyl (i.e. phenylmethyl). In addition, as used herein, the terms such as “Ci-C6-alkyl-NR ^a R ^b ” refer to the corresponding group, e.g. NR ^a R ^b , which are bonded to the remainder of the molecule via an alkyl group, preferably via a Ci-C4-alkyl group, more preferably via a Ci-C2-alkyl group.

As used herein, the term “alkylene” refers to a linking straight-chain or branched alkylene group having usually from 1 to 4 carbon atoms, e.g. 1 , 2, 3, or 4 carbon atoms. The alkylene group bridges a certain group to the remainder of the molecule. Preferred alkylene groups include methylene (CH2), ethylene (CH2CH2), propylene (CH2CH2CH2) and the like. A skilled person understands that, if it is referred, e.g., to CH2 that the carbon atom being tetravalent has two valences left for forming a bridge (-CH2-). Similarly, when it is referred, e.g., to CH2CH2, each carbon atom has one valence left for forming a bridge (-CH2CH2-). Furthermore, when is it referred, e.g., to CH2CH2CH2, each terminal carbon atom has one valence left for forming a bridge (-CH2CH2CH2-).

As used in the specification and the claims, the singular forms of “a” and “an” also include the corresponding plurals unless the context clearly dictates otherwise. The same applies for plural forms used herein, which also include the singular forms unless the context clearly dictates otherwise.

The terms “about” and “approximately” in the context of the present invention denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%.

It needs to be understood that the term “comprising” is not limiting. For the purposes of the present invention, the term “consisting of’ is considered to be a preferred embodiment of the term “comprising of’. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group, which preferably consists of these embodiments only.

The term “treatment” is to be understood as also including the option of “prophylaxis”. Thus, whenever reference is made herein to a “treatment” or “treating”, this is to be understood as “treatment and/or prophylaxis” or “treating and/or preventing”. The term “pharmaceutically acceptable excipient, carrier or diluent” refers to a solid or liquid filler, diluent or encapsulating substance, which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the host, which may be either humans or animals, to which it is administered. Depending upon the particular route of administration, a variety of pharmaceutically-acceptable carriers such as those well known in the art may be used. Nonlimiting examples include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water. Pharmaceutically acceptable carriers or excipients also include diluents (fillers, bulking agents, e.g. lactose, microcrystalline cellulose), disintegrants (e.g. sodium starch glycolate, croscarmellose sodium), binders (e.g. PVP, HPMC), lubricants (e.g. magnesium stearate), glidants (e.g. colloidal SiC>2), solvents/co-solvents (e.g. aqueous vehicle, propylene glycol, glycerol), buffering agents (e.g. citrate, gluconates, lactates), preservatives (e.g. Na benzoate, parabens (Me, Pr and Bu), BKC), anti-oxidants (e.g. BHT, BHA, ascorbic acid), wetting agents (e.g. polysorbates, sorbitan esters), thickening agents (e.g. methylcellulose or hydroxyethylcellulose), sweetening agents (e.g. sorbitol, saccharin, aspartame, acesulfame), flavouring agents (e.g. peppermint, lemon oils, butterscotch, etc.), humectants (e.g. propylene glycol, glycerol, sorbitol).

The term “mammal” as used herein includes a mouse, rat, monkey, cat, dog, rabbit, goat, sheep, horse, camel, lama, cow and a human.

The terms "subject" and "patient" are used interchangeably and refer to a mammal or a human.

The term "therapeutically effective amount" refer to a predetermined amount of the compound or pharmaceutical composition which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker ) or subjective (i.e., subject gives an indication of or feels an effect or physician observes a change).

Description of pharmaceutical compositions, medical uses and uses according to the present invention

The present invention also provides a pharmaceutical composition comprising the compound according to formula (I) and optionally a pharmaceutically acceptable excipient or carrier.

The pharmaceutical composition may be formulated for any suitable route of administration including oral, subcutaneous, intravenous, intravenous or epidural patient controlled analgesia (PCA and PCEA), intramuscular, intrathecal, epidural, intracistemal, intraperitoneal, transdermal, topical, buccal, sublingual, transmucosal, inhalation, intra-articular, intranasal, rectal or ocular administration. The pharmaceutical composition may be formulated as a sustained release or controlled release formulation.

The present invention also provides the compound according to formula (I) for use in medicine. In one embodiment, the compound according to formula (I) is for use in the treatment of an autophagy-related disease or condition. In one embodiment, the compound according to formula (I) is for use in the treatment of cancer, age-related diseases, and infections.

Thus, in one embodiment, the present invention relates to a compound according to formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof, wherein

R ¹ , R ² are independently of each other selected from H, CN, halogen, OR ^C , Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; or

R ¹ and R ² together with the atoms to which they are attached form a 5- or 6-membered partially or fully unsaturated or aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ³ is H, CN, halogen, OR ^C , Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or -O- Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ;

R ^N is H or Ci-C ₄ -alkyl;

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-Ci-C2- alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ^N and R ⁶ together with the atoms to which they are attached form a 4- to 6-membered saturated or partially unsaturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^x is Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^Y is halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , Ci-C4-alkyl-NR ^a R ^b , or two R ^Y form cyclopropyl;

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl;

R ^c is H, Ci-C4-alkyl, or phenyl; and m is 1 , 2 or 3, for use in the treatment of an autophagy-related disease or condition.

In a preferred embodiment, the compound according to formula (I) as defined above is for use in the treatment of cancer, age-related diseases, and infections.

In connection with the above embodiments regarding the compounds according to formula (I) for use in the treatment of an autophagy-related disease or condition as defined above and for the diseases as selected further below, it is to be understood that the preferred embodiments regarding the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^N , m as well as R ^x , R ^Y , R ^a , R ^b , and R ^c of the compounds of formula (I) as defined in detail above are also preferred embodiments in this connection.

In one embodiment, the compound according to formula (I) is for use in the treatment of a disease or condition selected from the group consisting of neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, systemic lupus erythematosus, epilepsy, cancer, liver diseases (e.g. nonalcoholic fatty liver disease (NAFLD)), a1 antitrypsin deficiency, Charcot Marie Tooth syndrome, Rett Syndrome, Sickle Cell disease, Wilson Disease, amyloidosis, Gaucher’s diseases, lysosomal and glycogen storage disorders (e.g., Glycogen Storage Disease type 1A (GSD1A)), cystic fibrosis; viral infection and diseases human cytomegalovirus (HCMV) infection, hepatitis B, human immunodeficiency virus infection, Zika virus infection, coronavirus infection, HCoV-229E, HCoV-NL63, betacoronavirus infection, such as HCoV-OC43, SARS-CoV-1 , HCoV-HKU1 , MERS-CoV or SARS-CoV-2, bacterial infections, metabolic disorders, diabetes, fibrosis, silicosis, diabetic retinopathy, glaucoma, cataracts, age-related macular degeneration, glomerulonephritis, glomerulosclerosis, wound healing disorders, Niemann-Pick type C (NPC) disease, fibrinogen storage disease (FSB), inclusion body disease (IBD), muscular dystrophy, Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, myopathy, myofibrillar myopathy, hereditary myopathy, diabetic cardiomyopathy, anti-inflammatory disorders, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, irritable bowel syndrome, Crohn’s disease, vascular disorders, stroke, coronary artery diseases, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, Behcet’s syndrome, giant cell arteritis, polymyalgia rheumatic, Wegener’s granulomatosis, Churg-Strauss syndrome, vasculitis, Henoch-Schonlein pruprua, Kawasaki disease, viral infection or replication, pox virus infection, herpes virus infection, asthma, allergic rhinitis, COPD, osteoporosis, organ transplant rejection, psoriasis, hypertrophic scarring (keloid formation), adhesion formations following general or gynecological surgery, lung fibrosis, liver fibrosis, kidney fibrosis, disorders caused by intracellular parasites, malaria, tuberculosis, neuropathic pain, post-operative phantom limb pain or postherpetic neuralgia, allergies, amyotrophic lateral sclerosis (ALS), antigen induced recall response, immune response suppression, muscle degeneration and atrophy, frailty in aging, spinal cord injury, and diseases and conditions involving misfolded and/or nonfolded proteins.

In one embodiment, the compounds provided herein are for use in the treatment of an autophagy- related disease selected from the group consisting of neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, systemic lupus erythematosus, epilepsy, cancer, liver diseases (e.g. nonalcoholic fatty liver disease (NAFLD)), a1 antitrypsin deficiency, Charcot Marie Tooth syndrome, Rett Syndrome, Sickle Cell disease, Wilson Disease, amyloidosis, Gaucher’s diseases, lysosomal and glycogen storage disorders (e.g., Glycogen Storage Disease type 1A (GSD1A)), cystic fibrosis; viral infection and diseases human cytomegalovirus (HCMV) infection, hepatitis B, human immunodeficiency virus infection, Zika virus infection, coronavirus infection, HCoV-229E, HCoV-NL63, betacoronavirus infection, such as HCoV-OC43, SARS-CoV-1 , HCoV-HKLH , MERS-CoV or SARS-CoV-2, metabolic disorders, diabetes, fibrosis, silicosis, diabetic retinopathy, glaucoma, cataracts, age-related macular degeneration, glomerulonephritis, glomerulosclerosis, wound healing disorders, Niemann-Pick type C (NPC) disease, fibrinogen storage disease (FSB), inclusion body disease (IBD), muscular dystrophy, Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, myopathy, myofibrillar myopathy, hereditary myopathy, diabetic cardiomyopathy, anti-inflammatory disorders, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, irritable bowel syndrome, Crohn’s disease, vascular disorders, stroke, coronary artery diseases, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, Behcet’s syndrome, giant cell arteritis, polymyalgia rheumatic, Wegener’s granulomatosis, Churg-Strauss syndrome, vasculitis, Henoch-Schonlein pruprua, Kawasaki disease, viral infection or replication, pox virus infection, herpes virus infection, asthma, allergic rhinitis, COPD, osteoporosis, organ transplant rejection, psoriasis, hypertrophic scarring (keloid formation), adhesion formations following general or gynecological surgery, lung fibrosis, liver fibrosis, kidney fibrosis, disorders caused by intracellular parasites, malaria, neuropathic pain, postoperative phantom limb pain or postherpetic neuralgia, allergies, amyotrophic lateral sclerosis (ALS), antigen induced recall response, immune response suppression, muscle degeneration and atrophy, frailty in aging, spinal cord injury, and diseases and conditions involving misfolded and/or nonfolded proteins.

In one embodiment, the compounds provided herein are for use in the treatment of an autophagy- related disease selected from the group consisting of neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, liver diseases (e.g. nonalcoholic fatty liver disease (NAFLD)), a1 antitrypsin deficiency, Charcot Marie Tooth syndrome, Rett Syndrome, Wilson Disease, amyloidosis, Gaucher’s diseases, lysosomal and glycogen storage disorders (e.g., Glycogen Storage Disease type 1A (GSD1A)), cystic fibrosis; viral infection and diseases human cytomegalovirus (HCMV) infection, hepatitis B, human immunodeficiency virus infection, Zika virus infection, coronavirus infection, HCoV-229E, HCoV-NL63, betacoronavirus infection, such as HCoV-OC43, SARS-CoV-1 , HCoV-HKU1 , MERS-CoV or SARS-CoV-2, fibrosis, silicosis, diabetic retinopathy, glaucoma, cataracts, age-related macular degeneration, glomerulonephritis, glomerulosclerosis, wound healing disorders, Niemann-Pick type C (NPC) disease, inclusion body disease (IBD), muscular dystrophy, Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, myopathy, myofibrillar myopathy, hereditary myopathy, diabetic cardiomyopathy, antiinflammatory disorders, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, irritable bowel syndrome, Crohn’s disease, vascular disorders, stroke, coronary artery diseases, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, Behcet’s syndrome, viral infection or replication, pox virus infection, herpes virus infection, lung fibrosis, liver fibrosis, kidney fibrosis, disorders caused by intracellular parasites, malaria, neuropathic pain, allergies, amyotrophic lateral sclerosis (ALS), immune response suppression, muscle degeneration and atrophy, frailty in aging, spinal cord injury, and diseases and conditions involving misfolded and/or nonfolded proteins.

In a preferred embodiment, the compound according to formula (I) is for use in the treatment of a neurodegenerative disease. In a preferred embodiment, the neurodegenerative disease is Alzheimer’s disease. In another preferred embodiment, the neurodegenerative disease is Parkinson’s disease. In yet another preferred embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In yet another preferred embodiment, the neurodegenerative disease is Huntington’s disease.

In another preferred embodiment, the compound according to formula (I) is for use in the treatment of an autophagy-related disease selected from the group consisting of lysosomal and glycogen storage disorders (e.g., Glycogen Storage Disease type 1A (GSD1A)), liver diseases (e.g. nonalcoholic fatty liver disease (NAFLD)), Parkinson’s disease and Alzheimer’s disease. In one embodiment, the compounds provided herein are for use in the treatment of Glycogen Storage Disease type 1 A (GSD1A).

In one embodiment, the compounds provided herein are for use in the treatment of nonalcoholic fatty liver disease (NAFLD).

In one embodiment, the compounds provided herein are for use in the treatment of Parkinson’s disease.

In one embodiment, the compounds provided herein are for use in the treatment of Alzheimer’s disease.

In one embodiment, the compound of formula (I) is selected from the group consisting of N-(5- chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(5-chloro-2- propoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, 2-(4-chloro-2-(((piperidin-4- ylmethyl)amino)methyl)phenoxy)ethan-1-ol hydrochloride, N-(5-chloro-2-(2-methoxyethoxy)benzyl)- 1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5-fluorobenzyl)-1 -(pipe rid in-4- yl)methanamine hydrochloride, N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4-yl)methanamin e hydrochloride, (S)-N-(5-chloro-2-ethoxybenzyl)-1 -(pyrrolidin-3-yl)methanamine hydrochloride, (R)- N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanamine hydrochloride, (R)-N-(5-chloro-2- ethoxybenzyl)-1-methylpiperidin-3-amine, N-(5-chloro-2-ethoxybenzyl)-1-ethylpiperidin-4-amine, N ¹ -(5-chloro-2-ethoxybenzyl)ethane-1 ,2-diamine hydrochloride, (1r, 4/')-/V ¹ -(5-chloro-2- ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2-ethoxybenzyl)pentane-1 ,5- diamine, N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-4-amine, A/-(5-chloro-2-ethoxybenzyl)-2- (piperazin-1 -yl)ethan-1 -amine hydrochloride, (R)-N-(5-chloro-2-ethoxybenzyl)pyrrolidin-3-amine hydrochloride, (1 r,3r)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclobutane-1 ,3-diamine hydrochloride, (1 S,3S)- N ¹ -(5-chloro-2-ethoxybenzyl)cyclopentane-1 ,3-diamine hydrochloride, (S)-N-(5-chloro-2- ethoxybenzyl)piperidin-3-amine hydrochloride, N-(5-chloro-2-ethoxybenzyl)azetidin-3-amine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1 -amine hydrochloride, 2-(2- aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine hydrochloride, N ¹ -(5-chloro-2- ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-ch loro-2-ethoxybenzyl)-2- methylpropane-1 ,2-diamine hydrochloride, N-(4-chloro-2-ethoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(4,5-dichloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamin e hydrochloride, N-(2-chloro-6-ethoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(3- chloro-4-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- methoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (trifluoromethyl) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2-

(cyclopropylmethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, 3-(4-chloro-2- (((pipendin-4-ylmethyl)amino)methyl)phenoxy)propan-1 -ol hydrochloride, N-(5-chloro-2-(3- methoxypropoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 1 -(6- chlorobenzo[d][1 ,3]dioxol-4-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, 1-(7-chloro- 2,3-dihydrobenzo[b][1 ,4]dioxin-5-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, N-(2- ethoxy-5-(trifluoromethoxy)benzyl)-1 -methylpiperidin-4-amine, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-methylpiperidin-4-amine, N ¹ -(2-ethoxy-5-(trifluoromethoxy)benzyl) cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine hydrochloride, N-(2-(2-methoxyethoxy)-5- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (1 r, 4r)-N ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, (1s, 4s)-/V ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, N-(5-chloro-2-(2- methoxyethoxy)benzyl)-1-methylpiperidin-4-amine, N-(2-ethoxy-5-fluorobenzyl)-1-methylpiperidin- 4-amine, N-(5-chloro-2-propoxybenzyl)-1 -methylpiperidin-4-amine, N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1-methylpiperidin-4-amine, N-(5-fluoro-2-propoxybenzyl)-1-(piperidin- 4-yl)methanamine hydrochloride, N-(4-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, /V-(4-chloro-2-(2-methoxyethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-5-fluorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-4-fluorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, A/-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl )methanamine hydrochloride, (SJ-N-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin- 3-yl)methanamine hydrochloride, N-(5-chloro-2-phenoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5- chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (R)-N-(5- chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin-3-yl)meth anamine hydrochloride, A/-(4-fluoro-2- propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(2-(cyclopropylmethoxy)-4,5- difluorobenzyl)-1 -(pi pe rid i n-4-y I) methanamine hydrochloride, (R)-N-(5-chloro-2-propoxybenzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, (R)-N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, N-(4-chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-1-(1-methylpiperidin-4- yl)methanamine, N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4-yl)me thanamine hydrochloride, N-(2-(benzyloxy)-5-chlorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, and N-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1-(piperidin-4-yl )methanamine hydrochloride.

In another embodiment, the compound of formula (I) is selected from the group consisting of N-(5- chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine, A/-(5-chloro-2-propoxybenzyl)-1-(piperidin-4- yl)methanamine, 2-(4-chloro-2-(((piperidin-4-ylmethyl)amino)methyl)phenoxy)e than-1-ol, N-(5- chloro-2-(2-methoxyethoxy)benzyl)-1-(piperidin-4-yl)methanam ine, N-(2-ethoxy-5-fluorobenzyl)-1- (piperidin-4-yl)methanamine, N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4-yl)methanamin e, (S)- N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanamine, (R)-N-(5-chloro-2-ethoxybenzyl)-1- (pyrrolidin-3-yl)methanamine, (R)-N-(5-chloro-2-ethoxybenzyl)-1-methylpiperidin-3-amine, N-(5- chloro-2-ethoxybenzyl)-1-ethylpiperidin-4-amine, N ¹ -(5-chloro-2-ethoxybenzyl)ethane-1 ,2-diamine, (1 r, 4r)-/V ¹ -(5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine, N ¹ -(5-chloro-2- ethoxybenzyl)pentane-1 ,5-diamine, N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-4-amine, A/-(5- chloro-2-ethoxybenzyl)-2-(piperazin-1-yl)ethan-1 -amine, (R)-N-(5-chloro-2-ethoxybenzyl)pyrrolidin- 3-amine, (1 r,3r)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclobutane-1 ,3-diamine, (1 S,3S)-N ¹ -(5-chloro-2- ethoxybenzyl)cyclopentane-1 ,3-diamine, (S)-N-(5-chloro-2-ethoxybenzyl)piperidin-3-amine, N-(5- chloro-2-ethoxybenzyl)azetidin-3-amine, N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1- amine, 2-(2-aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine, N ¹ -(5-chloro-2- ethoxybenzyl)cyclohexane-1 ,4-diamine, N ¹ -(5-chloro-2-ethoxybenzyl)-2-methylpropane-1 ,2- diamine, N-(4-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(4,5-dichloro-2- ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(2-chloro-6-ethoxybenzyl)-1-(piperidin-4- yl)methanamine, N-(3-chloro-4-ethoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(2-ethoxy-5- methoxybenzyl)-1 -(piperidin-4-yl)methanamine, N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1 -

(piperidin-4-yl)methanamine, N-(2-ethoxy-5-(trifluoromethyl)benzyl)-1-(piperidin-4-yl)met hanamine, N-(5-chloro-2-(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)me thanamine, N-(5-chloro-2-

(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl)methanamine , 3-(4-chloro-2-(((piperidin-4- ylmethyl)amino)methyl)phenoxy)propan-1-ol, N-(5-chloro-2-(3-methoxypropoxy)benzyl)-1-

(piperidin-4-yl)methanamine, 1 -(6-chlorobenzo[d][1 , 3]d ioxol-4-y l)-N-(piperid in-4-yl methyl) methanamine, 1 -(7-chloro-2,3-dihydrobenzo[b][1 , 4]d ioxi n-5-y I)- N- (pi perid i n-4-y I methy I) methanamine, N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-methylpiperidin-4- amine, N-(2-(2- methoxyethoxy)-5-(trifluoromethoxy)benzyl)-1-methylpiperidin -4-amine, N ¹ -(2-ethoxy-5-

(trifluoromethoxy)benzyl) cyclohexane-1 ,4-diamine, N ¹ -(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1 -(piperidin-4-yl)methanamine, (1 r, 4r)-N ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine, (1s, 4s)-/V ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine, N-(5-chloro-2-(2-methoxyethoxy)benzyl)-1- methylpiperidin-4-amine, N-(2-ethoxy-5-fluorobenzyl)-1 -methylpiperidin-4-amine, N-(5-chloro-2- propoxybenzyl)-1-methylpiperidin-4-amine, N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1- methylpiperidin-4-amine, N-(5-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine, N-(4-chloro- 2-propoxybenzyl)-1 -(piperidin-4-yl)methanamine, A/-(4-chloro-2-(2-methoxyethoxy)benzyl)-1 - (piperidin-4-yl)methanamine, N-(2-(cyclopropylmethoxy)-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine, N-(2-(cyclopropylmethoxy)-4-fluorobenzyl)-1-(piperidin-4-yl) methanamine, A/-(4- chloro-2-(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl)metha namine, (S)-N-(4-chloro-2-

(cyclopropylmethoxy)benzyl)-1-(pyrrolidin-3-yl)methanamin e, N-(5-chloro-2-phenoxybenzyl)-1- (piperidin-4-yl)methanamine, N-(5-chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1 -(piperidin-4- yl)methanamine, (R)-N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin- 3-yl)methanamine, N- (4-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine, A/-(2-(cyclopropylmethoxy)-4,5- difluorobenzyl)-1 -(piperidin-4-yl) methanamine, (R)-N-(5-chloro-2-propoxybenzyl)-1-(pyrrolidin-3- yl)methanamine, (R)-N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-(pyrrolidin-3- yl)methanamine, N-(4- chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4-yl)methanamin e, N-(5-chloro-2-ethoxybenzyl)-1-(1- methylpiperidin-4-yl)methanamine, N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4- yl)methanamine, N-(2-(benzyloxy)-5-chlorobenzyl)-1-(piperidin-4-yl)methanami ne, and N-(5-chloro- 2-((4-fluorobenzyl)oxy)benzyl)-1-(piperidin-4-yl)methanamine .

The compound according to formula (I) may be administered via any suitable route of administration including oral, subcutaneous, intravenous, intravenous or epidural patient controlled analgesia (PCA and PCEA), intramuscular, intrathecal, epidural, intracistemal, intraperitoneal, transdermal, topical, buccal, sublingual, transmucosal, inhalation, intra-articular, intranasal, rectal or ocular administration.

The compound according to formula (I) may be administered in any suitable dosing scheme ranging from hourly, daily, weekly, monthly to yearly administration. The dosing scheme may also include cyclic dosing schemes involving time periods without administration after which administration is resumed. The dosing scheme may be adapted for the route of administration applied. The compound according to formula (I) may be administered in a fixed amount or may be administered in an amount that is adapted to the patient’s weight.

The compound according to formula (I) may also be administered in combination with one or more further therapeutic agents. The compound according to formula (I) and the one or more further therapeutic agents may be provided in a combined formulation or in separate formulations. Administration may occur in parallel (at the same time point) or sequentially (at different time points). In one embodiment, compound according to formula (I) and the one or more further therapeutic agents are each administered according to their established dosing regimens.

The present invention also provides a method of treating a patient, wherein the method comprises administering a therapeutically effective amount of the compound according to formula (I) to a patient in need thereof. In one embodiment, the patient suffers from any of the diseases or conditions listed herein.

The present invention also provides a use of the compound according to formula (I) in a cosmetic method. The method may comprise the step of applying the compound according to formula (I) to the skin of a mammal. In one embodiment, the use is for reducing cutaneous aging.

It is yet a further object of the present invention to provide a use of the compound according to formula (I) for stimulating autophagy in an in-vitro assay. The assay may be a cell-based assay involving a fluorescent dye. Stimulation of autophagy may be analyzed by measuring increased acidic vesicle formation. In one embodiment, acidic vesical formation is increased by the compound according to formula (I) by at least 25%, by at least 50% or by at least 100% in comparison to untreated control cells. In one embodiment, the cell-based assay is a mammalian-cell based assay. The present invention is further illustrated by the following examples:

The compounds of the present invention were prepared according to the following synthetic procedures and Examples and are further exemplified by the following specific examples. Unless otherwise indicated in the following, the starting materials are obtained from commercial suppliers, which is indicated for example by the CAS numbers, and used without further purification. However, it is to be understood that in case the CAS number is not indicated below a starting material, this does not mean that the starting material was not obtained from commercial suppliers. Further, it is to be understood that the starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

Liquid chromatography mass spectrometry (LC-MS)

For compound 41 LC-MS spectra were recorded on a Waters 996 Photodiode Array Detector equipped with Waters Micromass ZQ detector

Standard set-up:

Column ID XTIMATE C184.6 x 150mm, 5pm

Machine Details Column temperature: 35°C, Auto sampler temperature: 15°C, Mobile Phase A: 5mM Ammonium Acetate and 0.1 % Formic acid (pH =3.50) in Milli Q water, Mobile Phase B: Methanol

Mobile phase gradient details T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1 .0 mL/min, Run Time:- 17 min, UV Detection Method:- PDA.

Mass parameter Probe: ESI, Mode of Ionisation: Positive and Negative, Cone voltage :-30 and 10 V, capillary voltage:- 3.0 KV, Extractor Voltage:-2 V, Rf Lens:- 0.1 V, Temperature of source:- 120°C, Temperature of Probe:- 400 °C, Cone Gas Flow:- 100 L/Hr, Desolvation Gas flow:-800 L/Hr.

For all other compounds, LC-MS spectra were recorded on a Waters Acquity Ultra performance LC system equipped with a Photodiode Array (PDA) detector with an attached Quadrupole Dalton (QDa) detector. Standard set-up:

Column ID X-BRIDGE BEH C18 2.1 x 50mm, 2.5|jm

Machine details Column temperature: 35°C, Auto sampler temperature: 5°C, Mobile Phase A: 0.1 % Formic acid in Milli Q water (pH= 2.70), Mobile Phase B: 0.1%Formic acid in Milli Q water : Acetonitrile (10:90).

Mobile phase gradient details T = 0 min (97% A, 3% B) flow : 0.8 mL/min; T = 0.75 min (97% A, 3% B) flow : 0.8 mL/min; gradient to T = 2.7 min (2% A, 98% B) flow : 0.8 mL/min; gradient to T = 3 min (0% A, 100% B) flow : 1 mL/min; T = 3.5 min (0% A, 100% B) flow : 1 mL/min; gradient to T= 3.51 min (97% A, 3% B) flow : 0.8 mL/min; end of run at T = 4 min (97% A, 3% B), Flow rate: 0.8 mL/min, Run Time:- 4 min, UV Detection Method:- PDA.

Mass parameter Probe:-ESI, Mode of Ionisation: Positive and Negative, Cone voltage :-30 V and 10 V, capillary voltage:- 0.8 KV, Extractor Voltage:- 1 V, Rf Lens:- 0.1 V, Temperature of source:- 120°C, Temperature of Probe:- 600°C Cone Gas Flow:- Default , Desolvation Gas flow:-Default.

Cas. No.635-93-8

Procedure:

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (5.0g, 31.93mmol) in DMF (50mL) at room temperature, potassium carbonate (8.8g, 63.86mmol) was added. The reaction mixture was then stirred at room temperature for 1 h and bromo ethane (6.95g, 63.80mmol) was then added. The reaction mixture was then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (80mL) and extracted with ethyl acetate (2 x 50mL). The combined organic fractions were washed with cold water (5 x 50mL), dried over sodium sulfate and evaporated under reduced pressure to provide 5-chloro-2-ethoxybenzaldehyde (5.1g, 86.50% yield) as white solid. LCMS [ESI, M+1]:185.1 (RT: 2.027 min, Purity: 99.80%),

¹ H NMR (400 MHz, cfe-DMSO): 6 10.22 (s, 1 H), 7.61 (dd, J = 8.9, 2.8 Hz, 1 H), 7.52 (d, J = 2.7 Hz, 1 H), 7.20 (d, J = 9.0 Hz, 1 H), 4.12 (q, J = 6.9 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H).

-1-

Procedure:

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (2.0g, 10.83mmol) in DCE (40mL) at room temperature, tert-butyl 4-(amino methyl) piperidine-1 -carboxylate (2.78g, 12.99mmol) and acetic acid (0.1 mL, 0.05V) were added. Then reaction mixture was stirred at room temperature for 2h. Then sodium triacetoxyborohydride (6.86g, 32.40mmol) was added portion wise into reaction mixture at 0°C. Then the reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into saturated sodium bicarbonate solution (60mL) and extracted with CH2CI2 (3 x 30mL). The combined organic fractions were washed with water (2 x 20mL) and dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography (SiC>2; 0-100% ethyl acetate in hexane) to provide tert-butyl 4-(((5- chloro-2-ethoxybenzyl)amino)methyl)piperidine-1 -carboxylate (3.0g, 72.32 % yield) as light yellow liquid.

LCMS [ESI, M+1]: 383.2 (RT: 1.880 min, Purity: 97.02%),

¹ H NMR (400 MHz, cfc-DMSO ): 6 7.47 (s, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 4.11 - 3.99 (m, 2H), 3.99 - 3.86 (m, 2H), 3.85 (s, 2H), 2.64 - 2.55 (m, 4H), 1 .91 (m, 2H), 1 .72 (d, J = 11 .9 Hz, 4H), 1 .38 (s, 9H), 1 .34 (t, J = 6.9 Hz, 3H),

Procedure:

To a stirred solution of tert-butyl 4-(((5-chloro-2-ethoxybenzyl)amino)methyl)piperidine-1- carboxylate (3.0g, 78.30mmol) in DCM (30mL) at 0°C, 4M HCI in Dioxane (15mL, 5V) was added. Then the reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The resulting crude product material was purified by triturated with diethyl ether to provide N-(5-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (2.2g, 88.01% yield) as a white solid.

LCMS [ESI, M+1]: 283.1 (RT: 0.814 min, Purity: 99.14%),

HPLC: RT: 3.580 min, Purity: 97.21%,

¹ H NMR (400 MHz, cfc-DMSO) : 6 9.28 (s, 2H), 9.09 (s, 1 H), 8.94 (s, 1 H), 7.65 (s, 1 H), 7.43 (d, J = 8.7 Hz, 1 H), 7.09 (d, J = 8.9 Hz, 1 H), 4.14 - 4.01 (m, 4H), 3.25 (d, J = 11.5 Hz, 2H), 2.84 (s, 4H), 2.08 (s, 1 H), 1 .96 (d, J = 13.2 Hz, 2H), 1 .50 - 1 .39 (m, 2H), 1 .37 (d, J = 6.6 Hz, 3H).

Experimental protocol for Compound 2:

CAS No.635-93-8

Procedure

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.5g, 3.19mmol) in DMF (5mL) at room temperature, K2CO3 (1.3g, 9.58mmol) was added. After 1 h, 1 -bromopropane (0.785g, 6.38mmol) was added to the reaction mixture at room temperature. The reaction mixture was then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (10 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic factions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product material was purified by column chromatography (SiC>2; 0-10% EtOAc/Hexane) to provide 5-chloro-2- propoxybenzaldehyde (0.580g, 91.48 yield) as a white solid. LCMS [ESI, M+1]: 199.0 (RT: 2.221 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO) : 6 10.40 (s, 1 H), 7.68 (d, J = 2.8 Hz, 1 H), 7.57 (dd, J = 2.8 Hz, 9.2 Hz, 1 H), 7.18 (d, J = 9.2 Hz, 1 H), 4.11 (t, J = 6.4 Hz, 2H), 1.91-1.86 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H).

Step-2: Synthesis of tert-butyl 4-(((5-chloro-2-propoxybenzyl)amino)methyl)piperidine-1- carboxylate:

Procedure

To a stirred solution of 5-chloro-2-propoxybenzaldehyde (0.2g, 1.00mmol) in DCE (2mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.26g, 1.2mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then, sodium triacetoxyborohydride (0.64g, 3.02mmol) was added portion-wise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (10 mL) and washed with sat. NaHCCh solution (5 mL) and water (5 mL) . The organic fraction was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-10% MeOH/ CH2CI2) to provide tert-butyl 4-(((5-chloro-2-propoxybenzyl)amino) methyl)piperidine- 1 -carboxylate (0.18g, 45.11% yield) as a yellow oil.

LCMS [ESI, M+1]: 397.2 (RT: 1.660 min, Purity: 98.01%),

¹ H NMR (400 MHz, CD3OD) : 6 7.33 (d, J = 2.4 Hz, 1 H), 7.28 (dd, J = 2.4 Hz, 8.6 Hz, 1 H), 6.99 (d, J = 8.6 Hz, 1 H), 4.08 (d, J = 12.4 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.88 (s, 2H), 3.07 (d, J = 6.4 Hz, 1 H), 2.76 (bs, 2H), 2.62 (d, J = 6.4 Hz, 2H), 1 .94 (s, 1 H), 1 .88-1 .83 (m, 2H), 1 .76-1 .67 (m, 3H), 1 .45 (s, 9H), 1.08 (t, J = 7.4 Hz, 3H).

Step-3: Synthesis of /V-(5-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (Compound 2):

Procedure

To a stirred solution of tert-butyl 4-(((5-chloro-2-propoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.18g, 0.45mmol) in CH2CI2 (2.0mL) at 0°C, 4.0 M HCI in dioxane (0.9mL, 5V) was added. The reaction mixture was then stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration using diethyl ether to provide /V-(5-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.0847g, 62.99% yield) as an off-white solid.

LCMS [ESI, M+1]: 297.1 (RT: 0.887 min, Purity: 98.09%), HPLC: RT: 3.590 min, Purity: 97.36%,

¹ H NMR (400 MHz, CD3OD) : 6 7.51 (d, J = 2.4 Hz, 1 H), 7.44 (dd, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 4.26 (s, 2H), 4.09 (t, J = 6.8 Hz, 2H), 3.46 (d, J = 12.8 Hz, 2H), 3.09-2.97 (m, 4H), 2.21-2.15 (m, 1 H), 2.07 (d, J = 14.4 Hz, 2H), 1.92-1.85 (m, 2H), 1.60-1.49 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H).

Experimental protocol for Compound 3:

Procedure

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.2g, 1.2mmol) in DMF (2mL) at room temperature, K2CO3 (0.55g, 3.98mmol) was added. The reaction mixture was stirred for 1 h. 2- bromoethanol (0.19g, 1.52mmol) was then added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (10mL) and extracted with ethyl Acetate (3 X 10mL). The combined organic fractions were washed with cold water 2-3 times, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-50% EtOAc/Hexane] to provide 5-chloro-2-(2-hydroxyethoxy) benzaldehyde (0.168g, 65.62% yield) as a white solid.

¹ H-NMR (400 MHz, cfe-DMSO) : 6 10.38 (s, 1 H), 7.70-7.67 (dd, J = 2.8 Hz, 9.2, 1 H), 7.60 (d, J = 2.8 Hz, 1 H), 7.29 (d, J = 9.2 Hz, 1 H), 5.00 (t, J = 6.0 Hz, 1 H), 4.15 (t, J = 4.8 Hz, 2H), 3.76 (q, J = 5.2 Hz, 2H).

Procedure

To a stirred solution of 5-chloro-2-(2-hydroxyethoxy) benzaldehyde (0.15g, 0.74mmol) in DCE (3mL) at room temperature, te/Y-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.19g, 0.89mmol) and acetic acid (0.008mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then, sodium triacetoxyborohydride (0.47g, 2.24mmol) was added portion-wise added to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (10mL) and washed with sat. NaHCCh solution (10mL) and water (10mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-100% EtOAc/Hexane] to provide tert-butyl 4-(((5-chloro-2-(2-hydroxy ethoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.139g, 46.64% yield) as a yellow oil.

LCMS [ESI, M+1]: 399.2 (RT: 1.380 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO) : 6 7.35 (d, J = 2.4 Hz, 1 H), 7.24 (dd, J = 2.4 Hz, 8.8 Hz, 1 H), 6.99 (d, J = 8.8 Hz, 1 H), 4.09 (bs, 1 H), 4.00 (t, J = 4.8 Hz, 2H), 3.92-3.89 (m, 2H), 3.70-3.67 (m, 4H), 3.16 (s, 3H), 2.41 (d, J = 6.0 Hz, 2H), 1.68 (d, J = 12.4 Hz, 2H), 1.59 (bs, 1 H), 1.38 (s, 9H), 1 .01 - 0.90 (m, 2H). i-1-ol

Procedure

To a stirred solution of tert-butyl 4-(((5-chloro-2-(2-hydroxyethoxy)benzyl)amino)methyl) piperidine- 1-carboxylate (0.1g, 0.25mmol) in CH2CI2 (1 .OmL) at 0°C was added 4.0 M HCI in Dioxane (0.5mL, 5V). The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration using diethyl ether to provide 2-(4-chloro-2-(((piperidin-4-ylmethyl)amino)methyl)phenoxy) ethan-1-ol hydrochloride (0.033g, 45.44% yield) as a light brown sticky solid.

LCMS [ESI, M+1]: 299.1 (RT: 0.639 min, Purity: 96.37%),

HPLC: RT: 3.626 min, Purity: 100.0%

¹ H NMR (400 MHz, CD3OD) : 6 7.50-7.45 (m, 2H), 7.15 (d, J = 8.8 Hz, 1 H), 4.29 (s, 2H), 4.24 (t, J = 4.4 Hz, 2H), 3.95 (t, J = 4.8 Hz, 2H), 3.45 (d, J = 13.2 Hz, 2H), 3.09-3.02 (m, 4H), 2.19-2.15 (m, 1 H), 2.09-2.04 (m, 2H), 1 .59-1 .50 (m, 2H).

CAS No.144222-22-0

CAS:6482-24-2

K2CO3,DMF, NaBH(OAc)3,

1 d, rt DCE.rt, 4h

Step-1 Step-2 Yield:73.17% Yield:69.20%

CAS: 635-93-8

Procedure

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.3g, 0.19mmol) in DMF (6mL, 20V) at room temperature, K2CO3 (0.78g, 5.74mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then 1-bromo-2-methoxyethane (0.79g, 0.57mmol) was added to the reaction mixture. Then reaction mixture was stirred at room temperature for 24h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into cold water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with cold water 3-4 times, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-20% EtOAc/Hexane) to provide 5-chloro-2-(2-methoxyethoxy)benzaldehyde_(0.300g, 73.17% yield) as a white solid.

LCMS [ESI, M+23]: 236.94 (RT: 1.774min, Purity: 100%)

¹ H NMR (400 MHz, cfe-DMSO): 6 10.3 (s, 1 H), 7.69 (dd, J = 8.8, 2.8 Hz, 1 H), 7.6(d, J = 2.8 Hz, 1 H) 7.3 (d, J = 8.8 Hz, 1 H), 4.27(t, J= 9.2, 4.4 Hz, 2H), 3.75-3.70(m, 2H), 3.33-3.31 (m, 3H) Step-2: tert-butyl 4-(((5-chloro-2-(2-methoxyethoxy)benzyl)amino)methyl)piperid ine-1 - carboxylate:

Procedure

To a stirred solution of 5-chloro-2-(2-methoxyethoxy)benzaldehyde (0.3g, 1.4mmol) in DCE (6 mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.36g, 1.6mmol) was added. Then reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.445g, 2.1 mmol) was then added to the reaction mixture in small portions at 0°C. The reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into saturated solution of sodium bicarbonate (15mL) and extracted with CH2CI2 (3 X 10mL). The combine organic fractions were washed with water (15mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product material was purified by column chromatography (SiC>2; 0-40% EtOAc/Hexane) to provide tert-butyl 4-(((5-chloro-2-(2- methoxyethoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.400g, 69.20% yield ) as a colorless liquid.

LCMS [ESI, M+1]:413.27 (RT: 1.538min, Purity: 100%)

¹ H NMR (400 MHz, cfe-DMSO): 6 7.37 (s, 1 H), 7.24 (dd, J=8.6,2.2 Hz,1 H), 6.99 (d, J=8.8 Hz,1 H), 4.10 (t , J=4.4 Hz, 2H), 3.91 (d, J=7.6Hz, 2H) 3.69-3.64 (m, 4H) ,3.0 (s, 3H), 2.66 (s, 2H), 2.41 (d, J=6.0 Hz, 2H), 1 .68 (d, J=13.2 Hz, 2H), 1 .59 (m, 2H), 1 .35 (s, 9H), 0.92-1 .0 (m, 2H)

Step-3: _ N-(5-chloro-2-(2-methoxyethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride (Compound 4):

Procedure

To a stirred solution of tert-butyl 4-(((5-chloro-2-(2-methoxyethoxy)benzyl)amino)methyl)piperid ine- 1 -carboxylate (0.200g, 0.53mmol) in CH2CI2 (1 mL) at 0°C, 4M HCI in Dioxane (0.3 mL, 1.5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure to get crude material. The crude material was triturated with diethyl ether to provide N-(5-chloro-2-(2-methoxyethoxy)benzyl)-1-(piperidin-4-yl)met hanamine hydrochloride (0.298g, 98.67%) as a white solid.

LCMS [ESI, M+1]:313.1 (RT: 0.728min, Purity: 100%),

HPLC: RT: 3.380min, Purity: 100%

¹ H NMR (400 MHz, CD3OD): 6 7.43 (d, J = 2.4 Hz, 1 H), 7.38 (dd, J = 8.8, 2.4 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.21 (d, J = 7.9 Hz, 4H), 3.80 - 3.69 (m, 2H), 3.39 (d, J = 10.0 Hz, 5H), 3.04 - 2.92 (m, 4H), 2.13 - 2.03 (m, 1 H), 2.00 (d, J = 13.8 Hz, 2H), 1.47 (dd, J = 24.0, 11.0 Hz, 2H).

CAS No.347-54-6

Procedure:

To a stirred solution of 2-hydroxy-5-fluorobenzaldehyde (0.500g, 3.56mmol) in DMF (5mL) at room temperature, potassium carbonate (0.98g, 7.13mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then bromo ethane (0.77g, 7.13mmol) was added into reaction mixture. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured in cold water (10mL) and extracted with ethyl acetate (3 X 5mL). The combined organic fractions were washed with cold water 3-4 times (5mL), dried over sodium sulfate and concentrated under reduced pressure to provide 2-ethoxy-5-fluorobenzaldehyde (0.500g, 83.32% yield) as an off-white solid.

LCMS [ESI, M+1]:169.1 (RT: 1.829min, Purity: 99.83%),

¹ H NMR (400 MHz, cfc-DMSO): 6 10.34 (dd, J = 11.2, 3.1 Hz, 1 H), 7.51 (tt, J = 18.4, 9.2 Hz, 1 H), 7.43 - 7.31 (m, 1 H), 7.27 (dd, J = 9.2, 4.1 Hz, 1 H), 4.18 (q, J = 7.0 Hz, 2H), 1.42 - 1.29 (m, 3H). Step-2: Synthesis of tert-butyl 4-(((2-ethoxy-5-fluorobenzyl)amino)methyl)piperidine-1- carboxylate:

Procedure:

To a stirred solution of 2-ethoxy-5-fluorobenzaldehyde (0.200g, 1.18mmol) in DCE (4mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.305g, 1.42mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then sodium triacetoxyborohydride (0.756g, 3.56mmol) was added portion wise to the reaction mixture at 0°C. After addition, the reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured in saturated solution of sodium bicarbonate (10 mL) and extracted with CH2CI2 (2 X 5mL). The combined organic fractions were washed with water (10 mL), and dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-70% ethyl acetate in hexane) to provide tert-butyl 4-(((2-ethoxy- 5-fluorobenzyl)amino)methyl)piperidine-1 -carboxylate (0.150g, 34.42% yield) as a light yellow liquid.

LCMS [ESI, M+1]:367.1 (RT: 1.450 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.16 (dd, J = 9.5, 3.1 Hz, 1 H), 7.02 - 6.91 (m, 2H), 4.02 (q, J = 6.9 Hz, 2H), 3.95 (d, J = 12.1 Hz, 2H), 3.66 (s, 2H), 2.73 (d, J = 24.1 Hz, 2H), 2.39 (d, J = 6.6 Hz, 2H), 1 .72 (d, J = 11 .4 Hz, 2H), 1 .65 - 1 .52 (m, 2H), 1 .41 (s, 9H), 1 .38 - 1 .29 (m, 3H), 1 .06 - 0.90 (m, 2H).

Step-3: Synthesis of N-(2-ethoxy-5-fluorobenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (Compound 5):

Procedure:

To a stirred solution of tert-butyl 4-(((2-ethoxy-5-fluorobenzyl)amino)methyl)piperidine-1- carboxylate (0.150g, 0.40mmol) in CH2CI2 (1.5mL) at 0°C, 4M HCI in Dioxane (0.75mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with diethyl ether to provide N-(2-ethoxy-5-fluorobenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.123g, 99.7% yield) as an off-white solid.

LCMS [ESI, M+1]: 267.1 (RT: 0.684 min, Purity: 100%),

HPLC: RT: 3.400 min, Purity: 96.54%,

¹ H NMR (400 MHz, CD3OD) : 6 7.31 (dd, J = 8.4, 2.8 Hz, 1 H), 7.22 (td, J = 8.6, 2.9 Hz, 1 H), 7.13 (dd, J = 9.0, 4.3 Hz, 1 H), 4.30 (s, 2H), 4.21 (q, J = 6.9 Hz, 2H), 3.49 (d, J = 12.9 Hz, 2H), 3.09 (dd, J = 17.5, 4.6 Hz, 4H), 2.29 - 2.16 (m, 1 H), 2.11 (d, J = 13.9 Hz, 2H), 1 .67 - 1 .54 (m, 2H), 1 .50 (t, J = 7.0 Hz, 3H).

Procedure:

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.200g, 1.27mmol) in DMF (2mL) at room temperature, potassium carbonate (0.353g, 2.55mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then 2-bromo propane (0.314g, 2.55mmol) was added into reaction mixture. The reaction mixture was then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured in cold water (10 mL) and extracted with ethyl acetate (2 X 5 mL). The combined organic fractions were washed with cold water (4 X 3mL), dried over sodium sulphate and concentrated under reduced pressure to provide 5-chloro-2- isopropoxybenzaldehyde (0.200g, 78.82% yield) as an off-white solid.

¹ H NMR (400 MHz, cfe-DMSO): 6 10.29 (s, 1 H), 7.65 (dt, J = 16.9, 8.4 Hz, 1 H), 7.58 (t, J = 9.2 Hz, 1 H), 7.32 (d, J = 9.0 Hz, 1 H), 4.88 - 4.72 (m, 1 H), 1 .33 (d, J = 6.0 Hz, 6H). Step-2: Synthesis of tert-butyl 4-(((5-chloro-2-isopropoxybenzyl)amino)methyl)piperidine-1- carboxy late:

Procedure:

To a stirred solution of 5-chloro-2-isopropoxybenzaldehyde (0.190g, 0.95mmol) in DCE (2mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.245g, 1.14mmol) and acetic acid (0.009mL, 0.05V) were added. Then reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.608g, 2.86mmol) was added portion wise to the reaction mixture at 0°C. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into saturated solution of sodium bicarbonate (8 mL) and extracted with CH2CI2 (2 X 3 mL). The combined organic fractions were washed with water(5 mL), dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70-75% ethyl acetate in hexane) to provide tert-butyl 4-(((5-chloro-2- isopropoxybenzyl)amino) methyl)piperidine-1 -carboxy late_(0.260g, 68.48% yield) as a light yellow liquid.

LCMS [ESI, M+1]:397.1 (RT: 1.606 min, Purity: 97.18%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.35 (d, J = 2.5 Hz, 1 H), 7.19 (dd, J = 8.7, 2.6 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 1 H), 4.59 (dt, J = 12.0, 6.0 Hz, 1 H), 3.91 (d, J = 9.7 Hz, 2H), 3.60 (s, 2H), 2.70 (d, J = 23.4 Hz, 2H), 2.35 (d, J = 6.4 Hz, 2H), 1.68 (d, J = 12.2 Hz, 2H), 1 .55 (d, J = 9.3 Hz, 1 H), 1.38 (s, 9H), 1 .25 (d, J = 6.0 Hz, 6H), 1 .02 - 0.87 (m, 2H).

Step-3: Synthesis of N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4-yl)methanamin e hydrochloride (Compound 6)

Procedure:

To a stirred solution of tert-butyl 4-(((5-chloro-2-isopropoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.250g, 0.62mmol) in CH2CI2 (2.5 mL) at 0°C, 4M HCI in Dioxane (1.2mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration with diethyl ether to provide N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4-yl)methanamin e hydrochloride (0.159g, 77.18% yield) as an off-white solid.

LCMS [ESI, M+1]: 297.1 (RT: 0.875 min, Purity: 100%),

HPLC: RT: 3.636 min, Purity: 98.31 %,

¹ H NMR (400 MHz, CD3OD): 6 7.45 (d, J = 2.4 Hz, 1 H), 7.37 (dd, J = 8.9, 2.5 Hz, 1 H), 7.08 (d, J = 8.9 Hz, 1 H), 4.71 (dt, J = 11.9, 6.0 Hz, 1 H), 4.18 (s, 2H), 3.40 (d, J = 13.1 Hz, 2H), 3.00 (t, J = 11.0 Hz, 4H), 2.17 - 2.06 (m, 1 H), 2.04 - 1.96 (m, 2H), 1.57 - 1.41 (m, 2H), 1 .35 (d, J = 6.0 Hz, 6H). Experimental protocol for Compound 7 and Compound 8:

Step-1 :tert-butyl 3-(((5-chloro-2-ethoxybenzyl)amino)methyl)pyrrolidine-1 -carboxylate: Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (1.0g, 5.41 mmol) in DCE (20 mL) at room temperature, tert-butyl 3-(aminomethyl)pyrrolidine-1 -carboxylate (1.29g, 6.49mmol) and acetic acid (0.05ml) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (3.43g, 16.2mmol) was added to the reaction mixture portion-wise at 0°C. Then the reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into saturated solution of sodium bicarbonate (100 mL) and extracted with CH2CI2 (3 X 150 mL). The combined organic fractions were washed with water (500 mL), dried over sodium sulfate and evaporated under reduced pressure . The crude material was purified by column chromatography (SiC>2; 0-30% EtOAc/Hexane) to provide pure tert-butyl 3-(((5-chloro-2- ethoxybenzyl)amino)methyl)pyrrolidine-1 -carboxylate (1.3g, 65.32% Yield) as a light yellow liquid.

LCMS [ESI, M+1]:369.1 (RT: 1.517 min, Purity: 100%)

HPLC: RT: 5.093min, Purity: 100%

Chiral HPLC: lsomer-1 : RT: 3.22min, Purity: 48.58% lsomer-2: RT:3.78min, Purity: 50.97%

¹ H NMR (400 MHz, cfe-DMSO): 6 7.40 (s, 1 H), 7.26 (d, J = 8.8 Hz, 1 H), 7.00 (d, J = 8.7 Hz, 1 H), 4.1 1 - 4.02 (m, 2H), 3.68 (s, 2H), 3.42 (s, 2H), 3.21 (s, 2H), 2.96 (s, 2H), 2.35 - 2.23 (m, 2H), 1 .94 (s, 1 H), 1 .62 - 1 .53 (m, 1 H), 1 .43 (s, 9H), 1 .37 (t, J = 7.0 Hz, 3H).

Step2: tert-butyl (S)-3-(((5-chloro-2-ethoxybenzyl)amino)methyl)pyrrolidine-1 -carboxylate and tert-butyl (R)-3-(((5-chloro-2-ethoxybenzyl)amino)methyl)pyrrolidine-1 -carboxylate

Procedure

Racemic tert-butyl 3-(((5-chloro-2-ethoxybenzyl)amino)methyl)pyrrolidine-1 -carboxylate (0.700g) was purified by chiral SFC Purification [A:0.1 % DEA in Heptane, B:IPA:ACN(70:30)] to isolate both enantiomers . tert-butyl(S)-3-(((5-chloro-2-ethoxybenzyl)amino)methyl)pyrr olidine-1 -carboxylate (0.25 g)

Isolated as a colorless liquid.

LCMS:FR1 :[ESI, M+1]369.1 (RT: 1.509 min, Purity: 98.56%)

Chiral HPLC: RT:3.45min, Purity: 98.40%

¹ H NMR (400 MHz, cfc-DMSO): 6 7.36 (s, 1 H), 7.22 (d, J = 8.6 Hz, 1 H), 6.96 (d, J = 8.7 Hz, 1 H), 4.03 (dd, J = 13.8, 6.9 Hz, 2H), 3.64 (s, 2H), 3.38 (s, 2H), 3.28 (s, 1 H), 2.97 - 2.86 (m, 2H), 2.31 (d, J = 22.3 Hz, 2H), 1 .91 (s, 1 H), 1 .59 - 1 .47 (m, 2H), 1 .39 (s, 9H), 1 .33 (t, J = 6.9 Hz, 3H). tert-butyl(R)-3-(((5-chloro-2-ethoxybenzyl)amino)methyl)pyrr olidine-1 -carboxylate (0.150g)

Isolated as a colorless liquid.

LCMS:FR1 :[ESI, M+1]369.1 (RT: 1.526 min, Purity: 100%)

Chiral HPLC: RT:4.0min, Purity: 95.57%

¹ H NMR (400 MHz, cfc-DMSO): 6 7.34 (t, J = 8.0 Hz, 1 H), 7.21 (dt, J = 17.6, 8.8 Hz, 1 H), 6.96 (d, J = 8.7 Hz, 1 H), 4.03 (q, J = 7.0 Hz, 2H), 3.64 (s, 2H), 3.44 - 3.37 (m, 1 H), 3.29 - 3.22 (m, 1 H), 3.16 (dd, J = 17.5, 9.4 Hz, 1 H), 2.92 (t, J = 8.6 Hz, 1 H), 2.47 - 2.36 (m, 2H), 2.35 - 2.22 (m, 1 H), 2.09 (s, 1 H), 1 .91 (d, J = 4.7 Hz, 1 H), 1 .60 - 1 .46 (m, 1 H), 1 .39 (s, 9H), 1 .36 - 1 .27 (m, 3H). Step-3:(S)-N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)me thanamine hydrochloride

(Compound 7):

Procedure

To a stirred solution of tert-butyl(S)-3-(((5-chloro-2-ethoxybenzyl)amino)methyl)pyrr olidine-1- carboxylate (0.25g, 0.67mmol) in CH2CI2 (1 mL) at 0°C, 4M HCI in Dioxane (1 mL, 4V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by triturated with diethyl ether to provide (S)-N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanami ne hydrochloride (0.177g, 97.25% Yield) as a white solid.

LCMS [ESI, M+1]:269.04(RT: 0.776min, Purity: 100%)

HPLC: RT:3.553min, Purity: 100%

¹ H NMR (400 MHz, CD3OD): 6 7.53 (d, J = 2.6 Hz, 1 H), 7.46 (dd, J = 8.8, 2.6 Hz, 1 H), 7.13 (d, J = 8.9 Hz, 1 H), 4.29 (s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 3.61 (dd, J = 11 .9, 7.9 Hz, 1 H), 3.49 (ddd, J = 12.4, 8.5, 4.2 Hz, 1 H), 3.30 - 3.21 (m, 3H), 3.09 (dd, J = 11 .9, 8.9 Hz, 1 H), 2.88 - 2.74 (m, 1 H), 2.38 (ddd, J = 20.3, 7.4, 4.3 Hz, 1 H), 1 .86 (dq, J = 13.2, 8.9 Hz, 1 H), 1.50 (t, J = 7.0 Hz, 3H).

Step-3A:(R)-N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-y l)methanamine hydrochloride (Compound 8)

Procedure

To a stirred solution of tert-butyl(R)-3-(((5-chloro-2-ethoxybenzyl)amino)methyl)pyrr olidine-1- carboxylate (0.150g,0.4mmol) in CH2CI2 (1 mL) at 0°C, 4M HCI in Dioxane (0.75 mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with diethyl to provide (R)-N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanami ne hydrochloride (0.093 mg, 85.32% Yield) as a white sticky solid.

LCMS [ESI, M+1]:269(RT:0.778min, Purity: 100%),

HPLC: RT:3.553 min, Purity: 96.91 %

¹ H NMR (400 MHz, CD3OD): 6 7.52 (d, J = 2.6 Hz, 1 H), 7.46 (dd, J = 8.8, 2.6 Hz, 1 H), 7.12 (d, J = 8.9 Hz,1 H), 4.32 - 4.25 (m, 2H), 4.22 (q, J = 7.0 Hz, 2H), 3.61 (dd, J = 11 .9, 7.9 Hz, 1 H), 3.49 (ddd, J = 12.4, 8.5, 4.2 Hz, 1 H), 3.39 - 3.35 (m, 1 H), 3.31 - 3.22 (m, 2H), 3.09 (dd, J = 1 1.9, 8.8 Hz, 1 H), 2.90 - 2.77 (m, 1 H), 2.38 (ddd, J = 20.3, 7.4, 4.2 Hz, 1 H), 1.86 (dq, J = 13.2, 8.9 Hz, 1 H), 1.50 (t, J = 7.0 Hz, 3H).

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.100g, 0.54mmol) in DCE (2.0mL, 20V) at room temperature, (R)-1-Methylpiperidin-3-amine (0.12g, 0.65mmol) was added. The reaction mixture was stirred at room temperature for 3h. Sodium triacetoxyborohydride (0.34g, 1.63mmol) was added to the reaction mixture portion-wise at 0°C. The reaction was stirred at room temperature for 5h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into saturated solution of sodium bicarbonate (15 mL) and extracted with CH2CI2 (3 X 10 mL). The combined organic fractions were washed with water (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiC>2; 0-100% ethyl acetate in hexane) to provide (R)-N-(5-chloro-2-ethoxybenzyl)-1-methylpiperidin-3-amine (0.023g, 15.52% Yield) as a light yellow sticky solid.

LCMS [ESI, M+1]: 284.6 (RT=0.774, purity= 98.14%)

HPLC: RT=3.680, Purity= 98.08%

¹ H NMR (400 MHz, cfc-DMSO ): 6 7.38 (s, 1 H), 7.23 (d, J = 8.7 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 4.01 (q, J = 6.9 Hz, 2H), 3.69 (m, 2H), 2.79 (d, J = 9.4 Hz, 1 H), 2.17 (s, 3H), 1.92 (d, J = 15.2 Hz, 1 H), 1.75 (s, 2H), 1.63 (d, J = 12.8 Hz, 1 H), 1.40 (d, J = 12.9 Hz, 1 H), 1.33 (t, J = 6.9 Hz, 3H), 0.99 (m, 1 H). (3H merge with solvent residual peak) N-(5-chloro-2-ethoxybenzyl)-1 -ethylpiperidin-4-amine (Compound 10):

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.100g, 0.54mmol) in DCE (2.0mL, 20V) at room temperature, 1 -ethylpiperidin-4-amine dihydrochloride (0.083g, 0.65mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.345g, 1 .63mmol) was added to the reaction mixture portion-wise at 0°C. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into saturated solution of sodium bicarbonate (15 mL) and extracted with CH2CI2 (3 X 10 mL). The combined organic fractions were washed with water (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-100% ethyl acetate in hexane) to provide N-(5-chloro-2-ethoxybenzyl)-1-ethylpiperidin-4-amine (0.018g, 11.90% yield) as a white sticky solid.

LCMS [ESI, M+1]:296.96 (RT: 0.820min, Purity: 100 %),

HPLC: RT: 3.319 min, Purity: 95.24%

¹ H NMR (400 MHz, cfc-DMSO): 6 7.31 (s, 1 H), 7.15 (d, J = 8.8 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 1 H), 4.03 (q, J = 6.7 Hz, 2H), 3.69 (s,2H), 2.85 (s, 2H), 2.27 (d, J = 21 .1 Hz, 4H), 1 .95 (m, 2H), 1 .82 (m, 2H), 1 .24 (t, J = 6.9 Hz, 5H), 0.91 (t, J = 6.9 Hz, 3H).

Experimental protocol for Compound 11 :

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.15g, 0.81 mmol) in DCE (3mL) at room temperature, tert-butyl (2-aminoethyl)carbamate (0.15g, 0.97mmol) and acetic acid (0.008mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then sodium triacetoxyborohydride (0.41g, 1.95mmol) was added portion-wise to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (10 mL) and washed with sat. NaHCCh solution (10 mL) and water (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-100% EtOAc/Hexane) to provide fert-Butyl (2-((5-chloro-2-ethoxybenzyl)amino)ethyl)carbamate (0.15g, 56.18% yield) as a yellow oil.

LCMS [ESI, M+1]: 329.1 (RT: 1.386 min, Purity: 98.67%),

¹ H-NMR (400 MHz, cfe-DMSO) : 6 7.33 (d, J = 2.4 Hz, 1 H), 7.22-7.19 (dd, J = 2.6 Hz, 8.8 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 6.74 (bs, 1 H), 4.01 (q, J = 6.8 Hz, 2H), 3.62 (s, 2H), 3.16 (d, J = 4.8 Hz, 1 H), 3.02-2.99 (m, 2H), 2.16 (bs, 2H), 1.39-1.30 (m, 12H).

-1,2-diamine

Procedure

To a stirred solution of te/Y-Butyl (2-((5-chloro-2-ethoxybenzyl)amino) ethylcarbamate (0.15g, 0.45 mmol) in CH2CI2 (1.5mL) at 0°C, 4.0 M HCI in Dioxane (0.8mL, 5V) was added. The reaction mixture was then stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration using diethyl ether to afford W-(5-chloro-2-ethoxybenzyl)ethane-1,2-diamine hydrochloride (0.126g, 91.97% yield) as an off-white solid.

LCMS [ESI, M+1]: 229.1 (RT: 0.722 min, Purity: 100%),

HPLC : RT: 3.399 min, Purity: 95.77%

¹ H-NMR (400 MHz, CD3OD) : 6 7.53 (d, J = 2.4 Hz, 1 H), 7.46-7.43 (dd, J = 2.4 Hz, 8.8 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), 4.31 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.42-3.38 (m, 4H), 1.49 (t, J = 7.2 Hz, 3H). ino)cyclohexyl)carbamate

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.20g, 1.08mmol) in DCE (4 mL) at room temperature, fert-butyl ((1/',4/')-4-aminocyclohexyl)carbamate (0.27g, 1.26mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then sodium triacetoxyborohydride (0.683g, 3.22mmol) was added portion-wise at 0 °C. Then reaction mixture was allowed to stir at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was diluted with CH2CI2 (10 mL) and washed with sat. NaHCCh solution (15mL) and water (15mL). The combined organic fractions were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70% EtOAc/Hexane) to provide fert-butyl ((1 r,4r)-4-((5-chloro-2- ethoxybenzyl)amino)cyclohexyl)carbamate (0.18g, 43.39% yield) as a yellow oil.

LCMS [ESI, M+1]: 383.3 (RT: 1.726 min, Purity: 99.21%),

¹ H-NMR (400 MHz, cfe-DMSO) : 6 8.57 (s, 1 H), 7.51 (s, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.06 (d, J = 8.8 Hz, 1 H), 6.77 (d, J = 7.2 Hz, 1 H), 4.06 (q, J = 6.8 Hz, 2H), 3.98 (s, 2H), 3.20 (bs, 1 H), 2.80 (bs, 1 H), 2.06 (d, J = 11.6 Hz, 2H), 1.90 (s, 1 H), 1.82 (d, J = 10.8 Hz, 2H), 1.37-1.30 (m, 13H), 1.21- 1.12 (m, 2H). -1 ,4-diamine

Procedure

To a stirred solution of te/Y-butyl ((1 r,4r)-4-((5-chloro-2-ethoxybenzyl)amino)cyclohexyl) carbamate (0.10g, 0.26mmol) in CH2CI2 (1.0mL) at 0°C, 4.0 M HCI in Dioxane (0.5mL, 5V) was added. The reaction mixture was then stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration using diethyl ether to provide (1 r,4r)-/V ¹ -(5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride (0.06111g, 82.74% yield) as a white solid.

LCMS [ESI, M+1]: 283.1 (RT: 0.790 min, Purity: 97.87%)

HPLC Purity: RT: 3.440 min, Purity: 95.65%

¹ H-NMR (400 MHz, CD3OD): 6 7.48-7.43 (m, 2H), 7.10 (d, J = 8.8 Hz, 1 H), 4.24-4.15 (m, 4H), 3.25- 3.19 (m, 2H), 2.36 (d, J = 12.0 Hz, 2H), 2.21 (d, J =12.0 Hz, 2H), 1 .66-1.58 (m, 4H), 1.48 (t, J = 7.2 Hz, 3H).

Step-2 Yield : 40.58 % Stepl : tert-butyl (5-((5-chloro-2-ethoxybenzyl)amino)pentyl)carbamate:

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.100g, 0.54mmol) in DCE (2 mL) at room temperature, tert-butyl (5-aminopentyl)carbamate (0.131g, 0.65mmol) and acetic acid (0.0075ml,) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.345g, 1.628 mmol) was added to the reaction mixture portion-wise at 0°C. The reaction mixture was stirred at room temperature for 1.5h. The progress of reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (10 mL) and extracted with CH2CI2 (3 X 15 mL). The combined organic fractions were washed with water (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70% EtOAc in hexane) to provide tert-butyl (5-((5-chloro-2- ethoxybenzyl)amino)pentyl) carbamate (0.135g, 67.19% yield) as a light yellow liquid.

LCMS [ESI, M+1]: 371.22(RT: 1.479 min, Purity: 99.65%)

Step 2: N1 -(5-chloro-2-ethoxybenzyl)pentane-1 ,5-diamine (Compound 13):

Procedure

To a stirred solution of tert-butyl (5-((5-chloro-2-ethoxybenzyl)amino)pentyl)carbamate (0.135g, 0.36mmol) in CH2CI2 (1 .3mL) at room temperature, 4M HCI in Dioxane (0.6 mL, 5) was added. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration with diethyl ether to provide N1-(5-chloro-2-ethoxybenzyl)pentane-1 ,5-diamine (0.040g, 40.58% yield) as a pale yellow solid.

LCMS [ESI, M+1]:271.05(RT: 0.813min, Purity: 98.63%),

HPLC: RT:3.452 min, Purity: 100%

¹ H NMR (400 MHz, CD3OD): 6 7.40 (d, J = 2.5 Hz, 1 H), 7.36 (dd, J = 8.8, 2.6 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 4.14 (s, 2H), 4.12 - 4.05 (m, 2H), 3.06 - 2.96 (m, 2H), 2.93 - 2.83 (m, 2H), 1.73 (dt, J = 13.9, 6.9 Hz, 2H), 1 .65 (dd, J = 15.5, 7.8 Hz, 2H), 1 .47 - 1 .42 (m, 1 H), 1 .40 (t, J = 7.0 Hz, 4H).

Experimental protocol for Compound 14:

Yield : 12.79% N-(5-chloro-2-ethoxybenzyl)-1-methylpiperidin-4-amine (Compound 14):

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.120g, 0.65mmol) in DCE (2.4 mL, 20V) at room temperature, 1-methylpiperidin-4-amine (0.089g, 0.78mmol) and acetic acid (0.001g, 0.0325mmol) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.414g, 1.95mmol) was added to the reaction mixture portion-wise at 0°C. The reaction was stirred at room temperature for 5h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15 mL) and extracted with CH2CI2 (3 X 10 mL). The combined organic fractions were washed with water (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-15% methanol in dichloromethane) to provide N-(5-chloro-2-ethoxybenzyl)-1- methylpiperidin-4-amine (0.023g, 12.79% yield) as a white sticky solid.

LCMS [ESI, M+1]: 283.1 (RT: 0.795 min, Purity: 100%),

HPLC: RT: 3.472 min, Purity: 97.27 %

¹ H NMR (400 MHz, cfc-DMSO): 6 7.33 (d, J = 2.1 Hz, 1 H), 7.17 (d, J = 8.6 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 3.95 (q, J = 6.9 Hz, 2H), 3.64 (s, 2H), 2.75 (d, J = 11.6 Hz, 2H), 2.16 (s, 3H), 2.00 (s, 2H), 1.83 - 1.71 (m, 2H), 1.32 (d, J = 10.2 Hz, 2H), 1.24 (t, J = 6.9 Hz, 3H). (two protons merge with solvent residual peak)

Experimental protocol for Compound 15:

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.12g, 0.81 mmol) in DCE (3mL) at room temperature, te/Y-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (0.18g, 0.78mmol) and acetic acid (0.006mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.41g, 1.95mmol) was portion-wise to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (10 mL) and washed with sat. NaHCCh solution (10 mL) and water (10 mL). The organic fraction was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70% EtOAc/Hexane) to provide fert-butyl 4-(2-((5-chloro-2-ethoxybenzyl)amino) ethyl)piperazine-1- carboxylate (0.081g, 31.39% yield) as a yellow oil.

LCMS [ESI, M+1]: 398.2 (RT: 1.429 min, Purity: 100%),

¹ H-NMR (400 MHz, CD3OD): 6 7.39-7.36 (m, 2H), 7.06 (d, J = 8.4 Hz, 1 H), 4.16 (q, J = 7.0 Hz, 2H), 4.08 (s, 2H), 3.35 (bs, 4H), 3.00 (t, J = 5.4 Hz, 2H), 2.61 (t, J = 5.6 Hz, 2H), 2.40 (t, J = 4.6 Hz, 4H), 1.49-1.46 (m, 12H). i-2 -(piperazin-1 -vl)ethan-1 -amine

Procedure

To a stirred solution of te/Y-butyl 4-(2-((5-chloro-2-ethoxybenzyl)amino)ethyl)piperazine-1- carboxylate (0.08g, 0.20mmol) in CH2CI2 (1.0mL) at 0°C , 4.0 M HCI in Dioxane (0.4mL, 5V) was added. The reaction mixture was then stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration with diethyl ether to provide /V-(5-chloro-2-ethoxybenzyl)-2-(piperazin-1-yl)ethan-1 -amine hydrochloride (0.0218g, 36.41% yield) as a brown sticky solid.

LCMS [ESI, M+1]: 298.1 (RT: 0.766 min, Purity: 100%),

HPLC Purity: RT: 3.652 min, Purity: 100.0%

¹ H-NMR (400 MHz, CD3OD): 6 7.52 (d, J = 2.4 Hz, 1 H), 7.46-7.43 (dd, J = 2.8 Hz, 8.8 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), 4.30 (s, 2H), 4.20 (q, J = 14.0 Hz, 2H), 3.67-3.60 (m, 1 H), 3.43-3.35 (m, 6H), 3.09 (bs, 5H), 1 .49 (t, J = 6.8 Hz, 3H).

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.100g, 0.54mmol) in DCE (2mL) at room temperature, tert-butyl (R)-3-aminopyrrolidine-1 -carboxylate (0.121g, 0.65mmol) and acetic acid (0.0075ml) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.345g, 1.628 mmol) was added to the reaction mixture portion-wise at 0°C. Then reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into water (10 mL) and the solid precipitate was isolated by filtration to provide tert-butyl (R)-3-((5- chloro-2-ethoxybenzyl)amino)pyrrolidine-1 -carboxylate (0.120g, 62.43% yield) as a white liquid.

LCMS [ESI, M-56]: 299.06 (RT: 1.409 min, Purity: 100%)

Procedure

To a stirred solution of tert-butyl (R)-3-((5-chloro-2-ethoxybenzyl)amino)pyrrolidine-1 -carboxylate (0.120g, 0.54mmol) in CH2CI2 (1.2 mL) at room temperature, 4M HCI in Dioxane (0.6 mL, 5V) was added. The reaction mixture was stirred at room temperature for 20 min. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude material which was purified by trituration with diethyl ether to provide (R)-N-(5-chloro-2-ethoxybenzyl) pyrrolidin-3-amine hydrochloride (0.049, 56.88%) as a white solid.

LCMS [ESI, M+1]: 255.05 (RT: 0.726min, Purity: 100%),

HPLC: RT:3.446 min, Purity: 100%

¹ H NMR (400 MHz, cfc-DMSO): 6 9.91 (br, 1 H), 9.67 (br, 3H), 9.51 (br, 1 H), 7.50 (s, 1 H), 7.37 (dd, J = 8.8, 2.4 Hz, 1 H), 7.02 (d, J = 8.9 Hz, 1 H), 4.16 - 3.94 (m, 4H), 3.83 (d, J = 21.2 Hz, 1 H), 3.15 (d, J = 11.4 Hz, 2H), 2.34 - 2.23 (m, 1 H), 2.15 (d, J = 17.5 Hz, 1 H), 1.93 (s, 1 H), 1.30 (t, J = 6.9 Hz, 3H).

>-1: tert-butvl ((1r,3r)-3-((5-chloro-2-ethoxvbenzvl)ami

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.100g, 0.54mmol) in DCE (2 mL) at room temperature, tert-butyl ((1 r,3r)-3-aminocyclobutyl)carbamate (0.121g, 0.65mmol) and acetic acid (0.0075 mL) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.345g, 1.628 mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (10 mL) and extracted with CH2CI2 ( 3 X 20 mL) . The combined organic fractions were washed with water (20 mL), dried over sodium sulfate and concentrated under reduced pressure The crude material was purified by column chromatography (SiC>2; 40% EtOAc in hexene) to provide tert-butyl ((1r,3r)-3-((5-chloro-2- ethoxybenzyl)amino) cyclo butyl)carbamate (0.150g, 78.04% yield) as a light yellow liquid.

LCMS [ESI, M+1]: 355.2(RT: 1.462 min, Purity: 99.16%)

Procedure

To a stirred solution of tert-butyl ((1 r,3r)-3-((5-chloro-2-ethoxybenzyl)amino)cyclobutyl)carbamate (0.150g, 0.43mmol) in CH2CI2 (1.3mL) at room temperature, 4M HCI in Dioxane (0.6 mL, 5V) was added. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude material which was purified by trituration with diethyl ether to provide (1r,3r)-N1-(5-chloro-2-ethoxybenzyl)cyclobutane-1,3- diamine hydrochloride (0.037g, 34.36%) as an off-white solid.

LCMS [ESI, M+1]:255(RT: 0.763min, Purity: 96.26%),

HPLC: RT: 3.120 min, Purity: 96.76%

¹ H NMR (400 MHz, cfc-DMSO): 6 9.64 (br, 2H), 8.33 (br, 3H), 7.40 (d, J = 2.6 Hz, 1 H), 7.36 (dd, J = 8.8, 2.6 Hz, 1 H), 7.02 (d, J = 8.9 Hz, 1 H), 4.10 (q, J = 6.9 Hz, 2H), 3.98 (m, 2H), 3.73 (dt, J = 22.5, 11 .4 Hz, 2H), 2.63 - 2.45 (m, 2H), 2.36 - 2.29 (m, 2H), 1 .27 (dd, J = 8.8, 5.0 Hz, 3H).

Experimental protocol for Compound 18:

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.100g, 0.54mmol) in DCE (2 mL) at room temperature, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (0.130g, 0.65mmol) and Acetic acid (0.0075mL) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.345g, 1.628 mmol) was added to the reaction mixture in small portions at 0°C. The reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (10 mL) and extracted with CH2CI2 (3 x 5 mL). The combined organic fractions were washed with water (5 mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 40% EtOAc in hexane) to provide tert-butyl ((1S,3S)-3-((5-chloro-2- ethoxybenzyl)amino)cyclopentyl)carbamate (0.113g, 56.55% yield) as a white liquid.

LCMS [ESI, M+1]: 369.17 (RT: 1.540 min, Purity: 100%)

Procedure

To a stirred solution of tert-butyl ((1S,3S)-3-((5-chloro-2- ethoxybenzyl)amino)cyclopentyl)carbamate (0.113g, 0.36mmol) in CH2CI2 (1.0 mL) at room temperature, 4M HCI in Dioxane (0.6 mL, 5V) was added. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with diethyl ether to provide (1S,3S)-N1-(5-chloro-2- ethoxybenzyl)cyclopentane-1 ,3-diamine hydrochloride (0.055g, 68.02%) as an off-white solid. LCMS [ESI, M+1]:269.1 (RT: 0.777min, Purity: 98.30%), HPLC: RT:3.453 min, Purity: 97.63%

¹ H NMR (400 MHz, CD3OD): 6 7.42 (d, J = 2.5 Hz, 1 H), 7.37 (dd, J = 8.8, 2.6 Hz, 1 H), 7.03 (d, J = 8.9 Hz, 1 H), 4.28 - 4.02 (m, 4H), 3.91 - 3.71 (m, 2H), 2.47 - 2.31 (m, 1 H), 2.23 (tdd, J = 21 .2, 13.9, 8.0 Hz, 3H), 1 .88 - 1 .76 (m, 1 H), 1 .70 (dt, J = 18.2, 7.3 Hz, 1 H), 1 .41 (t, J = 7.0 Hz, 3H).

Step-1 :tert-butyl (S)-3-((5-chloro-2-ethoxybenzyl)amino)piperidine-1 -carboxylate: Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.120g, 0.65mmol) in DCE (2.4mL, 20V) at room temperature, tert-butyl (S)-3-aminopiperidine-1-carboxylate (0.156g, 0.78mmol) and acetic acid (0.001g, 0.0325mmol) were added. Then reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.414g, 1.95mmol) was added to the reaction portion-wise at 0°C. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organic fractions were washed with water (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by trituration using n- pentane to provide tert-butyl (S)-3-((5-chloro-2-ethoxybenzyl)amino)piperidine-1 -carboxylate (0.230g, 95.92% yield) as a colourless liquid.

LCMS [ESI, M+1]: 369.17 (RT:1.618 min, Purity: 100%),

Procedure

To a stirred solution of tert-butyl (S)-3-((5-chloro-2-ethoxybenzyl)amino)piperidine-1 -carboxylate (0.230g, 0.625 mmol) in CH2CI2 (2.3mL, 10V) at room temperature, 4M HCI in dioxane (1.15mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration using CH2CI2 to provide (S)-N-(5-chloro-2-ethoxybenzyl)piperidin-3-amine hydrochloride (0.143g, 85.33% yield) as an off-white solid.

LCMS [ESI, M+1]:269.10 ,(RT:0.784 min, Purity:100 %),

HPLC: RT:3.440 , Purity:100 %

¹ H NMR (400 MHz, cfc-DMSO): 6 9.76 (s, 1 H), 9.53 (s, 2H), 9.42 - 9.29 (m, 1 H), 7.56 (d, J = 2.5 Hz, 1 H), 7.36 (dd, J = 8.8, 2.5 Hz, 1 H), 7.02 (d, J = 8.9 Hz, 1 H), 4.02 (dd, J = 17.7, 10.7 Hz, 4H), 3.54 (d, J = 10.7 Hz, 1 H), 3.37 (s, 1 H), 3.13 (d, J = 12.2 Hz, 1 H), 3.00 (s, 1 H), 2.73 (s, 1 H), 2.15 (s, 1 H), 1 .87 (s, 1 H), 1 .66 (s, 2H), 1 .30 (t, J = 6.9 Hz, 3H).

:tert-butyl 3-((5-chloro-2-ethoxybenzyl)amino)azetidine-1 -<

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.150g, 0.81 mmol) in DCE (3 mL) at room temperature, tert-Butyl 3-aminoazetidine-1 -carboxylate (0.16g, 0.97mmol) and acetic acid (0.0075ml) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.515g, 2.43mmol) was added to the reaction mixture portion-wise at 0°C. The reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate(15mL) and extracted with CH2CI2 (3 x 10mL). The combined organic fractions were washed with water (20mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-40% EtOAc in hexane) to provide tert-butyl 3-((5-chloro-2- ethoxybenzyl)amino)azetidine-1 -carboxylate (0.200g, 72.46%yield) as light yellow liquid.

LCMS [ESI, M-56]:285.01 (RT: 1.473 min, Purity: 100%)

¹ H NMR (400 MHz, cfc-DMSO): 6 7.25 (d, J = 2.6 Hz, 1 H), 7.14 (dd, J = 8.7, 2.6 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 1 H), 3.94 (q, J = 6.9 Hz, 2H), 3.79 (s, 2H), 3.47 (s, 2H), 3.40 (s, 4H), 1 .28 (s, 9H), 1 .24 (d, J = 6.9 Hz, 3H).

Step 2: N-(5-chloro-2-ethoxybenzyl)azetidin-3-amine hydrochloride (Compound 20):

Procedure

To a stirred solution of tert-butyl 3-((5-chloro-2-ethoxybenzyl)amino)azetidine-1-carboxylate (0.15g, 0.44mmol) in CH2CI2 (0.5 mL) at 0°C, 4M HCI in Dioxane (0.3 mL, 2V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude product material which was purified by trituration with diethyl followed by preparative HPLC (0.05% HCI in water/ACN as the mobile phase) to provide N-(5- chloro-2-ethoxybenzyl)azetidin-3-amine hydrochloride (0.042g, 40% yield) as a white solid.

LCMS [ESI, M+1]:241.05(RT: 0.755min, Purity: 100%),

HPLC: RT: 3.353 min, Purity: 100%

¹ H NMR (400 MHz, cf ₆ -DMSO): 6 10.27 (br, 2H), 9.51 (br, 1 H), 9.16 (br, 1 H), 7.46 (s, 1 H), 7.37 (dd, J = 8.8, 2.3 Hz, 1 H), 7.03 (d, J = 8.9 Hz, 1 H), 4.10 (s, 3H), 4.02 (dd, J = 13.6, 6.7 Hz, 4H), 3.96 (s, 2H), 1.30 (t, J = 6.8 Hz, 3H). Yield : 63.63% i-1 : Synthesis of N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1 -amine:

Procedure:

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.100g, 0.54mmol) in DCE (2 mL) at room temperature, 1-(2-aminoethyl)piperidine (0.083g, 0.64mmol) and acetic acid (0.005mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.344g, 1.95mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated sodium bicarbonate solution (5 mL) and extracted with CH2CI2 (3 x 5 mL). The combined organic fractions were washed with cold water (5 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2, 0-10% MeOH/CH2Cl2) to provide N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1-amine( 0.030g, 18.66% yield) as a light yellow liquid.

LCMS [ESI, M+1]:297.1 (RT: 0.774 min, Purity: 91.83%),

HPLC: RT: 3.58 min, Purity: 92.95%,

¹ H NMR (400 MHz, cfc-DMSO): 6 7.40 (d, J = 2.4 Hz, 1 H), 7.29 (dd, J = 8.7, 2.4 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H), 4.05 (dd, J = 14.0, 7.0 Hz, 2H), 3.78 (s, 2H), 3.17 (s, 1 H), 2.72 (t, J = 6.1 Hz, 2H), 2.45 (s, 4H), 1 .91 (s, 2H), 1 .56 - 1 .48 (m, 4H), 1 .40 (d, J = 4.9 Hz, 2H), 1 .35 (t, J = 6.9 Hz, 3H).

Step-2: Synthesis of N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1 -amine

Procedure:

To a stirred solution of N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1 -amine (0.03g, 0.10mmol) in CH2CI2 (0.3mL) at 0°C, 4M HCI in Dioxane (0.15mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide N- (5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan-1 -amine hydrochloride (0.027g, 63.63% yield) as an off-white solid.

LCMS [ESI, M+1]: 297.1 (RT: 0.777 min, Purity: 98.31 %),

HPLC: RT: 3.963 min, Purity: 95.47%,

¹ H NMR (400 MHz, CD3OD): 6 7.62 (d, J = 2.4 Hz, 1 H), 7.44 (dd, J = 8.9, 2.5 Hz, 1 H), 7.10 (d, J = 8.9 Hz, 1 H), 4.14 (d, J = 7.9 Hz, 2H), 4.13 - 4.04 (m, 2H), 3.59 - 3.39 (m, 7H), 2.93 (s, 3H), 1.78 (d, J = 25.9 Hz, 4H), 1 .38 (t, J = 6.9 Hz, 3H).

Procedures

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.150g, 0.81 mmol) in DCE (3 mL) at room temperature, tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (0.198g, 0.97mmol) and acetic acid (0.0075mL) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.515g, 2.43mmol) was added to the reaction mixture portion-wise at 0°C. The reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15mL) and extracted with CH2CI2 (3 x 10mL). The combined organic fractions were washed with water (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-40% EtOAc in hexane) to provide tert-butyl(2-(2-((5-chloro-2- ethoxybenzyl)amino)ethoxy)ethyl)carbamate (0.200g, 66.22% yield) as a light yellow liquid.

LCMS [ESI, M+1]:373.12(RT: 1.438 min, Purity: 98.49%)

Procedure

To a stirred solution of tert-butyl(2-(2-((5-chloro-2-ethoxybenzyl)amino)ethoxy)ethyl )carbamate (0.200g, 0.53mmol) in CH2CI2 (1 mL) at 0°C, 4M HCI in dioxane (0.5 mL, 2.5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide 2-(2-aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine hydrochloride(0.142g, 97.26% yield) as a white solid.

LCMS [ESI, M+1]:273.1 (RT: 0.788min, Purity: 99.65%),

HPLC: RT:3.453 min, Purity: 100%

¹ H NMR (400 MHz, cfc-DMSO): 6 9.24 (s, 2H), 8.15 (s, 3H), 7.60 (d, J = 2.6 Hz, 1 H), 7.35 (dd, J = 8.8, 2.6 Hz, 1 H), 7.02 (d, J = 8.9 Hz, 1 H), 4.02 (dd, J = 14.7, 7.7 Hz, 4H), 3.74 - 3.46 (m, 4H), 3.10 - 2.80 (m, 4H), 1 .29 (t, J = 6.9 Hz, 3H).

Experimental protocol for Compound 23:

Step-1 : Synthesis of tert-butyl (4-((5-chloro-2-ethoxybenzyl)amino)cvclohexyl)carbamate:

Procedure:

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.200g, 1.08mmol) in DCE (4mL) at room temperature, tert-butyl (4-aminocyclohexyl)carbamate (0.278g, 1.29mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.688g, 3.24mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into saturated sodium bicarbonate solution (5 mL) and extracted with CH2CI2 (3 x 5 mL). The combined organic fractions were washed with cold water (5 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70% EtOAc in hexane) to provide tert-butyl (4-((5-chloro-2- ethoxybenzyl)amino)cyclohexyl)carbamate (0.220g, 53.03% yield) as a light yellow liquid.

LCMS [ESI, M+1]:384.1 (RT: 1.490 min, Purity: 100%),

¹ H NMR (400 MHz, CD ₃ OD): 6 7.30 (d, J = 2.5 Hz, 1 H), 7.23 (dd, J = 8.7, 2.6 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 4.10 (p, J = 6.7 Hz, 2H), 3.77 (s, 2H), 3.58 (s, 1 H), 2.59 (s, 1 H), 1.67 (t, J = 16.9 Hz, 4H), 1 .62 - 1 .47 (m, 4H), 1 .45 (d, J = 5.4 Hz, 12H).

Step-2: Synthesis of N1-(5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride (Compound 23):

Procedure:

To a stirred solution of tert-butyl (4-((5-chloro-2-ethoxybenzyl)amino)cyclohexyl)carbamate (0.220g, 0.57mmol) in CH2CI2 (2.2 mL) at 0°C, 4M HCI in Dioxane (1.1 mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide N1- (5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride(0.130g, 71.03% yield) as an off-white solid.

LCMS [ESI, M+1]: 283.1 (RT: 0.834 min, Purity: 97.89%),

HPLC: RT: 3.466 min, Purity: 100%,

¹ H NMR (400 MHz, cfc-DMSO) : 6 9.03 (s, 1 H), 8.19 (s, 3H), 7.58 (d, J = 2.5 Hz, 1 H), 7.40 (dd, J = 8.8, 2.6 Hz, 1 H), 7.05 (d, J = 8.9 Hz, 1 H), 4.04 (dd, J = 13.8, 6.8 Hz, 4H), 3.24 (s, 1 H), 3.12 (s, 1 H), 1 .95 (dd, J = 25.5, 15.1 Hz, 2H), 1 .81 (t, J = 25.3 Hz, 4H), 1 .70 (d, J = 13.4 Hz, 2H), 1 .32 (t, J = 6.9 Hz, 3H).

Experimental protocol for Compound 24: -n -

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.120g, 0.65mmol) in DCE (2.4mL, 20V) at room temperature, tert-butyl (1-amino-2-methylpropan-2-yl)carbamate (0.135g, 0.78mmol) and acetic acid (0.001g, 0.0325mmol) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.414g, 1.95mmol) was added to the reaction mixture portion-wise at 0°C. The reaction mixture was stirred at room temperature for 5h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organic fractions were washed with water (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by trituration using n-pentane to provide tert-butyl (1-((5-chloro-2- ethoxybenzyl)amino)-2-methylpropan-2-yl)carbamate (0.220g, 94.84% yield) as a yellowish liquid.

LCMS [ESI, M+1]:357.2 (RT:1.652 min, Purity: 100%)

To a stirred solution of tert-butyl (1-((5-chloro-2-ethoxybenzyl)amino)-2-methylpropan-2- yl)carbamate (0.220g, 0.61 mmol) in CH2CI2 (2.2mL, 10V) at room temperature, 4M HCI in dioxane (1 .1 mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration using CH2CI2 to provide N1-(5-chloro-2-ethoxybenzyl)-2-methylpropane-1 ,2-diamine hydrochloride (0.122g, 76.44% yield) as an off-white solid.

LCMS [ESI, M+1]: 257.1 ,(RT:0.781 min, Purity:100 %),

HPLC: RT:3.473 , Purity: 100%

¹ H NMR (400 MHz, cfc-DMSO): 6 9.61 (s, 2H), 8.65 (s, 3H), 7.68 (d, J = 2.2 Hz, 1 H), 7.44 (dd, J = 8.8, 2.2 Hz, 1 H), 7.11 (d, J = 8.9 Hz, 1 H), 4.22 - 4.05 (m, 4H), 3.18 (d, J = 15.5 Hz, 2H), 1.37 (dd, J = 13.5, 6.5 Hz, 9H). Experimental protocol for Compound 25:

Step-1 : Synthesis of 4-chloro-2-ethoxybenzaldehyde:

Procedure:

To a stirred solution of 4-chloro-2-hydroxybenzaldehyde (0.300g, 1.91 mmol) in DMF (3mL) at room temperature, potassium carbonate (0.529g, 3.83mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Bromo ethane (0.417g, 3.83mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h . The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice cold water (10 mL). A solid precipitate was obtained which was isolated by filtration and dried under reduced pressure to provide 4-chloro-2-ethoxybenzaldehyde (0.300g, 84.80% yield) as an off-white solid.

LCMS [ESI, M+1]:184.1 (RT: 2.000 min, Purity: 100%),

¹ H NMR (400 MHz, CD ₃ OD): 6 10.34 (s, 1 H), 7.72 (d, J = 8.3 Hz, 1 H), 7.38 (d, J = 1.7 Hz, 1 H), 7.17 (dd, J = 8.3, 1 .1 Hz, 1 H), 4.26 (q, J = 7.0 Hz, 2H), 1 .42 (t, J = 7.0 Hz, 3H).

Step-2: Synthesis of tert-butyl 4-(((4-chloro-2-ethoxybenzyl)amino)methyl)piperidine-1- carboxylate:

Procedure:

To a stirred solution of 4-chloro-2-ethoxybenzaldehyde (0.150g, 0.81 mmol) in DCE (3mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate(0.208g, 0.97mmol) and acetic acid (0.007mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.516g, 2.43mmol) was added portion-wise at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate(3mL) and extracted with CH2CI2 (2 x 4mL). The organic layer was washed with water (2 x 3mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 80-85% ethyl acetate in hexane) to provide tert-butyl 4-(((4-chloro-2-ethoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.160g, 51.43% yield) as a light yellow liquid.

LCMS [ESI, M+1]:383.1 (RT: 1.525 min, Purity: 98.25%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.32 (d, J = 8.0 Hz, 1 H), 7.04 - 6.91 (m, 2H), 4.06 (q, J = 6.9 Hz, 2H), 3.93 (d, J = 8.8 Hz, 2H), 3.62 (s, 2H), 2.69 (s, 2H), 2.36 (d, J = 6.6 Hz, 2H), 1.69 (d, J = 12.6 Hz, 2H), 1.56 (d, J = 7.2 Hz, 1 H), 1.40 (s, 9H), 1.34 (t, J = 6.9 Hz, 3H), 0.96 (qd, J = 12.5, 3.9 Hz, 2H).

Step-3: Synthesis of N-(4-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (Compound 25)

Procedure:

To a stirred solution of tert-butyl 4-(((4-chloro-2-ethoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.160g, 0.67mmol) in CH2CI2 (1 .6mL) at 0°C, 4M HCI in Dioxane (0.8mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide N-(4-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.107g, 80.45% yield) as an off-white solid.

LCMS [ESI, M+1]: 283.1 (RT: 0.772 min, Purity: 99.66%),

HPLC: RT: 3.433 min, Purity: 98.70%,

¹ H NMR (400 MHz, cfc-DMSO) : 6 9.38 (s, 2H), 9.22 (s, 1 H), 9.08 (s, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.16 (s, 1 H), 7.07 (d, J = 7.7 Hz, 1 H), 4.1 1 (t, J = 10.6 Hz, 2H), 4.06 (s, 2H), 3.25 (d, J = 1 1.3 Hz, 2H), 2.82 (s, 4H), 2.06 (d, J = 31 .4 Hz, 1 H), 1.97 (d, J = 12.7 Hz, 2H), 1.53 - 1.40 (m, 2H), 1.38 (t, J = 6.6 Hz, 3H).

Procedure:

To a stirred solution of 4,5-dichloro-2-hydroxybenzaldehyde (0.200g. , 1 .04mmol) in DMF (4mL) at room temperature, potassium carbonate (0.289g., 2.09mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Bromo ethane (0.228g, 2.09mmol) was added. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into cold water (10 mL) and a precipitate was formed. The precipitate was isolated by filtration and concentrated under reduced pressure to provide 4,5-dichloro-2-ethoxybenzaldehyde (0.200g, 87.19% yield) as an off- white solid.

¹ H NMR (400 MHz, cfc-DMSO): 6 10.24 (s, 1 H), 7.77 (s, 1 H), 7.58 (s, 1 H), 4.23 (q, J = 6.9 Hz, 2H), 1.55 - 1.16 (m, 3H).

4-(((4,5-dichloro-2-ethoxybenzyl)amino)methyl)piperidine- 1-

Procedure:

To a stirred solution of 4,5-dichloro-2-ethoxybenzaldehyde (0.100g, 0.45mmol) in DCE (2mL) at room temperature, tert-butyl 4-(amino methyl) piperidine-1 -carboxylate (0.117g, 0.54mmol) and acetic acid (0.005mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.290g, 1.36mmol) was added portion-wise to the reaction mixture at 0°C. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (10 mL) and extracted with CH2CI2 (3 x 5 mL). The combined organic fractions were washed with water (10 mL), dried over sodium sulfate and concentrated under reduce pressure. The crude material was purified by column chromatography (SiC>2; 50% ethyl acetate in hexane) to provide tert-butyl 4-(((4,5-dichloro-2- ethoxybenzyl)amino)methyl)piperidine-1 -carboxylate (0.150g, 78.73% yield) as a light yellow liquid.

LCMS [ESI, M+1]:417.1 (RT: 1.690min, Purity: 100%),

¹ H NMR (400 MHz, cfe-DMSO): 6 7.52 (s, 1 H), 7.19 (s, 1 H), 4.05 (q, J = 7.0 Hz, 2H), 3.90 (s, 2H), 3.60 (s, 2H), 2.67 (s, 1 H), 2.35 (d, J = 6.7 Hz, 2H), 2.22 - 2.03 (m, 1 H), 1.66 (t, J = 18.8 Hz, 2H), 1 .55 (d, J = 8.5 Hz, 1 H), 1.36 (d, J = 17.2 Hz, 9H), 1.32 (t, J = 6.9 Hz, 3H), 0.96 (ddd, J = 16.0, 12.5, 4.2 Hz, 2H).

Step-3: Synthesis of N-(4,5-dichloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamin e hydrochloride (Compound 26):

Procedure:

To a stirred solution of tert-butyl 4-(((4,5-dichloro-2-ethoxybenzyl)amino)methyl)piperidine-1- carboxy late (0.150g, 0.340 mmol) in CH2CI2 (1.5mL) at 0°C, 4M HCI in Dioxane (0.75mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide N-(4,5-dichloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamin e hydrochloride (0.104g, 81.88% yield) as an off-white solid.

LCMS [ESI, M+1]: 317.25(RT: 0.964 min, Purity: 100%),

HPLC: RT: 3.840 min, Purity: 99.31 %,

¹ H NMR (400 MHz, CD3OD): 6 7.68 (s, 1 H), 7.32 (s, 1 H), 5.51 (s, 1 H), 4.24 (d, J = 10.5 Hz, 2H), 4.20 (q, J = 6.9 Hz, 2H), 3.46 (d, J = 13.0 Hz, 2H), 3.09 (d, J = 7.2 Hz, 3H), 2.19 (dd, J = 9.0, 5.7 Hz, 1 H), 2.08 (d, J = 13.9 Hz, 2H), 1.59 (dd, J = 19.4, 8.8 Hz, 2H), 1.49 (t, J = 7.0 Hz, 3H).

Procedure:

To a stirred solution of 2-chloro-6-hydroxybenzaldehyde (0.200g, 1.27mmol) in DMF (2mL) at room temperature, potassium carbonate (0.353g, 2.55mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then bromo ethane (0.278g, 2.55mmol) was added. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (5 mL) and extracted with ethyl acetate (2 x 4 mL). The combined organic fractions were washed with cold water 3-4 times, dried over sodium sulfate and concentrated under reduced pressure to provide 2-chloro-6-ethoxybenzaldehyde (0.200g, 84.80% yield) as an off- white solid.

LCMS [ESI, M+1]:185.1 (RT: 1.824 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 10.41 (s, 1 H), 7.58 (t, J = 8.3 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 1 H),

7.13 (d, J = 8.0 Hz, 1 H), 4.20 (q, J = 6.9 Hz, 2H), 1 .39 (t, J = 7.0 Hz, 3H).

Procedure:

To a stirred solution of 2-chloro-6-ethoxybenzaldehyde (0.100g, 0.54mmol) in DCE (2mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.139g, 0.64mmol) and acetic acid (0.005mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.344g, 1.62mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (4mL) and extracted with CH2CI2 (2 x 3mL). The combined organic fractions were washed with water (2 x 2mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70% ethyl acetate in hexane) to provide tert-butyl 4-(((2-chloro-6- ethoxybenzyl)amino)methyl)piperidine-1 -carboxylate (0.150g, 72.32% yield) as a light yellow liquid.

LCMS [ESI, M+1]:383.1 (RT: 1.535 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.24 (t, J = 8.2 Hz, 1 H), 7.00 (dd, J = 1 1 .8, 8.2 Hz, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.92 (d, J = 11 .2 Hz, 2H), 3.81 (s, 2H), 2.69 (s, 2H), 2.36 (d, J = 6.6 Hz, 2H), 1 .66 (d, J = 12.7 Hz, 2H), 1.61 - 1 .52 (m, 1 H), 1.38 (d, J = 8.0 Hz, 9H), 1.35 (d, J = 7.0 Hz, 3H), 0.93 (ddd, J = 16.2, 12.5, 4.1 Hz, 2H).

Step-3: Synthesis of N-(2-chloro-6-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (Compound 27):

Procedure:

To a stirred solution of tert-butyl 4-(((2-chloro-6-ethoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.150g, 0.37mmol) in CH2CI2 (1.5mL) at 0°C, 4M HCI in Dioxane (0.75mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide N-(2-chloro-6-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.114g, 91.20 yield) as an off-white solid.

LCMS [ESI, M+1]: 283.1 (RT: 0.754 min, Purity: 100%),

HPLC: RT: 3.326 min, Purity: 100%,

¹ H NMR (400 MHz, CD3OD) : 6 7.47 (t, J = 8.3 Hz, 1 H), 7.15 (dd, J = 16.4, 8.3 Hz, 2H), 4.50 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 3.47 (t, J = 19.8 Hz, 2H), 3.14 (dd, J = 9.5, 5.0 Hz, 2H), 3.13 - 3.01 (m, 2H), 2.26 (dtd, J = 14.9, 7.6, 3.8 Hz, 1 H), 2.12 (d, J = 14.1 Hz, 2H), 1.68 - 1.55 (m, 2H), 1 .56 - 1.45 (m, 3H).

Procedure:

To a stirred solution of 3-chloro-4-hydroxybenzaldehyde (0.200g.1 .27mmol) in DMF (2mL) at room temperature, potassium carbonate (0.353g.2.55mmol) was added. The reaction mixture was stirred at room temperature for 15min. Then Bromo ethane (0.278g, 2.55mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (5mL) and extracted with ethyl acetate (2 x 3mL). The combined organic fractions were washed with cold water (3x5mL), dried over sodium sulfate and concentrated under reduced pressure to provide 3-chloro-4-ethoxybenzaldehyde (0.180g, 76.32% yield) as an off-white solid.

LCMS [ESI, M+1]:185.1 (RT: 1.864 min, Purity: 99.14%),

¹ H NMR (400 MHz, cfc-DMSO): 6 9.87 (d, J = 12.4 Hz, 1 H), 8.00 - 7.77 (m, 2H), 7.34 (d, J = 8.5 Hz, 1 H), 4.24 (q, J = 6.9 Hz, 2H), 1 .39 (t, J = 7.0 Hz, 3H).

-1-

Procedure:

To a stirred solution of 3-chloro-4-ethoxybenzaldehyde (0.180g, 0.97mmol) in DCE (3.4mL) at room temperature, tert-butyl 4-(amino methyl) piperidine-1 -carboxylate (0.250g, 1.16mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.619g, 2.92mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (6mL) and extracted with CH2CI2 (3 x 4mL). The combined organic fractions were washed with water (2x3mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 45-50% ethyl acetate in hexane) to provide tert-butyl 4-(((3- chloro-4-ethoxybenzyl)amino)methyl)piperidine-1 -carboxylate (0.160g, 42.86% yield) as a light yellow liquid.

LCMS [ESI, M+1]:383.1 (RT: 1.523min, Purity: 98.97%),

1 H NMR (400 MHz, cfe-DMSO): 6 7.36 (d, J = 1.6 Hz, 1 H), 7.18 (t, J = 15.9 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 4.14 - 4.02 (m, 2H), 3.91 (d, J = 11.3 Hz, 2H), 3.59 (s, 2H), 2.67 (s, 2H), 2.31 (d, J = 6.6 Hz, 2H), 2.14(s, 1 H), 1.67 (d, J = 12.6 Hz, 2H), 1.49 (d, J = 31.1 Hz, 2H), 1.42 - 1.33 (m, 9H), 1 .04 - 0.80 (m, 3H).

Procedure:

To a stirred solution of tert-butyl 4-(((3-chloro-4-ethoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.160g, 0.41 mmol) in CH2CI2 (1.6mL) at at 0°C, 4M HCI in Dioxane (0.8mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with diethyl ether to provide N-(3-chloro-4-ethoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride (0.106g, 79.69% yield) as an off-white solid.

LCMS [ESI, M+1]: 283.1 (RT: 0.819 min, Purity: 95.48%),

HPLC: RT: 3.520 min, Purity: 100%,

¹ H NMR (400 MHz, CD3OD): 6 7.65 (d, J = 2.1 Hz, 1 H), 7.49 (dd, J = 8.5, 2.1 Hz, 1 H), 7.17 (d, J = 8.5 Hz, 1 H), 4.19 (dd, J = 13.8, 6.8 Hz, 4H), 3.48 (d, J = 13.0 Hz, 2H), 3.16 - 2.97 (m, 4H), 2.24 - 2.14 (m, 1 H), 2.14 - 2.01 (m, 2H), 1 .68 - 1.52 (m, 2H), 1.54 - 1.39 (m, 3H).

Procedure:

To a stirred solution of 2-hydroxy-5-methoxybenzaldehyde (0.300g, 1.97mmol) in DMF (3mL) at room temperature, potassium carbonate (0.545g, 3.94mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then bromo ethane (0.429g, 3.94mmol) was added. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (8mL) and extracted with ethyl acetate (2 x 5mL). The combined organic fractions were washed with cold water (5 x 7mL), dried over sodium sulfate and concentrated under reduced pressure to provide 2-ethoxy-5-methoxy benzaldehyde_(0.150g, 42.22% yield) as an off-white solid.

LCMS [ESI, M+1]:181.1 (RT: 1.789 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 10.38 (d, J = 11.3 Hz, 1 H), 7.26 (dd, J = 9.1 , 3.1 Hz, 1 H), 7.19 (dd, J = 8.2, 6.3 Hz, 2H), 4.15 (q, J = 6.9 Hz, 2H), 3.77 (s, 3H), 1 .38 (t, J = 7.0 Hz, 3H). i-2: Synthesis of tert-butyl 4-(((2-ethoxy-5-i -1-

Procedure:

To a stirred solution of 2-ethoxy-5-methoxybenzaldehyde (0.150g, 0.83mmol) in DCE (2mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.214g, 0.99mmol) and acetic acid (0.005mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.529g, 2.49mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (6mL) and extracted with CH2CI2 (3x5mL). The combined organic fractions were washed with water (2x5mL), dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-70% ethyl acetate in hexane) to provide tert-butyl 4-(((2-ethoxy- 5-methoxybenzyl)amino)methyl) piperidine-1 -carboxylate (0.200g, 63.48 % yield) as a light yellow liquid.

LCMS [ESI, M+1]:379.2 (RT: 1.485 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 6.91 (d, J = 2.9 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 6.71 (dd, J = 8.8, 2.9 Hz, 1 H), 3.94 (dd, J = 13.8, 6.9 Hz, 4H), 3.69 (d, J = 12.3 Hz, 3H), 3.61 (s, 2H), 2.35 (d, J = 6.5 Hz, 2H), 1 .90 (s, 2H), 1 .66 (t, J = 17.0 Hz, 2H), 1 .55 (d, J = 1 1 .2 Hz, 1 H), 1 .38 (s, 9H), 1 .29 (t, J = 6.9 Hz, 3H), 1 .06 - 0.87 (m, 2H).

Step-3: Synthesis of N-(2-ethoxy-5-methoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (Compound 29):

Procedure:

To a stirred solution of tert-butyl 4-(((2-ethoxy-5-methoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.200g, 0.53mmol) in CH2CI2 (2 mL) at 0°C, 4M HCI in Dioxane (0.1 OmL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with diethyl ether to provide N-(2-ethoxy-5-methoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride (0.165g, 99.39% yield) as an off-white solid.

LCMS [ESI, M+1]: 279.1 (RT: 0.715 min, Purity: 98.97%),

HPLC: RT: 3.759 min, Purity: 99.25%,

¹ H NMR (400 MHz, CD3OD): 6 7.06 (ddd, J = 11.8, 9.9, 2.7 Hz, 3H), 4.28 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 3.82 (s, 3H), 3.49 (d, J = 12.8 Hz, 2H), 3.17 - 3.00 (m, 4H), 2.29 - 2.16 (m, 1 H), 2.1 1 (d, J = 13.6 Hz, 2H), 1 .69 - 1 .52 (m, 2H), 1 .49 (t, J = 7.0 Hz, 3H).

Procedure:

To a stirred solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (0.100g, 0.48mmol) in DMF (10mL) at room temperature, potassium carbonate (0.134g, 0.54mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then Bromo ethane (0.105g, 1.95mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (5mL) and extracted with ethyl acetate (2 x 5mL). The combined organic fractions were washed with cold water (3 x 6mL), dried over sodium sulfate and concentrated under reduced pressure to provide 2-ethoxy-5- (trifluoromethoxy)benzaldehyde (0.250g, 73.35% yield) as an off- white solid.

LCMS [ESI, M+1]:235.1 (RT: 2.162 min, Purity: 100%),

¹ H NMR (400 MHz, cfe-DMSO): 6 10.33 (s, 1 H), 7.66 (dd, J = 9.1 , 2.6 Hz, 1 H), 7.54 (d, J = 2.3 Hz, 1 H), 7.35 (d, J = 9.1 Hz, 1 H), 4.23 (q, J = 7.0 Hz, 2H), 1 .39 (t, J = 7.0 Hz, 3H). tert-butyl 4-(((2-ethoxy-5-

(trifluoromethoxy)benzyl)amino)methyl)piperidine-1 -carboxylate:

Procedure:

To a stirred solution of 2-ethoxy-5-(trifluoromethoxy)benzaldehyde (0.200g, 0.85mmol) in DCE (4mL) at room temperature, tert-butyl 4-(amino methyl) piperidine-1 -carboxylate (0.219g, 1.02mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.543g, 2.56mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (6mL) and extracted with CH2CI2 (2 x 5mL). The combined organic fractions were washed with water (5mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70% ethyl acetate in hexane) to provide tert-butyl 4-(((2-ethoxy-5-(trifluoromethoxy)benzyl)amino)methyl)piperi dine-1 -carboxylate (0.160g,

43.32% yield) as a light yellow liquid.

LCMS [ESI, M+1]:433.1 (RT: 1.630 min, Purity: 99.32%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.32 (s, 1 H), 7.16 (d, J = 8.8 Hz, 1 H), 7.00 (d, J = 8.9 Hz, 1 H), 4.04 (q, J = 6.9 Hz, 2H), 3.91 (d, J = 11.2 Hz, 2H), 3.65 (s, 2H), 2.67 (s, 2H), 2.35 (d, J = 6.5 Hz, 3H), 1.68 (d, J = 12.8 Hz, 2H), 1.55 (d, J = 11.8 Hz, 1 H), 1.37 (d, J = 10.4 Hz, 9H), 1.33 (t, J = 6.9 Hz, 3H), 1.02 - 0.87 (m, 2H).

Step-3: Synthesis of N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)me thanamine hydrochloride (Compound 30)

Procedure:

To a stirred solution of tert-butyl 4-(((2-ethoxy-5-(trifluoromethoxy)benzyl)amino)methyl)piperi dine- 1-carboxylate (0.150g, 0.34mmol) in CH2CI2 (1.5mL) at 0°C, 4M HCI in Dioxane (0.7mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)me thanamine hydrochloride (0.073g, 53.67% yield) as an off-white solid.

LCMS [ESI, M+1]: 333.1 (RT: 0.930 min, Purity: 100%),

HPLC: RT: 4.247 min, Purity: 100%,

¹ H NMR (400 MHz, cfc-DMSO) : 6 9.35 (s, 2H), 9.11 (s, 2H), 8.97 (s, 2H), 7.64 (s, 1 H), 7.40 (d, J = 7.1 Hz, 1 H), 7.16 (d, J = 9.1 Hz, 1 H), 4.17 - 4.06 (m, 4H), 3.26 (d, J = 12.1 Hz, 2H), 2.85 (s, 4H), 2.09 (s, 1 H), 1 .95 (t, J = 15.6 Hz, 2H), 1 .54 - 1 .41 (m, 2H), 1 .37 (d, J = 6.9 Hz, 3H).

Cas.No.210039-65-9 p Yield : 85.72%

Procedure:

To a stirred solution of 2-hydroxy-5-(trifluoromethyl)benzaldehyde (0.200g.1 ,05mmol) in DMF (2mL) at room temperature, potassium carbonate (0.290g.2.10mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Bromo ethane (0.229g, 2.10mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice cold water (10 mL) to obtain a solid precipitate. The solid material was isolated by filtration and dried under reduced pressure to provide 2-ethoxy-5- (trifluoromethyl)benzaldehyde (0.110g, 47.93% yield) as an off-white Solid.

LCMS [ESI, M+1]:219 (RT: 2.083 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 10.37 (s, 1 H), 7.98 (t, J = 12.4 Hz, 1 H), 7.92 (s, 1 H), 7.44 (d, J = 8.8 Hz, 1 H), 4.30 (q, J = 6.9 Hz, 2H), 1 .47 - 1 .28 (m, 3H).

Procedure:

To a stirred solution of 2-ethoxy-5-(trifluoromethyl)benzaldehyde (0.110g, 0.50mmol) in DCE (2mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.129g, 0.60mmol) and acetic acid (0.005mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.320g, 1.51 mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (5mL) and extracted with CH2CI2 (2 x 3mL). The combined organic fractions were washed with water (2 x 2mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 58-60% ethyl acetate in hexane) to provide tert-butyl 4-(((2- ethoxy-5-(trifluoromethyl)benzyl)amino)methyl)piperidine-1 -carboxylate (0.180g, 85.72% yield) as a light yellow liquid.

LCMS [ESI, M-56]:361.1 (RT: 1.606 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.65 (d, J = 21.2 Hz, 1 H), 7.50 (t, J = 26.8 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 4.09 (dt, J = 27.5, 13.7 Hz, 2H), 3.92 (s, 2H), 3.63 (d, J = 35.8 Hz, 2H), 2.62 (d, J = 37.7 Hz, 2H), 2.35 (t, J = 10.5 Hz, 2H), 1 .90 (s, 1 H), 1 .77 - 1 .47 (m, 2H), 1 .48 (d, J = 74.4 Hz, 1 H), 1 .61 - 1 .06 (m, 9H), 1 .34 - 0.97 (m, 2H), 0.96 (dd, J = 20.4, 12.2 Hz, 2H).

Procedure:

To a stirred solution of tert-butyl 4-(((2-ethoxy-5-(trifluoromethyl)benzyl)amino)methyl)piperid ine-1- carbo xylate (0.180gm, 0.43mmol) in CH2CI2 (1 .8mL, 10v) at 0°C, 4M HCI in Dioxane (0.9mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with diethyl ether to provide N-(2-ethoxy-5-(trifluoromethyl)benzyl)-1-(piperidin-4-yl)met hanamine hydrochloride(0.089g, 58.55% yield) as a light brown sticky solid.

LCMS [ESI, M+1]: 317.6 (RT: 0.902 min, Purity: 100%),

HPLC: RT: 3.606min, Purity: 100%,

¹ H NMR (400 MHz, CD3OD) : 6 7.81 (d, J = 15.4 Hz, 1 H), 7.73 (t, J = 31.6 Hz, 1 H), 7.29 (d, J = 8.7 Hz, 1 H), 4.33 (d, J = 9.6 Hz, 2H), 4.29 (q, J = 7.0 Hz, 2H), 3.42 (dd, J = 38.2, 11 .2 Hz, 2H), 3.32 - 3.29 (m, 2H), 3.09 (dd, J = 16.7, 4.6 Hz, 2H), 2.25 - 2.16 (m, 1 H), 2.06 (t, J = 21.0 Hz, 2H), 1.63 - 1.53 (m, 2H), 1.53 (dd, J = 13.9, 6.9 Hz, 3H).

Procedure:

To a stirred solution of 5-chloro-2-(trifluoromethoxy) benzaldehyde (0.200g, 0.95mmol) in DCE (4mL) at room temperature, tert-butyl 4-(amino methyl) piperidine-1 -carboxylate (0.246g, 1.15mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxy borohydride (0.609g, 2.87mmol) was added portion- wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 8h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (5mL) and extracted with CH2CI2 (3 x 5mL). The combined organic fractions were washed with water (5mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 45-50% ethyl acetate in hexane) to provide tertbutyl 4-(((5-chloro-2-(trifluoromethoxy)benzyl)amino)methyl)piperi dine-1 -carboxylate) (0.250g, 66.38% yield) as a light yellow liquid.

LCMS [ESI, M-56]:368.1 (RT: 2.200 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.67 (d, J = 8.0 Hz, 1 H), 7.45 - 7.29 (m, 2H), 3.92 (d, J = 10.1 Hz, 2H), 3.71 (s, 2H), 2.68 (d, J = 6.8 Hz, 2H), 2.35 (d, J = 6.5 Hz, 2H), 1.69 (d, J = 12.6 Hz, 2H), 1.55 (d, J = 7.2 Hz, 1 H), 1.38 (s, 9H), 0.96 (qd, J = 12.5, 4.0 Hz, 2H). Step-2: Synthesis of N-(5-chloro-2-(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)me thanamine hydrochloride (Compound 32):

Procedure:

To a stirred solution of tert-butyl 4-(((5-chloro-2-(trifluoromethoxy)benzyl)amino)methyl)piperi dine- 1 -carboxylate (0.25g, 0.59mmol) in CH2CI2 (2.5mL) at 0°C, 4M HCI in Dioxane (0.75mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by preparative HPLC (0.05% HCI in Water/Acetonitrile as a mobile phase) to provide N-(5-chloro-2- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.043g, 20.28% yield) as a white solid.

LCMS [ESI, M+1]: 322.1 (RT: 0.816 min, Purity: 100%),

HPLC: RT: 3.459 min, Purity: 99.21 %,

¹ H NMR (400 MHz, CD3OD): 6 7.88 (s, 1 H), 7.64 (d, J = 8.9 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 1 H), 4.37 (s, 2H), 3.47 (d, J = 12.8 Hz, 2H), 3.13 (t, J = 8.5 Hz, 2H), 3.07 (t, J = 12.5 Hz, 2H), 2.21 (s, 1 H), 2.09 (d, J = 14.1 Hz, 2H), 1 .58 (dd, J = 24.1 , 11 .3 Hz, 2H).

Experimental protocol for Compound 33:

CAS

Procedure

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.3g, 1.9mmol) in DMF (6mL) at room temperature, potassium carbonate (0.79g, 5.74mmol) was added. The reaction mixture was stirred for 1 h. Then (bromomethyl)cyclopropane (0.78g, 5.74mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (15mL) and extracted with ethyl acetate (3 x 10mL). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 10% ethyl acetate in hexane) to provide 5-chloro-2-(cyclopropylmethoxy)benzaldehyde (0.35g, 86.84% yield) as a white solid.

LCMS [ESI, M+1]: 211.18 (RT: 2.187min, Purity: 100%)

¹ H NMR (400 MHz, cfc-DMSO): 6 10.26 (s, 1 H), 7.60 (dd, J = 8.9, 2.8 Hz, 1 H), 7.53 (d, J = 2.8 Hz, 1 H), 7.19 (d, J = 9.0 Hz, 1 H), 3.93 (d, J = 7.0 Hz, 2H), 1.25 - 1.10 (m, 1 H), 0.60 - 0.41 (m, 2H), 0.35 - 0.22 (m, 2H) tert-butvl4-(((5-chloro-2-

Procedure

To a stirred solution of 5-chloro-2-(cyclopropylmethoxy)benzaldehyde (0.35g, 1.6mmol) in DCE (6mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.42g, 1.9mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (1.05g, 4.9mmol) was added portion-wise to the reaction mixture at 0°C. The reaction was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15mL) and extracted with CH2CI2 (3 x 5mL). The combined organic fractions were washed with water (15mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 10% methanol/CH2Cl2) to provide tert-butyl4-(((5-chloro-2-

(cyclopropylmethoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.5g, 73.63% yield ) as a yellow liquid.

LCMS [ESI, M+1]: 409.22(RT: 1.675 min, Purity: 100%)

¹ H NMR (400 MHz, cfc-DMSO): 6 7.27 (s, 1 H), 7.11 (d, J = 8.6 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 3.82 (s, 2H), 3.74 (d, J = 6.8 Hz, 2H), 3.56 (s, 2H), 2.27 (t, J = 9.0 Hz, 2H), 1 .82 (s, 1 H), 1 .61 (d, J = 12.3 Hz, 2H), 1.48 (s, 1 H), 1.30 (s, 9H), 1.16 - 1.05 (m, 2H), 0.96 - 0.79 (m, 2H), 0.47 (d, J = 6.8 Hz, 2H), 0.23 (d, J = 4.6 Hz, 2H). i-1 -(piperidin-4-

Procedure

To a stirred solution of tert-butyl4-(((5-chloro-2-

(cyclopropylmethoxy)benzyl)amino)methyl)piperidine-1-carb oxylate (0.5g, 1 .3mmol) in CH2CI2 (2mL) at 0°C, 4M HCI in Dioxane (2mL, 4V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material triturated with diethyl ether to provide N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.375 g, 99.43%) as a white solid.

LCMS [ESI, M+1]: 309.1 (RT: 0.877min, Purity: 100%),

HPLC: RT: 3.746min, Purity: 100%

¹ H NMR (400 MHz, cfc-DMSO): 6 9.21 (s, 2H), 8.97 (s, 2H), 8.81 (s, 2H), 7.47 (d, J = 2.5 Hz, 1 H), 7.34 (dd, J = 8.8, 2.6 Hz, 1 H), 7.00 (d, J = 8.9 Hz, 1 H), 4.02 (s, 2H), 3.80 (d, J = 7.0 Hz, 2H), 3.19 (d, J = 12.8 Hz, 2H), 2.89 - 2.69 (m, 4H), 1.95 (d, J = 3.5 Hz, 1 H), 1.86 (d, J = 13.8 Hz, 2H), 1.37 - 1.23 (m, 2H), 1 .21 - 1.10 (m, 1 H), 0.55 - 0.41 (m, 2H), 0.27 (q, J = 4.9 Hz, 2H)

Experimental protocol for Compound 34:

CAS No.144222-22-0

CA

Procedure

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.3g, 1.9mmol) in DMF (6mL) at room temperature, potassium carbonate (0.79g, 5.74mmol) was added and the reaction mixture stirred for 1 h. Then 3-bromopropan-1-ol (0.79g, 5.74mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 24h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (15mL) and extracted with ethyl acetate (3 x 10mL). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 26% ethyl acetate in hexane) to provide 5-chloro-2-(3-hydroxypropoxy)benzaldehyde (0.395g, 96.34% yield) as a colorless liquid.

LCMS [ESI, M+23]:215.04 (RT: 1.531 min, Purity: 97.22 %)

¹ H NMR (400 MHz, cfe-DMSO): 6 10.3 (s, 1 H), 7.69 (dd, J = 8.8, 2.8 Hz, 1 H), 7.6(d, J = 2.8 Hz, 1 H) 7.3 (d, J = 8.8 Hz, 1 H), 4.27(t, J= 9.2, 4.4 Hz, 2H), 3.75-3.70(m, 2H), 3.33-3.31 (m, 3H)

Procedure

To a stirred solution of 5-chloro-2-(3-hydroxypropoxy)benzaldehyde (0.39g, 1.8mmol) in DCE (6mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.46g, 2.2mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (1.18g, 5.5mmol) was added portion-wise the reaction mixture at 0°C. The reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15mL) and extracted with CH2CI2 (3 x 10mL). The combined organic fractions were washed with water (15mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 10% methanol/CH2Cl2) to provide tert-butyl 4-(((5-chloro-2-(3- hydroxypropoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.63g, 83.77% yield) as a colorless liquid.

LCMS [ESI, M+1]: 413.12 (RT: 1.473 min, Purity: 100%)

¹ H NMR (400 MHz, cfc-DMSO): 6 7.35 (s, 1 H), 7.21 (dd, J=8.8,2.4 Hz,1 H), 6.96 (d, J=8.8 Hz,1 H), 5.75(s , 1 H), 4.02(t, J=6Hz, 2H), 3.90 (m, 2H), 3.64(s, 2H), 3.55(t, 2H), 2.6(s, 1 H) 2.37(d, J=6.4 Hz, 2H), 1.89(m, 2H), 1.84 (m, 2H), 1.68(d, J=12.8 Hz, 2H), 1.55(m, 1 H),1.38(s, 9H), 0.95(m, 2H) Step-3: 3-(4-chloro-2-(((piperidin-4-ylmethyl)amino)methyl)phenoxy)p ropan-1-ol hydrochloride (Compound 34):

Procedure

To a stirred solution of tert-butyl 4-(((5-chloro-2-(3-hydroxypropoxy)benzyl)amino)methyl)piperi dine- 1-carboxylate (0.63g, 1.5mmol) in CH2CI2 (2mL) at 0°C, 4M HCI in Dioxane (1 .2 mL, 2V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide 3-(4-chloro-2-(((piperidin-4-ylmethyl)amino)methyl)phenoxy)p ropan-1- ol hydrochloride, (0.30g, 62.89%) as a yellow sticky solid.

LCMS [ESI, M+1]: 313.01 (RT: 0.736min, Purity: 97.70%),

HPLC: RT: 4.785min, Purity: 96.14%

¹ H NMR (400 MHz, cfc-DMSO): 6 9.19 (s, 2H), 9.00 (s, 1 H), 8.84 (s, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.36 (dd, J = 8.8, 2.6 Hz, 1 H), 7.03 (d, J = 8.9 Hz, 1 H), 4.09 - 3.93 (m, 4H), 3.54 - 3.45 (m, 2H), 3.19 (d, J = 12.7 Hz, 2H), 2.77 (dd, J = 18.5, 9.5 Hz, 4H), 1.92 (s, 1 H), 1.87 - 1.71 (m, 4H), 1.27 (dd, J = 23.3, 11.2 Hz, 2H).

Experimental protocol for Compound 35:

Procedure:

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.200g.1 .27mmol) in DMF (4mL) at room temperature, potassium carbonate (0.353g.2.55mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then 1-bromo-3-methoxypropane (0.390g, 2.55mmol) was added. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (5mL) and extracted with ethyl acetate (3x4mL). The combined organic fractions were washed with cold water (4 x 5mL), dried over sodium sulfate and concentrated under reduced pressure to provide 5-chloro-2-(3-methoxypropoxy)benzaldehyde (0.260g, 89.01% yield) as an off- white solid.

LCMS [ESI, M+1]:229.0 (RT: 1.973 min, Purity: 99.24%),

¹ H NMR (400 MHz, cfc-DMSO): 6 10.30 (s, 1 H), 7.66 (dt, J = 15.3, 7.7 Hz, 1 H), 7.60 (d, J = 2.8 Hz, 1 H), 7.28 (d, J = 9.0 Hz, 1 H), 4.18 (t, J = 6.2 Hz, 2H), 3.50 (t, J = 6.2 Hz, 2H), 3.24 (s, 3H), 2.00 (p, J = 6.2 Hz, 2H).

4-(((5-chloro-2-(3-

Procedure:

To a stirred solution of 5-chloro-2-(3-methoxypropoxy)benzaldehyde (0.250g, 1.09mmol) in DCE (5mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.281g, 1.3mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.695g, 3.2mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (6mL) and extracted with CH2CI2 (2 x 5mL). The combined organic fractions were washed with water (5mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70-75% ethyl acetate in hexane) to provide tert-butyl 4-(((5- chloro-2-(3-methoxypropoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.250g, 53.56% yield) as a light yellow liquid.

LCMS [ESI, M+1]:427.1 (RT: 1.550min, Purity: 100%),

¹ H NMR (400 MHz, cfe-DMSO): 6 7.35 (d, J = 2.6 Hz, 1 H), 7.21 (dd, J = 8.7, 2.7 Hz, 1 H), 6.94 (t, J =

8.4 Hz, 1 H), 4.06 - 3.97 (m, 2H), 3.91 (d, J = 10.0 Hz, 2H), 3.66 - 3.56 (m, 2H), 3.50 - 3.42 (m, 2H), 3.23 (d, J = 8.2 Hz, 2H), 2.63 (d, J = 27.3 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H), 1.94 (td, J = 13.6,

7.4 Hz, 2H), 1 .68 (d, J = 11 .8 Hz, 2H), 1 .60 - 1 .48 (m, 2H), 1 .37 (d, J = 8.1 Hz, 9H), 0.96 (qd, J = 12.4, 4.4 Hz, 2H). i-1 -(pipe rid in-4-

Procedure:

To a stirred solution of tert-butyl 4-(((5-chloro-2-(3- methoxypropoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.240g, 0.56mmol) in CH2CI2 (2.4mL) at 0°C, 4M HCI in Dioxane (1.2mL, 5V) was added . The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with diethyl ether to provide N-(5-chloro-2-(3- methoxypropoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.080g, 39.21 % yield) as an off-white solid.

LCMS [ESI, M+1]: 297.1 (RT: 0.870 min, Purity: 100%),

HPLC: RT: 3.446 min, Purity: 97.52%,

¹ H NMR (400 MHz, CD3OD) : 6 7.27 (d, J = 2.2 Hz, 1 H), 7.23 (dd, J = 8.7, 2.3 Hz, 1 H), 6.96 (d, J = 8.7 Hz, 1 H), 4.10 (t, J = 6.2 Hz, 2H), 3.73 (s, 2H), 3.66 - 3.52 (m, 2H), 3.35 (d, J = 9.7 Hz, 3H), 3.03 (d, J = 12.4 Hz, 2H), 2.58 (dd, J = 12.4, 10.5 Hz, 2H), 2.43 (d, J = 6.7 Hz, 2H), 2.12 - 1.94 (m, 2H), 1.71 (t, J = 12.3 Hz, 2H), 1 .68 - 1.59 (m, 1 H), 1.11 (ddd, J = 15.7, 12.6, 3.9 Hz, 2H).

Experimental protocol for Compound 36:

Procedure

To a stirred solution of 2-hydroxy-3-methoxybenzaldehyde (5.0g, 32.86mmol) in acetic acid (25mL) at room temperature, /V-chlorosuccinimide (4.2g, 31.45mmol) was added. The reaction mixture was refluxed at 105°C for 2h and then allowed to stir at room temperature for 48h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (100 mL) and stirred for 10-15min. Solid material precipitated out, which was isolated by filtration and washed out with cold water (100 mL). The solid material was dissolved in a 10% MeOH/CH2Cl2 solution (100mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to provide 5-chloro-2-hydroxy-3- methoxybenzaldehyde (4.42g, 72.08% yield) as a yellow solid.

¹ H-NMR (400 MHz, cfc-DMSO): 6 10.43 (bs, 1 H), 10.24 (s, 1 H), 7.28 (d, J = 2.0 Hz, 1 H), 7.17 (d, J = 2.4 Hz, 1 H), 3.87 (s, 3H).

Procedure

To a stirred solution of 5-chloro-2-hydroxy-3-methoxybenzaldehyde (1.0g, 5.36mmol) in CH2CI2 (10mL) at 0 °C, boron tribromide (1.0M in CH2CI2) (4.03g, 16.08mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and then heated to 50 °C for 3h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (50mL) and extracted with CH2CI2 (3 x 20mL). The combined organic fractions were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 50% ethyl acetate/Hexane) to provide 5-chloro-2,3-dihydroxybenzaldehyde (0.81g, 87.58% yield) as a yellow solid.

LCMS [ESI, M+1]: 172.9 (RT: 1.398 min, Purity: 80.36%),

¹ H NMR (400 MHz, cfe-DMSO): 6 10.42-10.20 (m, 3H), 7.07 (d, J = 2.8 Hz, 1 H), 7.02 (d, J = 2.4 Hz, 1 H).

Procedure

To a stirred solution of 5-chloro-2,3-dihydroxybenzaldehyde (0.6g, 3.47mmol) in DMF (6mL) at room temperature, dibromomethane (0.18g, 10.43mmol) and K2CO3 (0.14g, 10.43mmol) were added. The reaction mixture was heated to 80 °C for 3h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (30mL) and extracted with ethyl acetate (3 x 20mL). The combined organic fractions were washed with ice cold water 3-4 times, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 50% ethyl acetate/Hexane) to provide 6-chlorobenzo[d][1 ,3]dioxole-4- carbaldehyde (0.34g, 52.98% yield) as a yellow solid.

LCMS [ESI, M+2]: 186.0 (RT: 7.125 min, Purity: 85.48%),

¹ H-NMR (400 MHz, cfc-DMSO): 6 9.97 (s, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 7.27 (d, J = 2.4 Hz, 1 H), 6.27 (s, 2H).

Procedure

To a stirred solution of 6-chlorobenzo[d][1 ,3]dioxole-4-carbaldehyde (0.2g, 1.08mmol) in DCE (4mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.28g, 1.3mmol) and acetic acid (0.01 mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then sodium triacetoxyborohydride (0.69g, 3.25mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was allowed to stir at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a sat. NaHCCh solution (10mL) and extracted with CH2CI2 (3 X 10mL). The combined organic fractions were washed with water (20mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 60% EtOAc/Hexane) to provide tert-butyl 4-((((6- chlorobenzo[d][1 ,3]dioxol-4-yl)methyl)amino)methyl)piperidine-1 -carboxylate (0.24g, 57.85% yield) as a colorless oil.

LCMS [ESI, M+1]: 383.5 (RT: 9.049 min, Purity: 93.84%),

¹ H-NMR (400 MHz, cfe-DMSO) : 6 6.93-6.92 (m, 2H), 6.04 (s, 2H), 3.90 (d, J = 9.6 Hz, 2H), 3.59 (s, 2H), 2.66 (bs, 2H), 2.32 (d, J = 6.8 Hz, 2H), 1.66 (d, J = 12.0 Hz, 2H), 1.51 (bs, 1 H), 1.37 (s, 9H), 0.99-0.89 (m, 2H).

Procedure

To a stirred solution of tert-butyl 4-((((6-chlorobenzo[d][1 ,3]dioxol-4-yl)methyl) amino)methyl) piperidine-1 -carboxylate (0.1g, 0.26mmol) in CH2CI2 (1.0mL) at 0°C, 4.0 M HCI in Dioxane (0.5mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration using diethyl ether to provide 1-(6-chlorobenzo[d][1,3]dioxol-4-yl)-N-(piperidin-4- ylmethyl)methanamine hydrochloride (0.050g, 67.70% yield) as a white solid. LCMS [ESI, M+1]: 283.2 (RT: 0.900 min, Purity: 95.02%),

HPLC Purity: RT: 3.126 min, Purity: 87.31 %

¹ H NMR (400 MHz, CD ₃ OD): 6 7.07 (d, J = 1.6 Hz, 1 H), 7.00 (d, J = 1.6 Hz, 1 H), 6.13 (s, 2H), 4.23 (s, 2H), 3.46 (d, J = 12.8 Hz, 2H), 3.08-3.02 (m, 4H), 2.17-2.15 (m, 1 H), 2.06 (d, J = 13.2 Hz, 2H), 1 .60-1.49 (m, 2H).

Experimental protocol for Compound 37:

Step 1 : Synthesis of 5-chloro-2-hvdroxy-3-methoxybenzaldehyde:

Procedure To a stirred solution of Ortho vanillin (3.0g, 19.7mmol) in CH3COOH(15mL), N-Chlorosuccinimide (2.44g, 18.3 mmol) was added. The reaction mixture was refluxed at 100°C for 2.5h and then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (150mL) and stirred for 1 h. The precipitate that formed was isolated by filtration and dried under reduced pressure to provide 5-chloro-2-hydroxy-3-methoxybenzaldehyde (2.7g, 73.77% yield) as a yellow solid.

LCMS [ESI, M-2]: 184(RT: 8.465min, Purity: 82.14%)

¹ H NMR (400 MHz, cfe-DMSO): 6 10.34 (s, 1 H), 10.18 (d, J = 7.9 Hz, 1 H), 7.20 (t, J = 5.8 Hz, 1 H), 7.10 (d, J = 1.9 Hz, 1 H), 3.79 (d, J = 5.6 Hz, 3H).

Step-2: Synthesis of 5-chloro-2,3-dihydroxybenzaldehyde:

Procedure

To a stirred solution of 5-chloro-2-hydroxy-3-methoxybenzaldehyde(1 ,0g,5.30mmol) in CH2CI2 (10mL) at 0°C, BBrs (1 M in DCM; 16ml,16.0mmol) was added. The reaction mixture was heated at 60°C for 1 h and then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (80mL) and extracted with CH2CI2 (3 x 80mL). The combined organic fractions were dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70% ethyl acetate in hexane) to provide 5- chloro-2,3-dihydroxybenzaldehyde (0.89g, 96.00% yield) as a yellow solid.

LCMS [ESI, M-1]: 171.33 (RT: 7.328min, Purity: 83.27%)

¹ H NMR (400 MHz, cfc-DMSO): 6 10.31 (s, 1 H), 10.18 (dd, J = 19.9, 5.0 Hz, 1 H), 10.12 (s, 1 H), 6.99 (t, J = 4.5 Hz, 1 H), 6.95 (t, J = 3.2 Hz, 1 H).

Step 3: Synthesis of 7-chloro-2,3-dihvdrobenzo[b1[1 ,41dioxine-5-carbaldehyde:

Procedure

To a stirred solution of 5-chloro-2,3-dihydroxybenzaldehyde(0.5g,2.89mmol) in DMF (10mL) at room temperature, potassium carbonate (1.19g, 8.69mmol) was added and the reaction mixture stirred for 1 h. Then 1 ,2-Dibromoethane (1 .63g,8.69mmol) was added to the reaction mixture. The reaction mixture was heated at 65°C for 2h and then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (50mL) and extracted with ethyl acetate (3 x 70mL). The combined organic fractions were washed with water (100mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 30% ethyl acetate in hexane) to provide 7-chloro-2,3- dihydrobenzo[b][1,4]dioxine-5-carbaldehyde (0.4g, 69.80% yield) as a yellow solid.

LCMS [ESI, M+1]: 199.04 (RT: 8.814min, Purity: 92.63%)

¹ H NMR (400 MHz, cfc-DMSO): 6 10.14 (s, 1 H), 7.22 (s, 1 H), 7.13 (d, J = 2.2 Hz, 1 H), 4.33 (d, J = 4.6 Hz, 2H), 4.28 (d, J = 4.3 Hz, 2H). ((7-chloro-2,3-( i-5- 1 -(

Procedure

To a stirred solution of 7-chloro-2,3-dihydrobenzo[b][1 ,4]dioxine-5-carbaldehyde (0.2g, I .Ommol) in DCE (4mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.25g, 1.2mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.63g, 3.0mmol) was added portion-wise to the reaction mixture at 0°C. The reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (20mL) and extracted with CH2CI2 (3 x 70mL). The combined organic fractions were washed with water (100mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 60% ethyl acetate in hexane) to provide tert-butyl4-((((7-chloro-2,3- dihydrobenzo[b][1 ,4]dioxin-5-yl)methyl)amino)methyl)piperidine-1 -carboxylate (0.18g, 45. 11% yield) as a yellow liquid.

LCMS [ESI, M+1]: 397.5(RT: 9.516 min, Purity: 91 .27%)

¹ H NMR (400 MHz, cfc-DMSO): 6 6.82 (s, 1 H), 6.77 (d, J = 2.3 Hz, 1 H), 4.22 (dd, J = 15.3, 4.8 Hz, 4H), 4.00 (d, J = 12.4 Hz, 2H), 3.75 (d, J = 8.7 Hz, 2H), 2.67 (s, 2H), 2.50 (d, J = 6.3 Hz, 2H), 1 .85 (d, J = 8.4 Hz, 1 H), 1.66 (d, J = 10.8 Hz, 3H), 1 .38 (s, 9H), 1.01 (dd, J = 22.7, 13.7 Hz, 2H).

Step-5: Synthesis of 1 -(7-chloro-2,3-dihvdrobenzorbiri ,4ldioxin-5-vl)-N-(piperidin-4-vlmethvl) methan amine hydrochloride (Compound 37):

Procedure

To a stirred solution of tert-butyl4-((((7-chloro-2,3-dihydrobenzo[b][1 ,4]dioxin-5- yl)methyl)amino)methyl) piperidine-1 -carboxylate (0.16g, 0.4mmol) in CH2CI2 (2mL) at 0°C, 4M HCI in Dioxane (0.6mL, 4V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with diethyl ether to provide 1-(7-chloro-2,3-dihydrobenzo[b][1 ,4]dioxin-5- yl)-N-(piperidin-4-ylmethyl)methan amine hydrochloride(0.100g, 84.03%) as a brown solid.

LCMS [ESI, M+1]: 296.91 (RT: 0.794min, Purity: 93.52%),

HPLC: RT: 3.452min, Purity: 91.18%

¹ H NMR (400 MHz, CD3OD): 6 6.99 (d, J = 2.0 Hz, 1 H), 6.94 (d, J = 2.2 Hz, 1 H), 4.33 (t, J = 5.9 Hz, 2H), 4.25 (d, J = 2.7 Hz, 2H), 4.15 (s, 2H), 3.38 (d, J = 12.7 Hz, 2H), 3.03 - 2.91 (m, 4H), 2.10 (s, 1 H), 1.99 (d, J = 13.8 Hz, 2H), 1.46 (dd, J = 23.6, 11.2 Hz, 2H).

Procedure:

To a stirred solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (3.0g, 14.55mmol) in DMF (30mL) at room temperature, Potassium carbonate (4.02g, 29.10mmol) was added. The reaction mixture was stirred at room temperature for 2h. Bromo ethane (3.17g, 29.10mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (100mL) and extracted with ethyl acetate (2 x 300mL). The combined organic fractions were washed with cold water (2 x 100mL), dried over Sodium Sulphate and concentrated under reduced pressure to provide 2-ethoxy-5- (trifluoromethoxy)benzaldehyde (2.58g, 72.61% yield) as an off-white liquid .

¹ H NMR (400 MHz, cfc-DMSO): 6 10.25 (s, 1 H), 7.60 (dd, J = 9.3, 2.6 Hz, 1 H), 7.48 (s, 1 H), 7.28 (d, J = 9.1 Hz, 1 H), 4.35 - 3.95 (m, 2H), 1 .31 (t, J = 6.9 Hz, 3H).

(Compound 38)

Procedure:

To a stirred solution of 2-ethoxy-5-(trifluoromethoxy)benzaldehyde (1.1g, 4.69mmol) in DCE (10mL) at room temperature, 1-methylpiperidin-4-amine (0.643g, 5.63mmol) and Acetic acid (0.1 mL) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (2.97g, 14.09mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (30mL) and extracted with CH2CI2 (3 x 30mL). The combined organic fractions were dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 30% ethyl acetate in hexane) to provide N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-methylpiperidin-4- amine (0.700g, 34.50% yield) as a white solid.

LCMS [ESI, M+1]: 332.97 (RT: 0.894 min, Purity: 99.15%),

HPLC: RT: 3.653, Purity: 97.79%

¹ H NMR (400 MHz, cfc-DMSO): 6 7.27 (s, 1 H), 7.08 (d, J = 8.7 Hz, 1 H), 6.92 (d, J = 8.9 Hz, 1 H), 3.96 (q, J = 6.9 Hz, 2H), 3.60 (s, 2H), 2.60 (d, J = 1 1.3 Hz, 2H), 2.23 (d, J = 9.7 Hz, 1 H), 2.04 (s, 3H), 1.76 (t, J = 10.7 Hz, 2H), 1.67 (d, J = 12.3 Hz, 2H), 1.25 (t, J = 6.9 Hz, 3H), 1.21 - 1.13 (m, 2H).

Experimental protocol for Compound 39:

Procedure:

To a stirred solution of 2-hydroxy-5-(trifluoromethoxy) benzaldehyde (2.0g, 9.70mmol) in DMF (20mL) at room temperature, Potassium carbonate (2.6g,19.40mmol) was added. The reaction mixture was stirred at room temperature for 15 min. 1-bromo-2-methoxyethane (2.6g, 19.40mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (25mL) and extracted with ethyl acetate (2 x 20mL). The combined organic fractions were washed with cold water (3x15mL), dried over Sodium Sulphate and concentrated under reduced pressure to provide 2-(2-methoxyethoxy)-5- (trifluoromethoxy)benzaldehyde (2.1g, 81.92% yield) as a light yellow liquid.

¹ H NMR (400 MHz, cfe-DMSO): 6 10.34 (s, 1 H), 7.69 (dd, J = 9.0, 2.6 Hz, 1 H), 7.56 (d, J = 2.2 Hz, 1 H), 7.40 (d, J = 9.1 Hz, 1 H), 4.38 - 4.25 (m, 2H), 3.78 - 3.67 (m, 2H), 3.33 (d, J = 2.5 Hz, 3H).

Procedure:

To a stirred solution of 2-(2-methoxyethoxy)-5-(trifluoromethoxy) benzaldehyde (0.600g, 2.27mmol) in DCE (12mL) at room temperature, 1-methylpiperidin-4-amine (0.311g, 2.27mmol) and acetic acid (0.03mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (1.4g, 6.8mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (6mL) and extracted with CH2CI2 (3 x 4mL). The combined organic fractions were washed with water (2 x 3mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70% ethyl acetate in hexane) to provide N-(2-(2-methoxyethoxy)-5- (trifluoromethoxy)benzyl)-1 -methylpiperidin-4-amine (0.606g, 73.63% yield) as a colourless liquid.

LCMS [ESI, M+1]:363.1 (RT: 0.851 min, Purity: 98.59%),

HPLC: RT: 3.873min, Purity: 95.74%,

¹ H NMR (400 MHz, cfc-DMSO): 6 7.35 (s, 1 H), 7.19 (d, J = 8.7 Hz, 1 H), 7.04 (d, J = 8.9 Hz, 1 H), 4.17 - 4.07 (m, 2H), 3.71 (s, 2H), 3.69 - 3.62 (m, 2H), 3.29 (d, J = 11 .9 Hz, 3H), 2.75 (d, J = 11 .4 Hz, 2H), 2.40 - 2.29 (m, 1 H), 2.18 (s, 3H), 1.96 (t, J = 10.3 Hz, 2H), 1.89 (s, 1 H), 1.78 (d, J = 11.3 Hz, 2H), 1 .31 (dd, J = 20.5, 9.8 Hz, 2H).

Procedure:

To a stirred solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (3.0g, 14.55mmol) in DMF (30mL) at room temperature, Potassium carbonate (4.02g, 29.10mmol) was added. The reaction mixture was stirred at room temperature for 2h. Bromo ethane (3.17g, 29.10mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (100mL) and extracted with ethyl acetate (2 x 300mL). The combined organic fractions were washed with cold water (2 x 100mL), dried over Sodium Sulphate and concentrated under reduced pressure to provide 2-ethoxy-5- (trifluoromethoxy)benzaldehyde (2.58g, 72.61% yield) as an off-white liquid .

¹ H NMR (400 MHz, cfc-DMSO): 6 10.25 (s, 1 H), 7.60 (dd, J = 9.3, 2.6 Hz, 1 H), 7.48 (s, 1 H), 7.28 (d, J = 9.1 Hz, 1 H), 4.35 - 3.95 (m, 2H), 1 .31 (t, J = 6.9 Hz, 3H).

Procedure:

To a stirred solution of 2-ethoxy-5-(trifluoromethoxy)benzaldehyde (1.58g, 6.74mmol) in DCE (15mL) at room temperature, tert-butyl (4-aminocyclohexyl)carbamate (1.73g, 8.09mmol) and Acetic acid (0.15mL) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (4.27g, 20.24mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (50mL) and extracted with CH2CI2 (3 x 200mL). The combined organic fractions were washed with water (3 x 50mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 40% ethyl acetate in hexane) to provide tert-butyl (4-((2-ethoxy-5- (trifluoromethoxy)benzyl)amino)cyclohexyl)carbamate (0.958g, 25.26% yield) as a white liquid.

LCMS [ESI, M+1]: 433.07 (RT: 1.626min, Purity: 93.72 %),

-1 ,4-diamine

Procedure:

To a stirred solution of tert-butyl (4-((2-ethoxy-5- (trifluoromethoxy)benzyl)amino)cyclohexyl)carbamate (0.958g, 2.21 mmol) in CH2CI2 (9.5 mL, 10V) at 0°C, 4M HCI in Dioxane (4.2ml, 5V) was added . The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration using Diethyl ether to provide N1-(2-ethoxy-5- (trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine hydrochloride (0.7g, 95.08% yield) as an off-white solid.

LCMS [ESI, M+1]: 332.97 (RT: 0.999 min, Purity: 100%),

HPLC: RT: 4.206 min, Purity: 98.80%,

¹ H NMR (400 MHz, cfe-DMSO): 6 9.16 (s, 2H), 8.10 (s, 2H), 7.51 (s, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 9.0 Hz, 1 H), 4.02 (d, J = 6.7 Hz, 4H), 2.91 (s, 2H), 2.12 (d, J = 12.0 Hz, 2H), 1.97 (d, J = 10.2 Hz, 2H), 1 .49 - 1.40 (m, 2H), 1.30 (dd, J = 14.8, 8.0 Hz, 5H).

Procedure:

To a stirred solution of 2-(2-methoxyethoxy)-5-(trifluoromethoxy) benzaldehyde (0.750g, 2.83mmol) in DCE (5mL) at room temperature, tert-butyl (4-aminocyclohexyl) carbamate (0.730g, 2.00mmol) and Acetic acid (0.037mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (1.804g, 8.51 mmol) was added portion-wise to the reaction mixture at 0°C. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (5mL) and extracted with CH2CI2 (2x3mL). The combined organic fractions were washed with water, dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 65-70% ethyl acetate in hexane) to provide tert-butyl (4-((2-(2- methoxyethoxy)-5-(trifluoromethoxy)benzyl)amino)cyclohexyl)c arbamate (1 ,3g, 99.01% yield) as a white solid.

LCMS [ESI, M-56]:463.1 (RT: 1.475 min, Purity: 97.91%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.35 (s, 1 H), 7.19 (s, 1 H), 7.06 (d, J = 8.8 Hz, 1 H), 6.68 (s, 1 H), 4.14 (s, 2H), 3.75 (s, 1 H), 3.67 (m, 4H), 3.17 (s, 1 H), 2.33 (s, 1 H), 1.91 (s, 2H), 1.74 (s, 1H), 1.59 (s, 2H), 1 .41 (s, 2H), 1 .37 (d, J = 2.8 Hz, 9H), 1 .10 (s, 4H). - I l l -

Step-2: Synthesis of N1-(2-(2-methoxyethoxy)-5-(trifluoromethoxy)benzyl)cyclohexa ne-1 ,4- diamine Hydrochloride (Compound 41):

Procedure:

To a stirred solution of tert butyl (4-((2-(2-methoxyethoxy)-5-(trifluoromethoxy) benzyl) amino) cyclohexyl) carbamate (1 .3g, 2.81 mmol) in CH2CI2 (13mL) at 0°C, 4M HCI in Dioxane (6.5mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with diethyl ether to provide N1 -(2-(2-methoxyethoxy)-5-(trifluoromethoxy) benzyl) cyclohexane-1 , 4-diamine hydrochloride (0.88 6g, 86.98% yield) as an off-white solid.

LCMS [ESI, M+1]: 263.1 (RT: 4.936 min, Purity: 99.22%),

¹ H NMR (400 MHz, CD3OD): 6 7.44 (dd, J = 26.3, 10.2 Hz, 2H), 7.23 (d, J = 9.0 Hz, 1 H), 4.32 (d, J = 6.9 Hz, 4H), 3.89 - 3.80 (m, 2H), 3.67 (s, 1 H), 3.46 (d, J = 4.5 Hz, 3H), 3.23 (d, J = 14.8 Hz, 1 H), 2.37 (d, J = 11 .5 Hz, 1 H), 2.22 (d, J = 11 .5 Hz, 1 H), 2.16 - 1 .90 (m, 4H), 1.71 - 1 .52 (m, 2H).

Experimental protocol for Compound 42: Step-1 : Synthesis of tert-butyl 4-(((2-(2-methoxyethoxy)-5-(trifluoromethoxy)benzyl)amino) methyl)piperidine-1 -carboxylate:

Procedure:

To a stirred solution of 2-(2-methoxyethoxy)-5-(trifluoromethoxy) benzaldehyde (0.750g, 2.838mmol) in DCE (10mL) at room temperature, tert-butyl 4-(amino methyl) piperidine-1 - carboxylate (0.608g, 2.838mmol) and Acetic acid (0.03mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 3h. Sodium triacetoxyborohydride (1 .804g, 8.516mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15 mL) and extracted with CH2CI2 (2 x 5ml). The combined organic fractions were washed with water, dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 50% ethyl acetate in hexane) to provide tert-butyl 4-(((2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.900g, 68.55% yield) as a light yellow liquid.

LCMS [ESI, M+1]:363.1 (RT: 1.579 min, Purity: 98.83%),

¹ H NMR (400 MHz, cfc-DMSO) : 6 7.33 (s, 1 H), 7.18 (d, J = 8.6 Hz, 1 H), 7.04 (d, J = 8.9 Hz, 1 H), 4.17 - 4.08 (m, 2H), 3.91 (d, J = 1 1.1 Hz, 2H), 3.65 (d, J = 7.4 Hz, 4H), 3.33 (d, J = 8.7 Hz, 1 H), 2.66 (m, 4H), 2.36 (d, J = 6.4 Hz, 2H), 1 .94 (d, J = 32.6 Hz, 1 H), 1 .65 (t, J = 15.6 Hz, 2H), 1 .54 (d, J = 1 1 .6 Hz, 1 H), 1 .36 (d, J = 8.7 Hz, 9H), 0.96 (dt, J = 20.3, 10.2 Hz, 2H).

Step-2: Synthesis of N-(2-(2-methoxvethoxv)-5-(trifluoromethoxv)benzvl)-1 -(piperidin-4- yl)methanamine hydrochloride (Compound 42):

Procedure:

To a stirred solution of tert-butyl 4-(((2-(2-methoxyethoxy)-5-(trifluoromethoxy)benzyl) amino) methyl) piperidine-1 -carboxylate (0.900g, 1.94mmol) in CH2CI2 (9mL) at 0°C, 4M HCI in Dioxane (4.5mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with Diethyl ether to provide N-(2-(2-methoxyethoxy)-5-(trifluoromethoxy)benzyl)-1- (piperidin-4-yl)methanamine hydrochloride (0.775g, 99.87% yield) as a light brown sticky Solid. LCMS [ESI, M+1]: 362.69 (RT: 0.83 min, Purity: 99.85%), HPLC: RT: 3.759 min, Purity: 97.62%,

¹ H NMR (400 MHz, CD3OD): 6 7.44 (s, 1 H), 7.35 (d, J = 9.0 Hz, 1 H), 7.18 (d, J = 9.0 Hz, 1 H), 4.27 (d, J = 6.2 Hz, 4H), 3.85 - 3.74 (m, 2H), 3.43 (d, J = 2.0 Hz, 1 H), 3.39 - 3.34 (m, 1 H), 3.27 (s, 2H), 3.11 - 2.93 (m, 4H), 2.22 - 2.08 (m, 1 H), 2.03 (d, J = 14.0 Hz, 2H), 1.62 - 1 .44 (m, 2H).

Procedure

To a stirred solution of 5-chloro-2-(2-methoxyethoxy)benzaldehyde (1.0g, 4.65mmol) in DCE (20mL) at room temperature, te/Y-butyl ((1 r,4r)-4-aminocyclohexyl)carbamate (1 ,2g, 5.59mmol) and acetic acid (0.05mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. sodium triacetoxyborohydride (2.96g, 13.97mmol) was added portion-wise added to the reaction mixture at 0°C. The reaction mixture was allowed to stir at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was diluted with CH2CI2 (50mL) and washed with sat. NaHCCh solution (50mL) and water (50mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (neutral alumina; 0-100% EtOAc/Hexane) to provide tert-butyl ((1 r,4r)-4-((5-chloro-2-(2- methoxyethoxy)benzyl)amino)cyclohexyl)carbamate (1.02g, 53.01% yield) as a white solid.

LCMS [ESI, M+1]: 413.17 (RT: 1.459 min, Purity: 100%),

¹ H-NMR (400 MHz, cfe-DMSO) : 6 7.35 (d, J = 2.0 Hz, 1 H), 7.22-7.20 (dd, J = 2.4 Hz, 8.8 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1 H), 4.09 (t, J = 4.2 Hz, 2H), 3.6 (s, 4H), 3.30 (s, 3H), 3.15 (bs, 1 H), 2.20 (bs, 1 H), 1 .86-1.83 (m, 2H), 1 .73-1.70 (m, 2H), 1.36 (s, 9H), 1.17-1.02 (m, 4H). Step-2: Synthesis of (1r, 4r)-/V ¹ -(5-chloro-2-(2-methoxyethoxy)benzyl)cyclohexane-1,4-d i amine hydrochloride (Compound 43)

Procedure

To a stirred solution of tert-butyl ((1 R,4R)-4-((5-chloro-2-(2-methoxyethoxy)benzyl)amino) cyclohexyl)carbamate (0.9g, 2.18mmol) in CH2CI2 (9.0mL) at 0°C, 4.0 M HCI in Dioxane (4.5mL, 5V) was added. The reaction mixture was then stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration using diethyl ether to provide (1r, 4r)-A/ ¹ -(5-chloro-2-(2-methoxyethoxy)benzyl) cyclohexane-1 , 4-diamine hydrochloride (0.720g, 94.98 Yield) as an off-white solid.

LCMS [ESI, M+1]: 313.0 (RT: 0.765 min, Purity: 97.34%),

HPLC Purity: RT: 3.586 min, Purity: 95.75%

¹ H-NMR (400 MHz, CD3OD) : 6 7.50-7.44 (m, 2H), 7.14 (d, J = 8.0 Hz, 1 H), 4.27 (s, 4H), 3.84-3.82 (m, 2H), 3.46 (s, 3H), 3.26-3.20 (m, 2H), 2.37 (d, J = 8.0 Hz, 2H), 2.22 (d, J = 8.0 Hz, 2H), 1.69- 1.52 (m, 4H).

Experimental protocol for Compound 44:

Step-1 : Synthesis of tert-butyl ((1s, 4s)-4-((5-chloro-2-(2-methoxyethoxy)benzyl)amino) cyclohexyDcarbamate

Procedure

To a stirred solution of 5-chloro-2-(2-methoxyethoxy)benzaldehyde (1.0g, 4.65mmol) in DCE (20mL) at room temperature, te/Y-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (1.2g, 5.59mmol) and acetic acid (0.05mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. sodium triacetoxyborohydride (2.96g, 13.97mmol) was added portion-wise to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was diluted with CH2CI2 (50mL) and washed with sat. NaHCCh solution (50mL) and water (50mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (neutral alumina; 70% EtOAc/Hexane) to provide tert-butyl ((1s,4s)-4-((5-chloro-2-(2- methoxyethoxy)benzyl)amino)cyclohexyl)carbamate (1.02g, 53.01% yield) as a colorless oil. LCMS [ESI, M+1]: 413.1 (RT: 1.359 min, Purity: 100%),

¹ H-NMR (400 MHz, cfe-DMSO) : 6 7.36 (s, 1 H), 7.23-7.20 (dd, J = 4.0 Hz, 8.0 Hz, 1 H), 6.97 (d, J = 8.0 Hz, 1 H), 6.67 (d, J = 8.0 Hz, 1 H), 4.10-4.08 (m, 2H), 3.66-3.62 (m, 4H), 3.34-3.30 (m, 5H), 1 .58-1 .56 (m, 4H), 1 .42-1 .37 (m, 13H).

Step-2: Synthesis of (1s, 4s)-/V ¹ -(5-chloro-2-(2-methoxyethoxy)benzyl)cyclohexane-1,4-d i amine hydrochloride (Compound 44)

Procedure

To a stirred solution of tert-butyl ((1s,4s)-4-((5-chloro-2-(2-methoxyethoxy)benzyl)amino) cyclohexyl)carbamate (1.0g, 2.42mmol) in CH2CI2 (lO.OmL) at 0°C, 4.0 M HCI in Dioxane (5.0mL, 5V) was added. The reaction mixture was then stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration using diethyl ether to provide (1s, 4s)-W-(5-chloro-2-(2-methoxyethoxy)benzyl) cyclohexane-1 , 4-diamine hydrochloride (0.75g, 99.09 Yield) as a white solid.

LCMS [ESI, M+1]: 313.0 (RT: 0.790 min, Purity: 100%),

HPLC Purity: RT: 3.667 min, Purity: 100.0%

¹ H-NMR (400 MHz, CD3OD): 6 7.53 (s, 1 H), 7.47-7.44 (dd, J = 4.0 Hz, 8.0 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 4.14 (d, J = 8.0 Hz, 1 H), 4.29 (s, 4H), 3.83 (t, J = 4.0 Hz, 2H), 3.45 (s, 4H), 3.38 (s, 1 H), 2.08-1.99 (m, 8H).

Experimental protocol for Compound 45:

CAS:41838-46-4

Synthesis of N-(5-chloro-2-(2-methoxyethoxy)benzyl)-1-methylpiperidin-4-a mine (Compound 45):

Procedure

To a stirred solution of 5-chloro-2-(2-methoxyethoxy)benzaldehyde (0.2g,0.93mmol) in DCE (4mL) at room temperature, 1-methylpiperidin-4-amine (0.127g, 1.18mmol) was added. Then reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.59g, 2.79mmol) was added portion-wise to the reaction mixture at 0°C. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (100mL) and extracted with ethyl acetate (3 x 100mL). The combined organic fractions were washed with water (100mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-3% methanol in CH2CI2) to provide N-(5-chloro-2-(2-methoxyethoxy)benzyl)-1-methylpiperidin-4-a mine(0.172g, 59.10% yield) as a white solid.

LCMS [ESI, M+1]:312.90(RT: 0.767 min, Purity:100%)

HPLC: RT: 3.313min, Purity: 99.33%

¹ H NMR (400 MHz, CD3OD): 6 7.35 - 7.20 (m, 2H), 6.98 (d, J = 8.6 Hz, 1 H), 4.17 (d, J = 3.9 Hz, 2H), 3.78 (s, 4H), 3.43 (s, 3H), 2.87 (d, J = 10.8 Hz, 2H), 2.43 (d, J = 9.5 Hz, 1 H), 2.26 (s, 3H), 2.05 (t, J = 11 .6 Hz, 2H), 1 .94 (d, J = 12.0 Hz, 2H), 1 .52 - 1 .40 (m, 2H).

Procedure

To a stirred solution of 5-fluoro-2-hydroxybenzaldehyde (3.0g, 21.4mmol) in DMF (30mL) at room temperature, potassium carbonate (5.91g, 42.8mmol) was added. The reaction mixture was stirred for 1 h. Then Bromoethane (4.66g, 42.8mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice- cold water (200mL) and extracted with ethyl acetate (3 x 150mL). The combined organic fractions were washed with cold water (1 L), dried over Sodium Sulphate and concentrated under reduced pressure to provide 2-ethoxy-5-fluorobenzaldehyde (3.3g, 97.66% yield) as an off-white solid.

LCMS [ESI, M+1]: 168.9(RT: 1.835min, Purity: 100%)

¹ H NMR (400 MHz, cfe-DMSO): 6 10.34 (d, J = 3.1 Hz, 1 H), 7.53 (td, J = 8.8, 3.3 Hz, 1 H), 7.40 (dd, J = 8.4, 3.2 Hz, 1 H), 7.28 (dd, J = 9.2, 4.0 Hz, 1 H), 4.19 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H).

Procedure

To a stirred solution of 2-ethoxy-5-fluorobenzaldehyde (0.2g, 1.18mmol) in DCE (4mL) at room temperature, 1-methylpiperidin-4-amine (0.16g, 1.42mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.75g, 3.5mmol) was added to the reaction mixture portion-wise at 0°C. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (100mL) and extracted with CH2CI2 (3 x 100mL). The combined organic fractions were washed with water (100mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-2% methanol in CH2CI2) to provide N-(2- ethoxy-5-fluorobenzyl)-1 -methyl pipe rid in-4-amine (0.083g, 26.77% yield) as a yellow liquid.

LCMS [ESI, M+1]:267.1 (RT: 0.683 min, Purity: 100%)

HPLC: RT: 3.312min, Purity: 99.19%

¹ H NMR (400 MHz, CD3OD): 6 7.08 (dd, J = 9.0, 2.5 Hz, 1 H), 7.03 - 6.88 (m, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.80 (s, 2H), 2.88 (d, J = 12.0 Hz, 2H), 2.56 - 2.42 (m, 1 H), 2.27 (s, 3H), 2.06 (t, J = 12.0 Hz, 2H), 1 .95 (d, J = 12.2 Hz, 2H), 1 .57 - 1 .27 (m, 5H).

CAS No.635-93-8

CAS:41838-46-4

Procedure

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (3.0g, 19.1 mmol) in DMF (30mL) at room temperature, potassium carbonate (5.29g, 38.3mmol) was added. The reaction mixture was stirred for 1 h. Then 1 -bromopropane (4.71g, 38.3mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice- cold water (200mL) and extracted with ethyl acetate (3x150mL). The combined organic fractions were washed with cold water (1 L), dried over sodium sulphate and concentrated under reduced pressure to provide 5-chloro-2-propoxybenzaldehyde (3.7g, 97.36% yield) as a light brown solid. LCMS [ESI, M+1]: 199.10(RT: 9.392min, Purity: 100%)

¹ H NMR (400 MHz, cfc-DMSO): 6 10.33 (s, 1 H), 7.70 (dd, J = 8.9, 2.8 Hz, 1 H), 7.62 (d, J = 2.7 Hz, 1 H), 7.29 (d, J = 9.0 Hz, 1 H), 4.11 (t, J = 6.4 Hz, 2H), 1 .85 - 1 .73 (m, 2H), 1 .01 (t, J = 7.4 Hz, 3H).

Step-2: Synthesis of N-(5-chloro-2-propoxybenzyl)-1-methylpiperidin-4-amine (Compound 47):

Procedure

To a stirred solution of 5-chloro-2-propoxybenzaldehyde (0.2g, 1 .Ommol) in DCE(4mL) at room temperature, 1-methylpiperidin-4-amine (0.171g, 1.5mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.96g, 4.5mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (100mL) and extracted with CH2CI2 (3 x 100mL). The combined organic fractions were washed with water (100mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 18% ethyl acetate in hexane) to provide N- (5-chloro-2-propoxybenzyl)-1-methylpiperidin-4-amine(0.205g, 68.79% yield) as a white solid.

LCMS [ESI, M+1]:297.04(RT: 0.909 min, Purity:95.06%)

HPLC: RT: 3.699min, Purity: 100%

¹ H NMR (400 MHz, CD3OD): 6 7.30 (d, J = 2.4 Hz, 1 H), 7.23 (dd, J = 8.7, 2.5 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 4.00 (t, J = 6.3 Hz, 2H), 3.79 (s, 2H), 2.88 (d, J = 12.2 Hz, 2H), 2.54 - 2.42 (m, 1 H), 2.27 (s, 3H), 2.06 (t, J = 11.9 Hz, 2H), 1.94 (d, J = 12.5 Hz, 2H), 1 .85 (dt, J = 13.7, 6.9 Hz, 2H), 1 .48 (dd, J = 21.9, 10.3 Hz, 2H), 1.09 (t, J = 7.4 Hz, 3H).

Procedure

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (3.0g, 19.1 mmol) in DMF (30mL) at room temperature, Potassium carbonate (7.91g, 57.3mmol) was added. The reaction was stirred for 1 h. Then (bromomethyl)cyclopropane (3.8g, 28.6mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (200mL) and extracted with ethyl acetate (3 x 150mL). The combined organic fractions were washed with cold water (2L), dried over Sodium Sulphate and concentrated under reduced pressure to provide 5-chloro-2-(cyclopropylmethoxy)benzaldehyde (3.9g, 96.77% yield) as a light brown solid.

LCMS [ESI, M+1]: 211.18(RT: 9.365min, Purity: 100%)

¹ H NMR (400 MHz, cfc-DMSO): 6 10.35 (s, 1 H), 7.69 (dd, J = 8.9, 2.8 Hz, 1 H), 7.62 (d, J = 2.7 Hz, 1 H), 7.28 (d, J = 9.0 Hz, 1 H), 4.05 (t, J = 13.5 Hz, 2H), 1.38 - 1.19 (m, 1 H), 0.70 - 0.51 (m, 2H), 0.46 - 0.30 (m, 2H). i-4-amine

Procedure

To a stirred solution of 5-chloro-2-(cyclopropylmethoxy)benzaldehyde (0.2g, 9.4mmol) in DCE (2mL) at room temperature, 1-methylpiperidin-4-amine (0.16g, 1.42mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.60g, 2.8mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (100mL) and extracted with CH2CI2 (3 x 100mL). The combined organic fractions were washed with water (300mL), dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 20% ethyl acetate in hexane) to provide N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1-methylpiperidin- 4-amine (0.101g, 34.47% yield) as a yellow liquid.

LCMS [ESI, M+1]:308.99(RT: 0.922 min, Purity:95.61%)

HPLC: RT: 3.806min, Purity: 100%

¹ H NMR (400 MHz, CD3OD): 6 7.30 (d, J = 2.6 Hz, 1 H), 7.22 (dd, J = 8.7, 2.7 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 3.89 (d, J = 6.9 Hz, 2H), 3.80 (s, 2H), 2.88 (d, J = 12.4 Hz, 2H), 2.56 - 2.44 (m, 1 H), 2.27 (s, 3H), 2.07 (t, J = 12.0 Hz, 2H), 1 .96 (d, J = 12.6 Hz, 2H), 1 .56 - 1 .43 (m, 2H), 1 .30 (dd, J = 9.3, 4.5 Hz, 1 H), 0.72 - 0.59 (m, 2H), 0.46 - 0.33 (m, 2H).

Experimental protocol for Compound 49: Step-1 : Synthesis of 5-fluoro-2-propoxybenzaldehyde:

Procedure

To a stirred solution of 5-fluoro-2-hydroxybenzaldehyde (3.0g, 21.42mmol) in DMF (30mL, 10V) at room temperature, potassium carbonate (5.92g, 42.84mmol) and 1 -bromopropane (5.27g, 042.84mmol) were added. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (100mL) and extracted with Ethyl Acetate (2 x100mL). The combined organic fractions were washed with cold water 3-4 times, dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by trituration with hexane to provide 5-fluoro-2-propoxybenzaldehyde (3.1g, 79.47% yield) as an off-white solid.

LCMS [ESI, M+1]:182.9 (RT:2.061 min, Purity:100 %)

Step-2: Synthesis of tert-butyl 4-(((5-fluoro-2-propoxybenzyl)amino)methyl)piperidine-1- carboxylate:

Procedure

To a stirred solution of 5-fluoro-2-propoxybenzaldehyde (0.2g, 1.09mmol) in DCE (4mL,20V) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.31g, 0.1.31 mmol) and Acetic acid (0.002g, 0.0549mmol) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.69g, 3.29mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15mL) and extracted with CH2CI2 (3 x 10mL). The combined organic fractions were washed with water (15 mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 40% ethyl acetate in hexane) to provide tert-butyl 4-(((5-fluoro-2-propoxybenzyl)amino)methyl)piperidine-1 -carboxylate (0.13g, 31.12% yield) as a colourless liquid.

LCMS [ESI, M+1]: 381.11 (RT: 1.663 min, Purity: 100 %)

Step-3: Synthesis of N-(5-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (Compound 49):

Procedure

To a stirred solution of tert-butyl 4-(((5-fluoro-2-propoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.130g, 0.342 mmol) in CH2CI2 (1.3mL, 10V) at room temperature, 4M Hydrochloric acid in dioxane (0.65mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration using CH2CI2 to provide N-(5-fluoro-2-propoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride (0.07g, 73.07% yield) as a white sticky solid.

LCMS [ESI, M+1]:281 ,(RT:0.842 min, Purity: 100%),

HPLC: RT: 3.546, Purity: 100%

¹ H NMR (400 MHz, CD3OD): 6 7.30 (dd, J = 8.5, 3.1 Hz, 1 H), 7.24 - 7.18 (m, 1 H), 7.12 (dd, J = 9.1 , 4.4 Hz, 1 H), 4.29 (s, 2H), 4.09 (t, J = 6.7 Hz, 2H), 3.48 (d, J = 12.8 Hz, 2H), 3.12 - 3.03 (m, 4H), 2.20 (ddd, J = 11.4, 7.7, 4.0 Hz, 1 H), 2.09 (d, J = 14.1 Hz, 2H), 1.89 (dt, J = 14.1 , 7.0 Hz, 2H), 1.57 (dd, J = 23.3, 11.5 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H).

Experimental protocol for Compound 50:

Step-1 :Synthesis of 4-chloro-2-propoxybenzaldehyde:

To a stirred solution of 4-chloro-2-hydroxybenzaldehyde (3.0g, 19.16mmol) in DMF (30mL, 10V) at room temperature, potassium carbonate (5.92g, 38.32mmol) and 1 -bromopropane (5.27g, 38.32mmol) were added. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was poured into cold water (100mL) and extracted with Ethyl Acetate (2 x 100mL). The combined organic fractions were washed with cold water 3-4 times, dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by trituration with hexane to provide 4-chloro-2-propoxybenzaldehyde_(3.8g, 99.83% yield) as an off-white liquid.

LCMS [ESI, M+1]:198.93 (RT:2.263 min, Purity:99.96 %), 4-(((4-chloro-2-i -1-

To a stirred solution of 4-chloro-2-propoxybenzaldehyde (0.2g, 1.09mmol) in DCE (4mL,20V) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.31g, 0.1.31 mmol) and Acetic acid (0.002g, 0.0549mmol) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.69g, 3.29mmol) was added portion-wise to the reaction mixture at 0°C. The reaction was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (15mL) and extracted with CH2CI2 (3 x 10mL). The combined organic fractions were washed with water (15 mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 40% ethyl acetate in hexane) to provide tert-butyl 4-(((4-chloro- 2-propoxybenzyl)amino)methyl)piperidine-1 -carboxylate (0.22g, 55.05% yield) as a colourless liquid.

LCMS [ESI, M+1]:397.11 (RT: 1.660min, Purity:99.11 %)

To a stirred solution of tert-butyl 4-(((5-fluoro-2-propoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.130g, 0.342 mmol) in CH2CI2 (1.3mL, 10V) at room temperature, 4M Hydrochloric acid in dioxane (0.65mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration using CH2CI2 to provide N-(4-chloro-2-propoxybenzyl)-1-(piperidin-4- yl)methanamine_hydrochloride (0.1g, 60.79% yield) as a white sticky solid.

LCMS [ESI, M+1]:,296.99(RT: 0.918min, Purity:99.14 %),

HPLC: RT:3.745 , Purity:100 %

¹ H NMR (400 MHz, CD3OD): 6 7.45 (d, J = 8 Hz 1 H), 7.17 (d, J = 1.6 Hz, 1 H), 7.08-7.06 (dd, J = 1.6 Hz, 2 Hz, 1 H),4.26 (m, 2H), 4.12-4.09 (m,2H), 3.47 (d, J = 12 Hz, 2H), 3.09-3.03 (m, 4H), 2.18- 2.17 (m, 1 H), 2.10-2.06 (m, 2H), 1.93-1.88 (m, 2H), 1.57-1.54 (m, 2H), 1.13-1.09 (m, 3H),

Procedure

To a stirred solution of 4-chloro-2-hydroxybenzaldehyde (0.5g, 6.38mmol) in DMF (5mL) at room temperature, potassium carbonate (1.32g, 9.56mmol) was added. The reaction mixture was stirred at room temperature for 30 min. Then 2-Bromoethyl Methyl Ether (0.885g, 6.36mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (10 mL) and extracted with Ethyl acetate (3 x 20 mL). The combined organic fractions were washed with ice cold water 3-4 times, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiC>2; 5% EtOAc/Hexane) to provide 4-chloro-2-(2- methoxyethoxy)benzaldehyde (0.58g, 84.61% yield) as a white solid.

LCMS [ESI, M+1]: 214.98 (RT: 1.726 min, Purity: 98.74%),

¹ H-NMR (400 MHz, cfc-DMSO) : 6 10.31 (s, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.39 (d, J = 2.0 Hz, 1 H), 7.17-7.14 (m, 1 H), 4.33-4.30 (m, 2H), 3.73-3.71 (m, 2H).

Note: -OCH3 protons may be merged with the solvent residual peak. Step-2: Synthesis of tert-butyl 4-(((4-chloro-2-(2-methoxyethoxy)benzyl)amino)methyl)- piperidine-1 -carboxylate

Procedure

To a stirred solution of 4-chloro-2-(2-methoxyethoxy)benzaldehyde (0.15g, 0.69mmol) in DCE (3mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.179g, 0.83mmol) and acetic acid (0.008mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then sodium triacetoxyborohydride (0.44g, 2.09mmol) was added portion-wise added to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 6h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (20mL) and washed with a sat. NaHCCh solution (15mL) and water (25mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 50% EtOAc/Hexane) to provide tert-butyl 4-(((4-chloro-2-(2- methoxyethoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.24g, 83.16% yield) as a colorless oil.

LCMS [ESI, M+1]: 413.1 (RT: 1.434 min, Purity: 99.81 %),

HPLC Purity: RT: 5.039 min, Purity: 100.0%

¹ H-NMR (400 MHz, cfe-DMSO) : 6 7.31 (d, J = 8.0 Hz, 1 H), 7.05 (d, J = 2.0 Hz, 1 H), 6.98-6.95 (dd, J = 2.0 Hz, 8.0 Hz, 1 H), 4.15-4.13 (m, 2H), 3.93-3.90 (m, 2H), 3.67-3.65 (m, 4H), 3.31 (s, 3H), 2.68- 2.66 (m, 2H), 2.38-2.33 (m, 2H), 1 .91 (s, 2H), 1 .55 (m, 1 H), 1 .66 (d, J = 12.8 Hz, 2H), 1 .38 (s, 9H).

Step-3: Synthesis of /V-(4-chloro-2-(2-methoxyethoxy)benzyl)-1-(piperidin-4-yl)me thanamine hydrochloride (Compound 51):

Procedure

To a stirred solution of tert-butyl 4-(((4-chloro-2-(2-methoxyethoxy)benzyl)amino)methyl) piperidine- 1 -carboxylate (0.24g, 0.58mmol) in CH2CI2 (2.4mL) at 0°C, 4.0 M HCI in Dioxane (1 ,2mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration using diethyl ether to provide /V-(4-chloro-2-(2-methoxyethoxy)benzyl)-1-(piperidin-4-yl)me thanamine hydrochloride (0.16g, 88.0 yield) as a white solid.

LCMS [ESI, M+1]: 312.9 (RT: 0.817 min, Purity: 100%),

HPLC Purity: RT: 3.399 min, Purity: 100.0%

¹ H-NMR (400 MHz, cfc-DMSO) : 6 9.19 (s, 2H), 8.98 (s, 1 H), 8.83 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 1.6 Hz, 1 H), 7.11-7.08 (dd, J = 1 .6 Hz, 8.0 Hz, 1 H), 4.22 (t, J = 4.4 Hz, 2H), 4.07 (bs, 2H), 3.72-3.70 (m, 2H), 3.34 (s, 3H), 3.26 (d, J = 12.0 Hz, 2H), 2.84-2.82 (m, 4H), 2.05-2.01 (m, 1 H), 1 .93 (d, J = 13.6 Hz, 2H), 1 .45-1 .35 (m, 2H).

Procedure:

To a stirred solution of 5-fluoro-2-hydroxybenzaldehyde (5.0g, 3.56mmol) in DMF (50 mL, 10 V) at room temperature, potassium carbonate (14.7g, 10.70mmol) was added. The reaction mixture was stirred at room temperature for 30 min. (Bromomethyl)cyclopropane (7.2g, 5.35mmol) was added to the reaction mixture at 0°C . The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with cold water (50mL) and extracted with Ethyl acetate (2 x 50mL). The combined organic fractions were dried over Sodium Sulphate and concentrated under reduced pressure to provide 2-(cyclopropylmethoxy)-5-fluorobenzaldehyde (0.55 g, 79.36% yield) as a light yellow liquid.

LCMS [ESI, M+1]: 194.88(RT: 2.024 min, Purity: 99.81 %),

-5-

Procedure:

To a stirred solution of 2-(cyclopropylmethoxy)-5-fluorobenzaldehyde (0.5 g, 2.83 mmol) in DCE (5.5 mL, 10 V) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.66 g, 3.39 mmol) and acetic acid (0.08 g, 1.41 mmol) were added. The reaction mixture was stirred for 2h. Sodium triacetoxy borohydride (1.6 g, 8.49 mmol) was added to reaction mixture at 0°C. Then the reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with a saturated solution of sodium bicarbonate (50mL) and extracted with CH2CI2 (3 x 50mL). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 63% EtOAc/Hexane) to provide tert-butyl 4-(((2-(cyclopropylmethoxy)-5-fluoro benzyl)amino)methyl)piperidine-1 -carboxylate (0.5 g, 49.48 % yield) as a light yellow liquid. LCMS [ESI, M+1]: 393.1 (RT: 1.641 min, Purity: 100%), i-1 -(piperidin-4-

Procedure:

To a stirred solution of tert-butyl 4-(((2-(cyclopropylmethoxy)-5- fluorobenzyl)amino)methyl)piperidine-1 -carboxylate (0.5 g, 1.27mmol) in CH2CI2 (5 mL, 10V) at 0°C , 4M HCI in Dioxane (3.5mL, 5V) was added. The reaction mixture was stirred at room temperature for 15 min. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration using Diethyl ether to provide N-(2-(cyclopropylmethoxy)-5- fluorobenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.204 g, 54.57 % yield) as a white solid.

LCMS [ESI, M+1]: 293.0 (RT 0.831 min, Purity: 100%)

HPLC: RT 3.500 min, Purity: 98.58%

¹ H NMR (400 MHz, CD3OD): 6 7.31-7.28 (s, 1 H), 7.22-7.17 (s, 1 H), 7.1 1 - 7.08 (m, 1 H), 4.30 (s, 2H), 3.96 (d, J = 8.0, 2H), 3.47 (d, J = 12.0, 2H), 3.13-3.04 (m, 4H), 2.24-2.19(m, 1 H), 2.10(d, J = 12.0, 2H), 1.63-1.52 (m, 2H), 1.38-1.32 (m, 1 H), 0.70-0.65 (m, 2H), 0.49-0.38 (m, 2H).

Procedure:

To a stirred solution of 4-fluoro-2-hydroxybenzaldehyde (5.0g, 3.56mmol) in DMF (5 mL, 10 V) at room temperature, potassium carbonate (14.7g, 10.70mmol) was added. The reaction mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (7.2g, 5.35mmol) was added at 0°C. Then the reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with cold water (60mL) and extracted with Ethyl acetate (3 x 60mL). The combined organic fractions were dried over Sodium Sulphate and concentrated under reduced pressure to provide 2-(cyclopropylmethoxy)-4-fluorobenzaldehyde (0.55 g, 79.36% yield) as a light yellow liquid.

LCMS [ESI, M+1]: 194.88 (RT: 2.024 min, Purity: 99.81 %).

Procedure:

To a stirred solution of 2-(cyclopropylmethoxy)-4-fluorobenzaldehyde (0.5 g, 2.57 mmol) in DCE (5mL, 10V) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.66g, 3.08mmol) and Acetic acid (0.08g, 1.41 mmol) were added. The reaction mixture was stirred for at room temperature for 2h. Sodium triacetoxy borohydride (1.6g, 8.49mmol) was added to reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with a saturated solution of sodium bicarbonate (50mL) and extracted with CH2CI2 (3 x 50mL). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 80%EtOAc/Hexane) to provide tert-butyl 4-(((2-(cyclopropylmethoxy)-4-fluorobenzyl) amino)methyl)piperidine-1 -carboxylate (0.65 g, 64.32%yield) as a light yellow liquid.

LCMS [ESI, M+1]: 393.1 (RT: 1.582 min, Purity: 91.32%). i-4-fluorobenzvl)-1 -(piperidin-4-

Procedure:

To a stirred solution of tert-butyl 4-(((2-(cyclopropylmethoxy)-4- fluorobenzyl)amino)methyl)piperidine-1 -carboxylate (0.5 g, 1.27 mmol) in CH2CI2 (6 mL, 12V) at 0°C, 4M HCI in Dioxane (3mL, 6V) was added. The reaction mixture was stirred at room temperature for 20 min. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration using Diethyl ether to provide N-(2- (cyclopropylmethoxy)-4-fluorobenzyl)-1-(piperidin-4-yl)metha namine hydrochloride (0.248 g, 66.57 % yield) as a white solid.

LCMS [ESI, M+1]: 293.0 (RT 0.903 min, Purity: 100%)

HPLC: RT 3.559 min, Purity: 100%

¹ H NMR (400 MHz, CD3OD): 6 7.51-7.48 (m, 1 H), 6.91 (dd, J = 2.4, 2.4 10.7 Hz 1 H), 6.81-6.76(m, 1 H), 4.28 (s, 2H), 3.97 (d, J = 8.0, 2H), 3.47 (d, J = 8.0, 2H), 3.11-3.04 (m, 4H), 2.23-2.19 (m, 1 H), 2.10 (d, J = 12.0 Hz, 2H), 1.63-1.53 (m, 2H), 1.39-1.30 (m, 1 H), 0.71-0.67 (m, 2H), 0.46-0.44 (m, 2H).

Procedure

To a stirred solution of 4-chloro-2-hydroxybenzaldehyde (1.5g, 9.58mmol) in DMF (15mL) at room temperature, potassium carbonate (3.96g, 9.56mmol) was added. The reaction mixture was stirred at room temperature for 30 min. Then (bromomethyl)cyclopropane (2.58g, 19.16mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (50 mL) and extracted with Ethyl acetate (3 x 20 mL). The combined organic fractions were washed with ice cold water 3-4 times, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 5% EtOAc/Hexane) to provide 4-chloro-2- (cyclopropylmethoxy)benzaldehyde (2.0g, 99.10% yield) as a white solid.

LCMS [ESI, M ⁺ ]: 210.9 (RT: 2.223 min, Purity: 93.90%),

Procedure

To a stirred solution of 4-chloro-2-(cyclopropylmethoxy)benzaldehyde (0.3g, 1.42mmol) in DCE (6mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.36g, 1.70mmol) and acetic acid (0.015mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then, sodium triacetoxyborohydride (0.9g, 4.27mmol) was added portion-wise added to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (30mL) and washed with sat. sodium bicarbonate solution (15mL) and water (25mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 50% EtOAc/Hexane) to provide tert-butyl 4-(((4-chloro-2- (cyclopropylmethoxy)benzyl)amino) methyl)piperidine-1 -carboxylate (0.36g, 61.81 % yield) as a colorless oil.

LCMS [ESI, M+1]: 409.1 (RT: 1.661 min, Purity: 98.66%),

¹ H-NMR (400 MHz, cfe-DMSO) : 6 7.30 (d, J = 8.0 Hz, 1 H), 6.96 (d, J = 2.0 Hz, 1 H), 6.95-6.92 (dd, J = 2.0 Hz, 8.0 Hz, 1 H), 3.91 (d, J = 12.0 Hz, 2H), 3.86 (d, J = 6.8 Hz, 2H), 3.63 (s, 2H), 2.36-2.33 (m, 4H), 1.68 (d, J = 12.4 Hz, 2H), 1.59-1.54 (m, 2H), 1.38 (s, 9H), 1 .01-0.94 (m, 2H), 0.59-0.54 (m, 2H), 0.34-0.32 (m, 2H).

Step-3: Synthesis of A/-(4-chloro-2-(cvclopropylmethoxy)benzyl)-1-(piperidin-4-yl ) methanamine hydrochloride (Compound 54):

Procedure

To a stirred solution of tert-butyl 4-(((4-chloro-2-(cyclopropylmethoxy)benzyl)amino)methyl) piperidine-1 -carboxylate (0.35g, 0.85mmol) in CH2CI2 (3.5mL) at 0°C, 4.0 M HCI in Dioxane (1 .75mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration using diethyl ether to provide W-(4-chloro-2- (cyclopropylmethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride (0.26g, 98.37 yield) as a white solid.

LCMS [ESI, M+1]: 308.99 (RT: 0.969 min, Purity: 98.68%),

HPLC Purity: RT: 3.813 min, Purity: 99.20%

¹ H-NMR (400 MHz, CD3OD) : 6 7.46 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 2.0 Hz, 1 H), 7.07-7.05 (dd, J = 2.0 Hz, 8.4 Hz, 1 H), 4.29 (S, 2H), 3.98 (d, J = 7.2 Hz, 2H), 3.47 (d, J = 12.8 Hz, 2H), 3.12-3.04 (m, 4H), 2.24-2.18 (m, 1 H), 2.10 (d, J = 14.4 Hz, 2H), 1 .63-1.53 (m, 2H), 1.40-1.31 (m, 1 H), 0.71-0.67 (m, 2H), 0.46-0.42 (m, 2H).

Procedure

To a stirred solution of 4-chloro-2-(cyclopropylmethoxy)benzaldehyde (0.3g, 1.42mmol) in DCE (6mL) at room temperature, tert-butyl (R)-3-(aminomethyl)pyrrolidine-1-carboxylate (0.34g, 1.70mmol) and acetic acid (0.015mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.9g, 4.27mmol) was added portion-wise to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (30mL) and washed with sat. NaHCCh solution (15mL) and water (25mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 50% EtOAc/Hexane) to provide tert-butyl (S)-3-(((4-chloro-2- (cyclopropylmethoxy)benzyl)amino)methyl)pyrrolidine-1 -carboxylate (0.36g, 64.01% yield) as a colorless oil.

LCMS [ESI, M+1]: 395.0 (RT: 1.624 min, Purity: 79.1798.66%),

¹ H-NMR (400 MHz, cfe-DMSO) : 6 7.30 (d, J = 8.0 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 6.95-6.92 (dd, J = 2.0 Hz, 8.0 Hz, 1 H), 3.86 (d, J = 6.8 Hz, 2H), 3.65 (s, 2H), 3.39-3.37 (m, 2H), 3.18-3.14 (m, 2H), 2.93-2.88 (m, 1 H), 2.48-2.43 (m, 2H), 2.27-2.26 (m, 1 H), 1.54-1.52 (m, 1 H), 1 .38 (s, 9H), 1.25-1.18 (m, 1 H), 0.59-0.54 (m, 2H), 0.34-0.31 (m, 2H). i-1 -(pyrrol id in-3-

Procedure

To a stirred solution of tert-butyl (R)-3-(((4-chloro-2-(cyclopropylmethoxy)benzyl)amino) methyl)pyrrolidine-1-carboxylate (0.35g, 0.88mmol) in CH2CI2 (3.5mL at 0°C), 4.0 M HCI in Dioxane (1 .75mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration using diethyl ether to provide (Sj-N-(4-chloro-2- (cyclopropylmethoxy)benzyl)-1-(pyrrolidine-3-yl)methanamine hydrochloride (0.243g, 93.01 yield) as a white solid.

LCMS [ESI, M ⁺ ]: 294.9 (RT: 0.995 min, Purity: 100.0%),

HPLC Purity: RT: 3.722 min, Purity: 99.23%

Chiral HPLC Purity: RT: 2.21 min, Purity: 100.0%

¹ H-NMR (400 MHz, cfe-DMSO) : 6 7.56 (d, J = 8.0 Hz, 1 H), 7.14 (d, J = 2.0 Hz, 1 H), 7.08-7.05 (dd, J = 2.0 Hz, 8.4 Hz, 1 H), 4.08 (t, J = 5.2 Hz, 2H), 3.93 (d, J = 7.2 Hz, 2H), 3.37 (s, 1 H), 3.23-3.20 (m, 1 H), 3.13-2.95 (m, 4H), 2.74-2.68 (m, 1 H), 2.16-2.12 (m, 1 H), 1.73-1.68 (m, 1 H), 1.31-1.27 (m, 1 H), 0.62-0.57 (m, 2H), 0.39-0.36 (m, 2H).

Experimental protocol for Compound 56:

CAS No.6361 -23-5 Cl

Step-1 : Synthesis of 5-chloro-2-phenoxybenzaldehyde:

Procedure:

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.5g, 2.85mmol) in DMAC (5mL, 10V) at room temperature, potassium carbonate (0.591g, 4.28mmol) was added. The reaction mixture was stirred at room temperature for 30min. Phenol (0.295g, 3.14mmol) was added at room temperature. The reaction mixture was stirred at 170°C for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with cold water (100 mL) and extracted with Ethyl acetate (2 x 50mL). The combined organic fractions were dried over Sodium Sulphate and concentrated under reduced pressure to provide 5-chloro-2- phenoxybenzaldehyde (0.3 g, 40.38% yield) as a white sticky liquid.

¹ H NMR (400 MHz, CDCI ₃ ): 6 10.46 (d, J = 16.0 Hz, 1 H), 7.91 (d, J = 2.7 Hz, 1 H), 7.50 - 7.39 (m, 3H), 7.25 (dd, J = 17.4, 10.0 Hz, 1 H), 7.14 - 7.04 (m, 2H), 6.87 (d, J = 8.9 Hz, 1 H).

Step-2: Synthesis of tert-butyl 4-(((5-chloro-2-phenoxybenzyl)amino)methyl)piperidine-1- carboxylate

Procedure:

To a stirred solution of 5-chloro-2-phenoxybenzaldehyde (0.3g, 1.28mmol) and tert-butyl 4-(amino methyl)piperidine-1 -carboxylate (0.33g, 1.54 mmol) in DCE (3mL, 10V) at room temperature, Acetic acid (0.08g, 1.41 mmol) was added. The reaction mixture was stirred at rt for 2h, Then sodium triacetoxy borohydride (0.81g, 3.86mmol) was added to reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with a saturated solution of sodium bicarbonate (50mL) and extracted with CH2CI2 (3 x 50mL). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 30%EtOAc/Hexane) to provide tert-butyl 4-(((5-chloro-2-phenoxybenzyl) amino)methyl)piperidine-1 -carboxylate (0.16g, 28.79% yield) as an off-white solid.

LCMS [ESI, M+1]: 431.17 (RT: 1.671 min, Purity: 94.83%),

Step-3: Synthesis of N-(5-chloro-2-phenoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (Compound 56)

Procedure:

To a stirred solution of tert-butyl tert-butyl 4-(((5-chloro-2-phenoxybenzyl)amino)methyl)piperidine- 1-carboxylate (0.160g, 3.713mmol) in CH2CI2 (2mL, 12.5V) at 0°C, 4M HCI in Dioxane (1 mL, 6.25V) was added. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by trituration with Diethyl ether to provide N-(5-chloro-2-phenoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride (0.140g, 94.26% yield) as an off-white solid.

LCMS [ESI, M+1]: 330.95 (RT: 1.089 min, Purity: 97.96%)

HPLC: RT 3.992 min, Purity: 98.39%

¹ H NMR (400 MHz, D2O): 6 7.47 (d, J = 2.6 Hz, 1 H), 7.40 - 7.28 (m, 3H), 7.18 (t, J = 7.5 Hz, 1 H), 7.03 (d, J = 7.8 Hz, 2H), 6.87 (d, J = 8.9 Hz, 1 H), 4.23 (s, 2H), 3.35 (d, J = 13.2 Hz, 2H), 3.01 - 2.80 (m, 4H), 2.02 (s, 1 H), 1.91 (d, J = 14.5 Hz, 2H), 1.38 (d, J = 11.9 Hz, 2H).

Experimental protocol for Compound 57:

CA Step-1 : Synthesis of pyrimidin-2-ylmethyl methanesulfonate:

Procedure:

To a stirred solution of pyrimidin-2-ylmethanol (0.5g, 4.54 mmol) in CH2CI2 (5mL, 10V), TEA (1 ,2mL, 9.08mmol) was added. Then reaction mixture was stirred at room temperature for 30 min. Mesyl chloride (1.04g, 9.08mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was diluted with cold water (40mL) and extracted with CH2CI2 (3X40mL). The combined organic fractions were dried over Sodium Sulphate and concentrated under reduced pressure to provide pyrimidin-2-ylmethyl methanesulfonate (0.520g, 60.85% yield) as a yellow liquid. LCMS [ESI, M+1]: 188.93 (RT: 0.684 min, Purity: 53.27%)

>-2: Synthesis of 5-chloro-2-(pyrimidin-2-'

Procedure:

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (0.3g, 4.54mmol) in DMF (5mL, 10V) at room temperature, potassium carbonate (0.79, 5.74mmol) was added. The reaction mixture was stirred at rt for 30 min. Pyrimidin-2-ylmethyl methanesulfonate (0.432 g, 2.29mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 3h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of reaction, the reaction mixture was diluted with cold water (30 mL) and extracted with Ethyl acetate (3 x 30mL). The combined organic fractions were dried over Sodium Sulphate and concentrated under reduced pressure to provide 5-chloro-2-(pyrimidin-2-ylmethoxy)benzaldehyde (0.520g, 73.46% yield) as a pale yellow liquid.

LCMS [ESI, M+1]: 248.93 (RT: 1.552 min, Purity: 99.85%)

¹ H NMR (400 MHz, cfe-DMSO): 6 10.43 (s, 1 H), 8.84 (d, J = 4.9 Hz, 2H), 7.66 (dd, J = 7.9, 2.4 Hz, 2H), 7.49 (t, J = 4.9 Hz, 1 H), 7.29 (dd, J = 7 A, 2.0 Hz, 1 H), 5.54 (s, 2H). -butyl 4-(((5-chloro-2-(pyrimidin-2-'

Procedure:

To a stirred solution of 5-chloro-2-(pyrimidin-2-ylmethoxy)benzaldehyde (0.35g, 1.40mmol) in DCE (3.5mL, 10V) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.36g, 1.68mmol) and Acetic acid (0.08g, 1.41 mmol) were added. The reaction mixture was stirred at room temperature for 2h. Then sodium triacetoxyborohydride (0.89g, 4.22mmol) was added to reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with a saturated solution of sodium bicarbonate (20mL) and extracted with CH2CI2 (3X 20mL). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 62%EtOAc/Hexane) to provide tert-butyl 4-(((5-chloro-2-(pyrimidin-2- ylmethoxy)benzyl)amino)methyl)piperidine-1 -carboxylate (0.35g, 55.63% yield) as a pale yellow liquid.

LCMS [ESI, M+1]:447.12(RT: 1.418min, Purity: 99.99%), i-1 -(pi peridi De¬ procedure:

To a stirred solution of tert-butyl 4-(((5-chloro-2-(pyrimidin-2-ylmethoxy) benzyl)amino)methyl) piperidine-1 -carboxylate (0.35g, 7.83mmol) in CH2CI2 (3.5mL 10V) at 0°C, 4M HCI in Dioxane(1 ,5mL, 4.2V) was added. The reaction mixture was stirred at room temperature for 25 min. The Progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material purified by Trituration with Diethyl ether to provide N-(5-chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.214g, 78.79% yield) as a pale yellow solid.

LCMS [ESI, M+1]: 346.9 (RT: 0.787 min, Purity: 96.89%)

HPLC: RT 3.313 min, Purity: 100%

¹ H NMR (400 MHz, D2O): 6 8.72 (t, J = 4.9 Hz, 2H), 7.44 (t, J = 5.0 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 9.0 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 5.40 (s, 2H), 4.26 (s, 2H), 3.36 (d, J = 13.2 Hz, 2H), 3.02 (d, J = 7.0 Hz, 2H), 2.91 (t, J = 11 .8 Hz, 2H), 2.06 (d, J = 3.8 Hz, 1 H), 1 .99 - 1 .84 (m, 2H), 1.49 - 1 .32 (m, 2H).

Procedure

To a stirred solution of 5-chloro-2-(cyclopropylmethoxy)benzaldehyde (0.25g,1 .18mmol) in DCE (5mL) at room temperature, tert-butyl (S)-3-(aminomethyl)pyrrolidine-1 -carboxylate (0.283g, 1.41 mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.750g, 3.5mmol) was added to the reaction mixture in small portions at 0°C. The reaction was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (100mL) and extracted with CH2CI2 (3 x 100mL). The combined organic fractions were washed with water (100mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 5% methanol in CH2CI2) to get tert-butyl(S)-3-(((5-chloro-2- (cyclopropylmethoxy)benzyl)amino)methyl)pyrrolidine-1-carbox ylate(0.25g, 53.41% yield) as a colorless liquid.

LCMS [ESI, M+1]:395.01(RT: 1.662 min, Purity: 96.64%)

Chiral HPLC: RT: 2.78min, Purity: 100%

¹ H NMR (400 MHz, cfc-DMSO): 6 7.35 (d, J = 2.8 Hz, 1 H), 7.20 (dd, J = 2.8, 2.4 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 3.83 (d, J = 6.8 Hz, 2H), 3.66 (s, 2H), 3.16 (m, 1 H), 2.92 (t, J = 9.2, 9.6 Hz, 1 H), 2.33-2.27(m, 1 H), 1.99 (s, 1 H), 1.91 (s, 1 H), 1.53-1.51 (m, 1 H), 1.39 (s, 9H), 1.24-1.16 (m, 5H), 0.58-0.54(m, 2H), 0.34(s, 2H). i-1 -( pyrrol id in-3-

Procedure

To a stirred solution of tert-butyl(S)-3-(((5-chloro-2-(cyclopropylmethoxy)benzyl)ami no)methyl) pyrrolidine-1 -carboxylate (0.25g, 0.63mmol) in DCM (1 ,25mL) at 0°C, 4M HCI in Dioxane (1.25mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material triturated with diethyl ether to provide (R)-N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin- 3- yl)methanamine hydrochloride (0.180, 96.77%) as an off-white sticky solid.

LCMS [ESI, M+1]:294.79 (RT: 0.892 min, Purity: 99.75%)

HPLC: RT: 3.733min, Purity: 100%

Chiral HPLC: RT: 3.33min, Purity: 100%

¹ H NMR (400 MHz, D2O): 6 7.37 (dd, J = 2.8, 2.8 Hz, 1 H), 7.32 (d, J = 2.4 Hz, 1 H), 6.98(d, J = 8.8 Hz, 1 H), 4.22 (s, 2H), 3.87 (d, J = 7.2 Hz, 2H), 3.56-3.51 (m, 1 H), 3.40-3.37(m, 1 H), 3.29-3.14(m, 3H), 2.95(dt, J = 9.2, 9.2 Hz, 1 H),2.71 (m, 1 H), 2.27 (m, 1 H), 1.75-1.69(m, 1 H), 1.22(m, 1 H), 0.57- 0.52(m, 2H), 0.29-0.26(m, 2H)

Experimental protocol for Compound 59:

Synthetic scheme

Step-1 : Synthesis of 4-fluoro-2-propoxybenzaldehyde

Procedure

To a stirred solution of 4-fluoro-2-hydroxybenzaldehyde (0.25g, 1.78mmol) in DMF (2.5mL) at room temperature, K2CO3 (0.73g, 5.35mmol) was added. The reaction mixture was stirred at room temperature for 30 min. 1 -bromopropane (0.43g, 3.56mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (10 mL) and extracted with Ethyl acetate (3 x 15 mL). The combined organic fractions were washed with ice cold water 3-4 times, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-10% EtOAc/Hexane) to provide 4-fluoro-2- propoxybenzaldehyde (0.31g, 95.36% yield) as a white solid.

LCMS [ESI, M+1]: 182.83 (RT: 2.004 min, Purity: 96.41%), i-2: Synthesis of tert-butyl 4-(((4-fluoro-2-i

Procedure

To a stirred solution of 4-fluoro-2-propoxybenzaldehyde (0.3g, 1.64mmol) in DCE (6mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.38g, 1.81 mmol) and acetic acid (0.015mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then, sodium triacetoxyborohydride (1.04g, 4.93mmol) was added portion-wise to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (30mL) and washed with sat. NaHCCh solution (15mL) and water (25mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-50% EtOAc/Hexane) to provide tert-butyl 4-(((4-fluoro-2-propoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.45g, 71.82% yield) as a colorless oil.

LCMS [ESI, M+1]: 381.3 (RT: 1.549 min, Purity: 98.1%),

¹ H-NMR (400 MHz, cfc-DMSO) : 6 7.40 (t, J = 7.8 Hz, 1 H), 6.93-6.90 (dd, J = 2.2 Hz, 11 .4 Hz, 1 H), 6.79-6.74 (td, J = 2.4 Hz, 8.4 Hz, 1 H), 3.99-3.91 (m, 4H), 3.83 (s, 2H), 2.69-2.67 (m, 2H), 2.58 (d, J = 5.2 Hz, 2H), 1 .78-1 .69 (m, 5H), 1 .39 (s, 9H), 1 .00 (t, J = 7.4 Hz, 5H).

Step-3: Synthesis of A/-(4-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine

Procedure

To a stirred solution of tert-butyl 4-(((4-fluoro-2-propoxybenzyl)amino)methyl)piperidine-1- carboxylate (0.42g, 1.1 mmol) in CH2CI2 (4.2mL) at 0°C , 4.0 M HCI in Dioxane (2.1 mL, 5V) was added. The reaction mixture was then stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration using diethyl ether to provide /V-(4-fluoro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride (0.214g, 69.15 yield) as an off-white solid.

LCMS [ESI, M ⁺ ]: 280.9 (RT: 0.867 min, Purity: 100%),

HPLC Purity: RT: 3.586 min, Purity: 97.73%

¹ H-NMR (400 MHz, D2O) : 6 7.28 (t, J = 8.4 Hz, 1 H), 6.84-6.81 (dd, J = 2.4 Hz, 11.2 Hz, 1 H), 6.71- 6.66 (td, J = 2.4 Hz, 8.4 Hz, 1 H), 4.17 (s, 2H), 3.98 (t, J = 6.8 Hz, 2H), 3.39 (d, J = 13.2 Hz, 2H), 3.04-2.91 (m, 4H), 2.11-2.00 (m, 1 H), 1.95 (d, J = 14.4 Hz, 2H), 1.78-1.69 (m, 2H), 1.47-1.36 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

Experimental protocol for Compound 60

Synthetic scheme

Step-1 : Synthesis of 2-(cvclopropylmethoxy)-4,5-difluorobenzaldehvde

Procedure

To a stirred solution of 4,5-difluoro-2-hydroxybenzaldehyde (0.5g, 3.16mmol) in DMF (5mL) at room temperature, K2CO3 (1.30g, 9.42mmol) was added. The reaction mixture was stirred at room temperature for 30 min. Then, (bromomethyl)cyclopropane (0.85g, 6.29mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (10 mL) and extracted with Ethyl acetate (3 x 20 mL). The combined organic fractions were washed with ice cold water 3-4 times, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-5% EtOAc/Hexane) to provide 2- (cyclopropylmethoxy)-4,5-difluorobenzaldehyde (0.55g, 81.96% yield) as a white solid.

LCMS [ESI, M-29]: 182.5 (RT: 2.116 min, Purity: 97.86%),

¹ H-NMR (400 MHz, CDCI3): 6 10.43 (s, 1 H), 7.69-7.64 (m, 1 H), 6.81-6.77 (m, 1 H), 3.91 (d, J = 6.8 Hz, 2H), 1.34-1.27 (m, 1 H), 0.73-0.68 (m, 2H), 0.42-0.38 (m, 2H).

Procedure

To a stirred solution of 2-(cyclopropylmethoxy)-4,5-difluorobenzaldehyde (0.3g, 1.41 mmol) in DCE (6mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.36g, 1 .69mmol) and acetic acid (0.015mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then, sodium triacetoxyborohydride (0.89g, 4.24mmol) was portion-wise added to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (20mL) and washed with sat. NaHCCh solution (15mL) and water (25mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-50% EtOAc/Hexane) to provide tert-butyl 4-(((2-(cyclopropylmethoxy)- 4, 5-difluorobenzyl)amino)methyl)piperidine-1 -carboxylate (0.32g, 55.14% yield) as a colorless oil.

LCMS [ESI, M+1]: 411.1 (RT: 1 .692 min, Purity: 98.68%),

HPLC Purity: RT: 5.378 min, Purity: 98.94%

¹ H-NMR (400 MHz, CDCI3): 6 7.15-7.11 (m, 1 H), 6.67-6.62 (m, 1 H), 4.16-4.12 (m, 2H), 3.79-3.77 (m, 4H), 2.68-2.50 (m, 2H), 2.06-2.01 (m, 2H), 1.70-1 .67 (m, 2H), 1.66-1.52 (m, 1 H), 1.31-1.22 (m, 2H), 1.42 (s, 9H), 1.17-1.07 (m, 1 H), 0.68-0.63 (m, 2H), 0.37-0.34 (m, 2H).

Step-3: Synthesis of N-(2-(cyclopropylmethoxy)-4,5-difluorobenzyl)-1-(piperidin-4 -yl) methanamine hydrochloride (Compound 60)

Procedure

To a stirred solution of tert-butyl 4-(((2-(cyclopropylmethoxy)-4,5-difluorobenzyl)amino)methyl) piperidine-1 -carboxylate (0.3g, 0.73mmol) in CH2CI2 (3.0mL) at 0°C, 4.0 M HCI in Dioxane (1.5mL, 5V) was added. The reaction mixture was then stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by trituration using diethyl ether to provide /V-(2-(cyclopropylmethoxy)-4,5-difluorobenzyl)-1- (piperidin-4-yl)methanamine hydrochloride (0.195g, 83.76 yield) as a white solid.

LCMS [ESI, M+1]: 311.0 (RT: 0.926 min, Purity: 100.0%),

HPLC Purity: RT: 4.079 min, Purity: 98.34%

¹ H-NMR (400 MHz, D2O): 6 7.26-7.22 (m, 1 H), 6.97-6.93 (m, 1 H), 4.21 -4.18 (d, J = 12.0 Hz, 2H), 3.84 (d, J = 6.4 Hz, 2H), 3.40 (d, J = 12.8 Hz, 2H), 3.02-2.98 (m, 2H), 2.95-2.91 (m, 2H), 2.12-2.02 (m, 1 H), 1.97 (d, J = 14.0 Hz, 2H), 1.48-1.38 (m, 2H), 1.25-1.16 (m, 1 H), 0.57-0.52 (m, 2H), 0.25- 0.28 (m, 2H). Experimental protocol for Compound 61

Synthetic scheme

Step-1 : Synthesis of tert-butyl (S)-3-(((5-chloro-2-propoxybenzyl)amino)methyl)pyrrolidine-1 - carboxylate

Procedure

To a stirred solution of 5-chloro-2-propoxybenzaldehyde(0.25g,1 .25mmol) in DCE (5mL) at room temperature, tert-butyl (S)-3-(aminomethyl)pyrrolidine-1-carboxylate (0.300g, 1.5mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.794g, 3.75mmol) was added to the reaction mixture in small portions at 0°C. The reaction mixture was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (100mL) and extracted with CH2CI2 (3 x 100mL). The combined organic fractions were washed with water (100mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 18% EtOAc/hexene) to provide tert-butyl (S)-3-(((5-chloro-2- propoxybenzyl)amino)methyl)pyrrolidine-1-carboxylate(0.280g, 58.21% yield) as a yellow liquid.

LCMS [ESI, M+1]:383.06(RT: 1.636 min, Purity: 97.73%)

Chiral HPLC: RT: 2.39min, Purity: 100%

¹ H NMR (400 MHz, cfc-DMSO): 6 7.35 (d, J = 2.4 Hz, 1 H), 7.22 (dd, J = 2.8, 2.4 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 3.93(t, J = 6.4 Hz, 2H), 3.66 (s, 2H), 3.16 (m, 1 H), 2.92 (t, J = 7.6 Hz, 1 H), 2.3-2.26 (m, 1 H), 1.91 (s, 1 H), 1.76-1.69 (m, 2H), 1.54-1.39 (m, 2H), 1.39 (s, 9H), 1.24 (s, 3H), 0.98 (t, J =

5.4 Hz, 3H).

Procedure

To a stirred solution of tert-butyl (S)-3-(((5-chloro-2-propoxybenzyl)amino)methyl)pyrrolidine-1 - carboxylate(0.28g, 0.73mmol) in CH2CI2 (1.4mL) at 0°C, 4M HCI in Dioxane (1.4mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material triturated with diethyl ether to provide (R)-N-(5-chloro-2-propoxybenzyl)-1 -(pyrrolidin-3-yl)methanamine hydrochloride (0.205, 99.51%) as a white solid.

LCMS [ESI, M+1]:282.89 (RT: 0.963 min, Purity: 95.06%)

HPLC: RT: 3.932min, Purity: 100%

Chiral HPLC: RT: 1.77min, Purity: 100%

¹ H NMR (400 MHz, D2O): 6 7.37 (dd, J = 2.4, 2.8 Hz, 1 H), 7.32 (d, J = 2.4 Hz, 1 H), 7.00 (d, J = 9.2 Hz, 1 H), 4.19 (s, 2H), 4.00 (t, J = 6.4, 6.8 Hz, 2H), 3.55-3.50 (m, 1 H), 3.42-3.37(m, 1 H), 3.26(s, 1 H), 3.24-3.11 (m, 2H), 2.93 (dt, J = 9.2 Hz, 1 H), 2.91-2.69(m, 1 H), 2.27-2.24(m, 1 H), 1.75-1.67(m, 3H), 0.91 (t, J = 7.6, 7.2 Hz, 3H)

Synthetic scheme

Procedure

To a stirred solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (5.0g, 24.2mmol) in DMF (50mL) at room temperature, K2CO3 (10.03g, 72.6mmol) was added. The reaction mixture was stirred for 1 h. Then Bromoethane (3.95g, 36.3mmol) was added to the reaction mixture. Then reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice-cold water (250mL) and extracted with ethyl acetate (3 x 200mL). The combined organic fractions were dried over Sodium Sulphate and concentrated under reduced pressure to provide 2-ethoxy-5-(trifluoromethoxy)benzaldehyde (3.7g, 65.14% yield) as a yellow liquid.

LCMS [ESI, M+1]: 234.83(RT: 2.150min, Purity: 99.04%)

¹ H NMR (400 MHz, cfe-DMSO): 6 10.34 (s, 1 H), 7.68(dd, J =3.2, 2.8 Hz, 1 H), 7.56 (d, J = 2.8 Hz, 1 H), 7.36 (d, J = 9.2 Hz, 1 H), 4.24 (q, J = 6.8 Hz, 2H), 1 ,40(t, J = 7.2, 6.8 Hz, 3H)

Procedure

To a stirred solution of 2-ethoxy-5-(trifluoromethoxy)benzaldehyde (0.25g, 1 .06mmol) in DCE (5mL) at room temperature, tert-butyl(S)-3-(aminomethyl)pyrrolidine-1-carboxylate(0.25g , 1.28mmol) was added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (0.673g, 3.18mmol) was added to the reaction mixture in small portions at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (50mL) and extracted with CH2CI2 (3 x 100ml). The combined organic fractions were washed with water (100mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 3% methanol in CH2CI2) to provide tert-butyl(S)-3-(((2-ethoxy-5-

(trifluoromethoxy)benzyl)amino)methyl)pyrrolidine-1 -carboxy late (0.25g, 56.05% yield) as a colorless liquid.

LCMS [ESI, M+1]: 419.11(RT: 1.677 min, Purity: 100%)

Chiral HPLC: RT: 3.54min, Purity: 100%

¹ H NMR (400 MHz, cfc-DMSO): 6 7.33(s,1 H), 7.17(d, J = 10.8 Hz, 1 H), 7.07(d, J = 8.8 Hz, 1 H), 4.04(m, 3H), 3.67(s, 2H), 3.16(m, 2H), 2.92(m, 1 H), 2.33(m, 1 H), 1.90(s, 1 H), 1.51 (m, 2H), 1.39(s, 9H), 1.34(t, J = 7.2, 6.8Hz, 2H), 1.24(s, 3H) i-1 -(pyrrolidin-3-

Procedure

To a stirred solution of tert-butyl(S)-3-(((2-ethoxy-5-

(trifluoromethoxy)benzyl)amino)methyl)pyrrolidine-1 -carboxylate (0.25g, mmol) in CH2CI2 (2mL) at 0°C, 4M HCI in Dioxane (1.25mL, 5V) was added. The reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material triturated with diethyl ether to provide (R)-N-(2-ethoxy-5- (trifluoromethoxy)benzyl)-1-(pyrrolidin-3-yl)methanamine hydrochloride (0.181g, 95.26%) as an off-white sticky solid.

LCMS [ESI, M+1]: 319.16(RT: 4.705min, Purity: 100%),

HPLC: RT: 3.946min, Purity: 100%

Chiral HPLC: RT: 5.297min, Purity: 100%

¹ H NMR (400 MHz, D2O): 6 7.34(dd, J = 2.4,2 Hz, 1 H), 7.29 (s, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.22(s, 2H), 4.13(q, J= 7.2 Hz, 2H), 3.53-3.41 (m, 1 H), 3.40-3.37(m, 1 H), 3.29-3.11 (m, 3H), 2.94(td, J= 9.2, Hz, 1 H), 2.71 (m, 1 H), 2.29-2.25(m, 1 H), 1.74-1.68(m, 1 H), 1.33(t, J=7.2, 6.8 Hz, 3H) Experimental protocol for Compound 63

Synthetic scheme

Step-1 : Synthesis of 4-chloro-2-ethoxy-5-fluorobenzaldehyde

Procedure

To a stirred solution of 4-chloro-5-fluoro-2-hydroxybenzaldehyde (0.5g, 2.86mmol) in DMF (5mL) at room temperature, K2CO3 (1.18g, 8.59mmol) was added. The reaction mixture was stirred at room temperature for 30 min. Then, bromoethane (0.62g, 5.72mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into cold water (10 mL) and extracted with Ethyl acetate (3 x 20 mL). The combined organic fractions were washed with ice cold water 3-4 times, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-5% EtOAc/Hexane) to provide 4-chloro-2-ethoxy-5-fluorobenzaldehyde (0.5g, 86.15% yield) as a white solid.

LCMS [ESI, M-29]: 174.8 (RT: 2.087 min, Purity: 100.0%),

¹ H-NMR (400 MHz, CDCI3) : 6 10.41 (s, 1 H), 7.61 (d, J = 8.8 Hz, 1 H), 7.04 (d, J = 5.6 Hz, 1 H), 4.17-4.12 (q, J = 7.0 Hz, 2H), 1.51 (t, J = 7.0 Hz, 3H). Step-2: Synthesis of tert-butyl 4-(((4-chloro-2-ethoxy-5-fluorobenzyl)amino)methyl)piperidin e -1 -carboxylate

Procedure

To a stirred solution of 4-chloro-2-ethoxy-5-fluorobenzaldehyde (0.3g, 1.48mmol) in DCE (6mL) at room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.38g, 1.77mmol) and acetic acid (0.015mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Then, sodium triacetoxyborohydride (0.94g, 4.44mmol) was added portion-wise to the reaction mixture at 0 °C. The reaction mixture was allowed to stir at room temperature for 16h . The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (20mL) and washed with sat. NaHCCh solution (15mL) and water (25mL). The combined organic fractions were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 0-50% EtOAc/Hexane) to provide tert-butyl 4-(((4-chloro-2-ethoxy-5- fluorobenzyl)amino)methyl)piperidine-1 -carboxylate (0.35g, 58.96% yield) as a colorless oil.

LCMS [ESI, M+1]: 401.1 (RT: 1.620 min, Purity: 99.23%),

HPLC Purity: RT: 5.232 min, Purity: 100.0%

¹ H-NMR (400 MHz, CDCI3) : 6 7.13 (d, J = 9.2 Hz, 1 H), 6.86 (d, J = 6.0 Hz, 1 H), 4.16-4.10 (m, 2H), 4.06-4.01 (m, 2H), 3.80 (s, 2H), 3.38 (bs, 3H), 2.73-2.68 (m, 2H), 2.52 (d, J = 6.4 Hz, 2H), 1.74- 1 .67 (m, 2H), 1 .46 (s, 9H), 1 .44-1 .40 (m, 3H).

Step-3: Synthesis of N-(4-chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4-yl)metha namine hydrochloride (Compound 63)

Procedure

To a stirred solution of tert-butyl 4-(((4-chloro-2-ethoxy-5-fluorobenzyl)amino)methyl) piperidine-1 - carboxylate (0.3g, 0.74mmol) in CH2CI2 (3.0mL) at 0°C, 4.0 M HCI in Dioxane (1.5mL, 5V) was added. The reaction mixture was then stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration using diethyl ether to provide W-(4-chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine hydrochloride (0.204g, 88.86 yield) as a white solid.

LCMS [ESI, M+1]: 300.9 (RT: 0.884 min, Purity: 100.0%),

HPLC Purity: RT: 3.912 min, Purity: 100.0%

¹ H-NMR (400 MHz, D2O): 6 7.21-7.14 (m, 2H), 4.16 (s, 2H), 4.09-4.04 (q, J = 6.8 Hz, 2H), 3.39 (d, J = 13.2 Hz, 2H), 2.99-2.90 (m, 4H), 2.07-2.05 (m, 1 H), 1.95 (d, J = 14.0 Hz, 2H), 1.47-1.40 (m, 2H), 1.37-1.29 (m, 3H). Experimental protocol for Compound 64

Synthetic scheme

Procedure

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.150g, 0.81 mmol) in DCE (3 mL, 20V) at room temperature, (1 -methylpiperidin-4-yl) methanamine (0.125g, 0.97mmol) and acetic acid (0.0075mL ,0.05V) were added. The reaction mixture was stirred at room temperature for 2h Sodium triacetoxyborohydride (0.516g, 2.437 mmol) was added to the reaction mixture in small portions wise at 0°C. The reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (10 mL) and extracted with

CH2CI2 (3 x 10 mL). The combined organic fractions were washed with water (5 mL), dried over

Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 10% MeOH in CH2CI2) to provide N-(5-chloro-2-ethoxybenzyl)-1 - ine (0.110g 45.61% yield) as a white liquid.

LCMS [ESI, M+1]: 296.8[M+1] (RT: 0.816 min, Purity: 100%)

HPLC Purity: RT: 3.566 min, Purity: 98.38%

¹ H-NMR (400 MHz, cfc-DMSO): 6 7.35 (d, J = 2.4 Hz, 1 H), 7.22-7.19 (dd, J = 2.8 Hz, 8.8 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 4.04-3.99 (m, 2H), 3.60 (s, 2H), 2.71 (d, J = 11 .6 Hz, 2H), 2.34 (d, J = 6.4 Hz, 2H), 2.13 (s, 3H), 1.80 (t, J = 6.8 Hz, 2H), 1.77(d, J = 2.4 Hz, 2H), 1.36(m, 4H), 1.24(m, 2H). thyl)-3,3- >-1 -carboxylate

Procedure:

To a stirred solution of 5-chloro-2-ethoxybenzaldehyde (0.500g, 2.70mmol) in DCE (10mL) at room temperature, tert-butyl 4-(aminomethyl)-3,3-difluoropiperidine-1 -carboxylate (0.813g, 3.24mmol) and Acetic acid (0.025mL, 0.05V) were added. The reaction mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (1.7g, 8.12mmol) was added portion-wise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was poured into a saturated solution of sodium bicarbonate (8 mL) and extracted with CH2CI2 (2 x 10 mL). The combined organic fractions were washed with water (5 mL), dried over Sodium Sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2; 70-75% ethyl acetate in hexane) to provide tertbutyl 4-(((5-chloro-2-ethoxybenzyl)amino)methyl)-3,3-difluoropiper idine-1 -carboxylate (1.0g, 88.14% yield) as a light yellow liquid.

LCMS [ESI, M+1]:419.0 (RT: 1.604 min, Purity: 100%),

¹ H NMR (400 MHz, cfc-DMSO): 6 7.35 (d, J = 2.5 Hz, 1 H), 7.20 (dd, J = 8.7, 2.6 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 1 H), 4.03 (q, J = 7.0 Hz, 2H), 3.91 (d, J = 9.7 Hz, 2H), 3.64 (d, J = 9.7 Hz, 2H), 3.32 (s, 2H), 2.88 (s, 1 H), 2.83 (dd, J = 8.7, 2.6 Hz, 2H), 2.40 (d, J = 6.4 Hz, 1 H), 2.18-2.11 (m, 1 H), 1.99 (d, J = 12.2 Hz, 1 H), 1.39 (s, 9H), 1.25 (t, J = 7.0 Hz, 3H). Step-2: Synthesis N-(5-chloro-2-ethoxybenzyl)-1 -(3,3-difluoropiperidin-4-yl)methanamine hydrochloride (Compound 65)

Procedure:

To a stirred solution of tert-butyl 4-(((5-chloro-2-ethoxybenzyl)amino)methyl)-3,3-difluoropiper idine- 1-carboxylate (1.0g, 2.39mmol) in CH2CI2 (10 mL) at 0°C, 4M HCI in Dioxane (5.0mL, 5V) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material was purified by trituration with Diethyl ether to provide N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4-yl)me thanamine hydrochloride (0.700g, 82.54% yield) as a white solid.

LCMS [ESI, M+1]: 318.6 (RT: 0.843 min, Purity: 99.86%),

HPLC: RT: 3.672 min, Purity: 100%,

¹ H NMR (400 MHz, CD3OD) : 6 7.51 (d, J = 2.4 Hz, 1 H), 7.46 (dd, J = 8.9, 2.5 Hz, 1 H), 7.13 (d, J = 8.9 Hz, 1 H), 4.33 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 3.94 - 3.80 (m, 1 H), 3.61 - 3.47 (m, 3H), 3.30 - 3.15 (m, 2H), 2.85 (s, 1 H), 2.36 (d, J = 14.7 Hz, 1 H), 1.87 (dd, J = 22.9, 12.0 Hz, 1 H), 1.49 (t, J = 7.0 Hz, 3H).

Experimental protocol for salt breaking

The salts of the compounds of the present invention are converted into the free base of the compounds of the present invention as follows.

10 V of MTBE and 7 V of water is added to 1 eq. of the hydrochloride salt of a compound of the present invention. The mixture is cooled to 8°C at a rate of 0.3°C/min. Aqueous ammonia (NH3-H2O, 25%) is added to adjust the pH of the solution to 9-10. The mixture is stirred at 8°C for 15min. The organic phase is separated, and the aqueous phase is extracted twice with 8V of MTBE. The organic phases are combined and dried over anhydrous sodium sulfate. The solids are filtered off and washed three times with 2V of MTBE. The combined organic phases are concentrated under vacuum at room temperature and subsequently the oil is vacuum dried at 40°C for 3h.

Abbreviations:

TLC Thin Layer Chromatography

LCMS Liquid chromatography-mass spectrometry

DMF Dimethylformamide

DMSO Dimethylsulfoxide

DCE Dichloroethane

DCM Dichloromethane

MTBE Methyl tert-butyl ether Table 1 : Compounds 1 to 67 of the present invention with chemical name

Biological assays and data

As stated above, the compounds of the present invention induce and/or stimulate autophagy and are useful in treating autophagy-related diseases. The biological activity of the compounds of the present invention can be determined by any appropriate test to determine the ability to induce and/or stimulate autophagy.

In addition, the compounds show good pharmacokinetic properties and thus are likely to be active in disease in humans. For example, after an oral dose of 30 mg/kg in CD1 mice Compound 1 has a half-life of 14 hours and an oral bioavailability of 42%. Under the same conditions, Compound 2 has a half-life of 7.6 hours and an oral bioavailability of 21%. Compound 40 has a half-life of 10 hours and an oral bioavailability of 33%, with a maximum concentration of 947 ng/ml in the brain after 24 hours indicating it is suitable for oral dosing in diseases of the central nervous system.

Assessment of stimulation of autophagy

Lysosomes play a fundamental role in the autophagic pathway by fusing with autophagosomes and creating ‘autolysosomes’ in order to digest their contents. Stimulation of lysosome and autolysosome formation by a compound is indicative of a stimulation of autophagy. The ability of compounds to stimulate lysosome and autolysosome formation, and thus autophagy, in live cells was assessed via fluorescent microscopy using various fluorescent stains for labelling and tracking acidic organelles (including lysosomes and autolysosomes) such as: LysoViewTM 650 (70059 and 70059-T, Biotium), LysoViewTM633 (70058 and 70058-T, Biotium) and LysoTracker™ Deep Red (L12492, ThermoFisher Scientific). The cellular phenotype was quantitatively assessed for the induction of acidic vesicle formation and compared to a non-treated control, thus providing a measure of the ability of the compound under investigation to stimulate autophagy.

Representative procedure using LysoViewTM633 dye or LvsoT racker™ Deep Red dye: Human osteosarcoma U2OS cells (40,000 cells/well) were seeded in a 24 well glass bottom plate (Sensoplate, Greiner Bio-One) and were incubated overnight in a humidified atmosphere at 37°C and 5% CO2. Cells were grown in DMEM (Gibco) supplemented with 10% Fetal Bovine Serum (FBS) and 100 units/ml penicillin and 100 pg/ml streptomycin (Invitrogen). After the attachment period, cells were treated with different compounds of interest (at various concentrations in DMSO) or DMSO (non-treated control) in cell culture medium and were incubated for 24 hours. Compoundcontaining medium was removed and cells were incubated with pre-warmed cell culture medium containing 1x LysoViewTM 633 (70058 and 70058-T, Biotium) or 50 nM LysoTracker™ Deep Red (L12492, ThermoFisherScientific) for 45 minutes at 37°C. Finally, cell nuclei were stained for 10 minutes using Hoechst 33342 (1 ug/mL) and then the medium was replaced with fresh. The 24 well plate was then fitted into a heated stage on the microscope and cells maintained at 37°C. Images were captured using appropriate filter set for Cy5 and DAPI detection with the EVOS M7000 Microscope (ThermoFisher Scientific). The cellular phenotype was visually assessed for the induction of acidic vesicle formation relative to the non-treated control; multiple images were acquired and analysed using Imaged or Cell Profiler.

Compounds 1-67 showed increased acidic vesicle formation in human osteosarcoma U2OS cells relative to a DMSO-treated control (non-treated control) of at least 25% at a concentration of 10 |j.M. This is evidence for significant stimulation of autophagy by these compounds under these conditions.

Selected compounds of this invention were also found to show increased acidic vesicle formation in human osteosarcoma U2OS cells relative to a DMSO-treated control (non-treated control) at a concentration of 0.8 |j.M. This is evidence for significant stimulation of autophagy by these compounds under these conditions. Table 2 shows this data for selected compounds. Compounds having an activity designated as “+” provided a percentage increase in acidic vesicle formation of between 10% and 30% over the DMSO-treated control. Compounds having an activity designated as “++” provided a percentage increase in acidic vesicle formation of between 30% and 50% over the DMSO-treated control. Compounds having an activity designated as “+++” provided a percentage increase in acidic vesicle formation of between 50% and 100% over the DMSO-treated control. Compounds having an activity designated as “++++” provided a percentage increase in acidic vesicle of greater than 100% over the DMSO-treated control

Table 2

Certain of compounds of this invention also showed increased acidic vesicle formation in other cell types, relative to a DM SO-treated control (non-treated control). For example, compounds 1 , 66 and 67 showed significantly greater (>25%) acidic vesicle formation in adult human dermal fibroblast cells (HDFa cells) relative to a DMSO-treated control at a concentration of 10 JJ.M. This is evidence for significant stimulation of autophagy by these compounds under these conditions.

Based on these results this is evidence that these compounds induce autophagy. Evidence that this activity will be therapeutic in various autophagy-related diseases are disclosed in the following examples.

Assessment of activity in models of various diseases and conditions

Demonstration of activity in an induced pluripotent stem cell (iPSC) model of Glycogen Storage Disease type 1A (GSD1A) derived from human patient cells.

Compounds 1 and 66 were selected as example compounds of this invention to evaluate in this model.

Timetable for treatment of cells with the compounds:

Day 1. Differentiated hepatocyte GSD1A disease model cells (DefiniGEN Ltd) were cultured in a collagen I coated 48-well plate. Empty wells were filled with PBS.

Day 9. Compound 1 or Compound 66 (as solutions in DMSO) were added to the disease model cells.

Day 11. Media for disease model cells was replaced with fresh media with compounds. Day 12. Cells were washed once in PBS and once in HBSS and 30 pl of NP40 Lysis buffer supplied with Phosphatase and Protease inhibitor cocktail was added to each well. Plate was immediately placed on dry ice.

Lysate preparation: Cell lysates were thawed and 30 pl of RIPA buffer supplied with Phosphatase and Protease inhibitor cocktail was added to each.

Protein quantification: An aliquot of the lysates was used for protein quantification using BCA.

Glycogen quantification: An aliquot of the lysates was boiled at 96 °C for 5 minutes. Boiled lysates were then centrifuged at 1000 xg for 5 minutes to remove precipitates. Supernatant was used for Glycogen quantification using MAK016 kit (Merck), following manufacturer’s instructions. Briefly, in 2 aliquots 2 pl of each supernatant was transferred to a half-area 96-well plate. 8 pl of Hydrolysis buffer from the kit was added to one aliquot from each sample (-HE; to quantify free glucose content of the lysate). The other sample was supplied with 8 pl of Hydrolysis buffer supplied with Hydrolysis Enzyme (+HE; to quantify free glucose + glycogen content of the lysate). After 30 minutes of incubation at room temperature, 10 pl of probe mix was added to each well and the absorbance at 570 nm was measured after 30 minutes incubation at room temperature. A570 readings were first adjusted based on the blank readings. Glycogen content of the cells was estimated by subtracting -HE readings from +HE readings, and the values were normalised to DMSO only control. Note that the quantification experiment was performed twice.

Triglyceride quantification: Boiled supernatants from the previous experiment were also used for Triglyceride quantification using MAK266 kit (Merck), following manufacturer’s instructions. Briefly, 2 pl of each supernatant was transferred to a half-area 96-well plate. 8 pl of Lipase reaction mix from the kit was added each sample. After 20 minutes of incubation at room temperature, 10 pl of probe mix was added to each well and the absorbance at 570 nm was measured after 30 minutes incubation at room temperature. A570 readings were first adjusted based on the blank readings and the values were normalised to DMSO only control. Note that the quantification experiment was performed twice.

Results: Compound 1 at a concentration of 2 micromolar successfully reduced cellular glycogen and triglycerides in hepatocytes differentiated from GSD1A patient derived iPSCs (by over 25% and 40%, respectively) when compared with the DMSO-only control. Compound 66, at a concentration of 10 micromolar successfully reduced cellular glycogen and triglycerides in hepatocytes differentiated from GSD1 A patient derived iPSCs (by over 45% and 50%, respectively) when compared with the DMSO-only control.

Conclusion-. The demonstrated breakdown of glycogen in patient-derived differentiated hepatocytes strongly supports efficacy for these compounds in the treatment of GSD1A. The breakdown of glycogen is a specific type of autophagy known as glycophagy.

Demonstration of activity in a cellular model of nonalcoholic fatty liver disease cells Compounds 1 , 66 and 67 were selected as example compounds of this invention to evaluate in this model.

Method: HepG2 cells were transfected with GFP-PNPLA3 (1148>M) overexpression plasmid using Lipofectamine LTX in DMEM media supplied with 1% Oleic Acid-BSA and were left overnight. The following day, cells were trypsinated and were seeded in a 96-well plate in DMEM media supplied with 1% Oleic Acid-BSA. After 7 hours, media was changed to standard DMEM supplied with compounds of interest (Compound 1 or Compound 66 or Compound 67). After 24 hours, cells were washed once with PBS and were lysed in RIPA buffer. Lysates were collected, centrifuged and the supernatants were mixed with Laemmli buffer (without DTT or boiling) and were loaded on a 4-20% SDS-PAGE gel. After electrophoresis, gels were directly imaged in the FITC channel to visualise the GFP signal.

Results:

The following compounds at a concentration of 10 JJ.M showed an increase in GFP breakdown of Bafilomycin-sensitive-product signal versus an inactive control demonstrating that these compounds are responsible for lysosomal breakdown of mutated PNPLA3 in this model:

The I148>M mutated form of PNPLA3 is associated with increased risk of Non-Alcohol Fatty Liver Disease [NAFLD], Therefore, this model functions as an in vitro model of NAFLD, and it is an example of conditions and diseases relating to degradation of misfolded proteins. Activity in this model is also further evidence that compounds of this invention are active versus various diseases involving misfolded proteins.

Demonstration of activity in a cellular model of Parkinson’s disease (PD)

Compounds 1 and 33 and 66 were selected as example compounds of this invention to evaluate in this model. This model (run by Neuro-Sys SAS, France) is based on a primary culture of dopaminergic Tyrosine hydroxylase (TH)-positive neurons injured with the dopaminergic neurons-specific toxin (DA-toxin) 1-methyl-4-phenyl-1 ,2,3,6 tetrahydropyridine (MPTP) (Dauer and Przedborski, 2003). Any substances reducing DA-toxin neurotoxicity may be useful as a new therapeutic agent for the treatment or prevention of PD.

Methods

Primary culture of mesencephalic neurons: Rat dopaminergic neurons were cultured as described by Visanji et al., 2008 and Callizot et al., 2019. Briefly, pregnant female rat (Wistar) of 15 days of gestation were killed using a deep anesthesia with CO2 chamber and a cervical dislocation. The midbrains obtained from 15-day-old rat embryos (Janvier, France) were dissected under a microscope. The embryonic midbrains will be removed and placed in ice-cold medium of Leibovitz (L15) containing 2% of Penicillin-Streptomycin (PS) and 1% of bovine serum albumin (BSA). The ventral portion of the mesencephalic flexure, a region of the developing brain rich in dopaminergic neurons, was used for the cell preparations.

The midbrains were dissociated by trypsin isation for 20 min at 37°C (solution at a final concentration of 0.05% trypsin and 0.02% EDTA). The reaction was stopped by the addition of Dulbecco’s modified Eagle’s medium (DMEM) containing DNAase I grade II (0.5 mg/mL) and 10% of foetal calf serum (FCS). Cells were then mechanically dissociated by 3 passages through a 10 ml pipette. Cells were then centrifuged at 180 x g for 10 min at +4°C on a layer of BSA (3.5%) in L15 medium. The supernatant was discarded and the cell pellets re-suspended in a defined culture medium consisting of Neurobasal supplemented with B27 (2%), L-glutamine (2 mM) and 2% of PS solution and 10 ng/mL of Brain-derived neurotrophic factor (BDNF) and 1 ng/mL of Glial-Derived Neurotrophic Factor (GDNF). Viable cells were counted in a Neubauer cytometer using the trypan blue exclusion test. The cells were seeded at a density of 40, 000 cells/well in 96 well-plates (precoated with poly-L- lysine) and maintained in a humidified incubator at 37°C in 5% CO2/95% air atmosphere. Half of the medium was changed every 2 days with fresh medium. The wells of first and last lines and columns were used (to avoid any edge effect) and were be filled with sterile water.

Test compounds and MPP+ :

(i) Pre-incubation. On day 6 of culture, the test compounds were dissolved in PBS or DMSO and incubated for 1 hour before the MPP+ exposure.

(ii) Injury. One hour after the application of test compound, MPP+ was added to a final concentration of 4pM, diluted in control medium still in presence of compounds/inhibitors for 48h.

Test compounds were tested on one culture in 96-well plate (n = 6 culture wells per condition) End point evaluation:

Immunostaining: TH and a-Synuclein. 48 Hours after intoxication, the cell culture supernatant was removed, and the cells were fixed by a solution of 4% paraformaldehyde in PBS, pH =7.3 for 20 min at room temperature. The cells were washed twice in PBS, and then permeabilized. Nonspecific sites were blocked with a solution of PBS containing 0.1% of saponin and 1% FCS for 15 min at room temperature. The cultures were incubated with: (a) monoclonal anti-Tyrosine Hydroxylase (TH) antibody produced in mouse at dilution of 1/10000 in PBS containing 1 % FCS, 0.1 % saponin, for 2 hours at room temperature, and (b) polyclonal anti-alpha synuclein (a- synuclein) antibody produced in rabbit at dilution of 1/200 in PBS containing 1% FCS, 0.1 % saponin, for 2 h at room temperature. These antibodies were revealed with Alexa Fluor 488 goat anti-mouse IgG at the dilution 1/800 and with Alexa Fluor 568 goat anti-rabbit IgG at the dilution 1/400 in PBS containing 1% FCS, 0.1 % saponin, for 1 h at room temperature.

Automatic computer analysis. For each condition, 20 pictures (representing the whole well area) were automatically taken using ImageXpress® (Molecular Devices) at 10x magnification (20 pictures, for TH and a-synuclein into TH neurons) using the same acquisition parameters. From images, analyses was directly and automatically performed by MetaXpress® (Molecular Devices).

The following read-outs were measured:

(i) Analysis of total number of TH neurons (TH positive neurons)

(ii) Total neurite network of TH positive neurons (in pm)

(iii) a-Synuclein aggregation (overlapping between TH and a-syn staining)

Compounds 1 and 33 displayed neuroprotective effects in this in vitro model of PD based on MPP+ injury.

Compound 33 improved neuronal survival and protected the neurite network at a concentration of 10 pM. It also reduced a-Synuclein aggregation in dopaminergic neurons at all investigated concentrations (10 pM, 1 pM, 500 nM and 100 nM).

Compound 1 displayed significant and large protective effects at all concentrations (10 pM, 1 pM, 500 nM and 100 nM), on all readouts. Compound 1 was able to fully prevent the degeneration of TH neurons.

Compound 66 significantly reduced a-Synuclein aggregate accumulation at concentrations of 100 nM, 500 nM and 1 pM.

This model functions as an in vitro model of Parkinson’s disease. Activity in this model strongly supports that compounds of this invention are efficacious in the treatment of Parkinson’s disease and other autophagy-related neurodegenerative diseases or conditions. References:

Callizot N, Combes M, Henriques A, Poindron P. Necrosis, apoptosis, necroptosis, three modes of action of dopaminergic neuron neurotoxins. PLoS ONE 14(4): e0215277

Dauer W., Przedborski S. Parkinson's disease: mechanisms and models. Neuron 2003, 39(6):889- 909

Visanji NP, Orsi A, Johnston TH, Howson PA, Dixon K, Callizot N, Brotchie JM and Rees DD. PYM50028, a novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced by MPP+ in mesencephalic neurons and by MPTP in a mouse model of Parkinson's disease. FASEB J. 2008; 22(7):2488-97

Demonstration of activity in a cellular model of Alzheimer’s disease (AD)

Compound 1 was selected as an example compound of this invention to evaluate in a human induced pluripotent stem cell (iPSC)-derived neuronal model of monogenic Alzheimer’s disease (APPV717I mutants) run by Talisman Therapeutics Inc., United Kingdom.

Human cortical (excitatory) neurons used in this study were generated using proprietary methods (based on Shi et al., 2012, Nature Protocols7: 1836-46) from Amyloid Precursor Protein (APP) V717I iPSCs: Autosomal dominant causal mutation for familial Alzheimer’s Disease (fAD) -London mutation (Moore et al. ,2015, Cell Reportsl 1 :689-96; Hung & Livesey, 2018, Cell Reports25:3647- 60).

Compound were assessed for one or more of the following:

1. Toxicity in neuronal iPSC-derived neuronal cultures

Compounds were assessed for potential cytotoxicity on neuronal iPSC-derived neuronal cultures by: (a) density of cultures by phase contrast imaging, and (b) extracellular LDH release

2. Autophagy modulation

Compounds were assessed for their ability to modulate autophagy in human APPV717I iPSC- derived neuronal cultures by quantitative immunoblotting of LC3 protein.

3. Correction of endosome and lysosome defects in human APPV717I neurons APPV717I neurons have defects in early endosomes, lysosomes and autophagy (Hung & Livesey, 2018, Cell Reports25:3647-60). Prioritized compounds were assessed for their efficacy in correcting endosome and lysosome defects in human AD (APPV717I) neurons by high-content imaging of endosome and lysosome size and number, and quantitative immunoblotting of key early endosome and lysosome resident proteins. Human APPV717I neurons have significantly increased size and number of early endosomes and late endosomes/lysosomes compared with non-disease control neurons. An intervention that is able to successfully reverse endolysosomal dysfunction in APPV717I neurons should exhibit a reduced total endosome/lysosome mass in these neurons.

Results:

Compound 1 at a concentration of 10 JJ.M showed no significant cytotoxic effects on iPSC- derived neuronal cultures over a 24 hour period.

Compound 1 at a concentration of 10 |j.M significantly modulated autophagy in neuronal cultures over a 24 hour period compared with vehicle-treated cultures, consistent with induction of autophagy, based on an increased LC3-II/LC3-I ratio.

Acute (24 hour) treatment of monogenic AD neurons with Compound 1 at a concentration of 10 |j.M:(a) reversed the increase in endolysosomal number in human APPV717I neurons, based on high-content confocal imaging of early endosome and lysosome size and number, (b) reduced the levels of the key early endosome resident protein Rab5a in human APPV717I neuronal cultures, based on immunoblotting analysis, and (c) reduced levels of neurodegeneration-related protein, a-synuclein, in human APPV717I neuronal cultures, based on immunoblotting analysis.

Collectively, these data show that with acute treatment, Compound 1 is able to modulate autophagy in human APPV717I neurons to promote a general clearance of endolysosomal vesicles in these AD neurons, consistent with rescue of the disease-relevant phenotype. That is acute (24 hour) administration of Compound 1 reversed the pathological accumulation of late endosomes and lysosomes in monogenic AD neurons, indicating that autophagy modulation is potentially an effective therapeutic strategy in AD.

This model functions as an in vitro model of Alzheimer’s disease. Activity in this model strongly supports that compounds of this invention are efficacious in the treatment of Alzheimer’s disease and other autophagy-related neurodegenerative diseases or conditions.

Methods:

Cell culture and treatments

Neuronal cultures Neuronal induction: Projection neuronal (PN) differentiation of human pluripotent stem cells was carried out as described by Shi et al. (2012), with minor modifications.

Maintenance of neuronal cultures: Neurons were final plated at d35 on Matrigel-coated 12-well plates (STARLAB) for lysate collection and 96-well imaging plates (PerkinElmer) for confocal imaging. Neurons were maintained at 37°C, 5% CO2 in N2B27 neural maintenance medium.

Treatment of neuronal cultures

Compound addition: A complete media change was performed on d60 neuronal cultures. 24h later, cultures were treated with compounds, diluted in N2B27, for a period of 24h (10 micromolar test compounds, 20 micromolar for 4-(2-chlorophenoxazin-10-yl)-/V,/V-diethylbutan-1 -amine hydrochloride (10-NCP) and 2-[(3chlorophenyl)hydrazinylidene]propanedinitrile (the mitochondrial respiratory chain uncoupler, CCCP), 200 nanomolar for Bafilomycin A1 , 0.1% DMSO final for all treatments). Three wells were treated per compound.

Phase contrast imaging: Neuronal cultures were imaged every four hours during the treatment period by phase contrast microscopy using an IncuCyte S3 live-cell imaging system to monitor cell health.

LDH cytotoxicity assay: Acute cytotoxic effects of treatments were assessed using the cyQUANT LDH Cytotoxicity Assay (Thermo), according to manufacturer’s protocol.

Western immunoblottina

Protein extraction: Neuronal cultures were lysed using RIPA buffer (Sigma) supplemented with protease inhibitors (complete Mini Protease Inhibitor Cocktail, Roche). Total protein concentration was determined using the Pierce BCA Protein Assay Kit (Thermo).

Western immunoblotting:20 pg total protein was loaded onto 4-15% Mini-PROTEAN TGX precast gels (Bio-Rad) and protein separation was performed at 60-120 V. Separated protein was transferred onto 0.2 pm PVDF membranes using the Trans-Blot Turbo Transfer System (Bio-Rad). Membranes were blocked in 5% dried skimmed milk (Marvel) in PBS/0.1% Tween for one hour at room temperature (RT).

Antibody incubation: Membranes were probed overnight at RT with relevant primary antibody (see antibody table), diluted in blocking solution. Membranes were subsequently incubated for two hours at RT with relevant HRP-conjugated secondary antibody (see antibody table), diluted in blocking solution.

Membrane visualisation: Protein detection was carried out using Clarity Western ECL Substrate (Bio-Rad) and visualised using a ChemiDoc Imaging System (Bio-Rad). Loading controls: Following protein detection, membranes were stripped using Restore PLUS Western Blot Stripping Buffer (Thermo), incubated in blocking solution for one hour at RT and reprobed with anti-p-actin mouse monoclonal primary antibody (Sigma), diluted 1 :1000 in blocking solution, followed by anti-mouse IgG-HRP-conjugated secondary antibody (Sigma), diluted 1 :2000 in blocking solution, p-actin protein was then visualised as described above.

Quantification: Protein quantification was performed by densitometry analysis of immunoblots using Image Lab software (Bio-Rad). All quantification data were normalised to p-actin data.

Confocal imaging

Fixing: Following cell treatments, cultures were fixed with 4% paraformaldehyde (PFA) at RT for 20 mins. The PFA was then removed and cultures were washed twice with PBS prior to labelling.

Fluorescent labelling of fixed cultures: Fixed cultures were permeabilised with 0.1% Triton X-100 in PBS for 1 h at RT and then blocked with 2% BSA in PBS for 2h at RT. Following blocking, cultures were incubated with relevant primary antibodies (see antibody table), diluted in blocking solution, overnight at 4°C. The following day, cultures were washed three times with PBS and then incubated with species-specific Alexa Fluor-conjugated secondary antibodies (see antibody table), diluted in blocking solution, at RT and protected from light for 2h. Following secondary antibody labelling, cultures were washed three times with PBS and stored in PBS at 4°C prior to imaging.

High-content confocal imaging: Fluorescently-labelled neuronal cultures were imaged using an Opera Phenix high-content imaging system (PerkinElmer). Images were acquired using a 63X objective in a single plane from three channels (568:LAMP1 or Rab5a, 647:MAP2, DAPknuclei). Three wells were imaged per compound treatment per endolysosomal marker (LAMP1 or Rab5a). 25 fields of view were imaged per well.

Image analysis: Acquired images were processed and analysed using a custom-written CellProfiler analysis pipeline. A MAP2-positive mask was applied to images so that only LAMP1-or Rab5a- positive vesicles within neurons were analysed. The total area of LAMP1-/Rab5a-positive puncta within neurons, normalised to MAP2 area, was calculated per field of view and the distribution of data were presented in violin plots. Data for mean puncta size within neurons and total puncta count within neurons, normalised to MAP2area, were also calculated. Each data point in violin plots represents an individual field of view, and statistical analysis was performed from n=3 wells per treatment. Antibodies

Primary antibodies

Secondary antibodies

In particular, the present invention relates to the following items. 1 . A compound according to formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof, wherein

R ¹ , R ² are independently of each other selected from H, halogen, OR ^C , Ci-C4-haloalkyl, C1-C4- alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; or

R ¹ and R ² together with the atoms to which they are attached form a 5- or 6-membered partially or fully unsaturated or aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ³ is H, halogen, OR ^C , Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or -O-Ci-C4-alkylene- OR ^C , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ;

R ^N is H or Ci-C ₄ -alkyl;

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-Ci-C2- alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ^N and R ⁶ together with the atoms to which they are attached form a 4- to 6-membered saturated or partially unsaturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^x is phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^Y is halogen, Ci-C ₄ -alkyl, NR ^a R ^b , or Ci-C ₄ -alkyl-NR ^a R ^b ;

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl;

R ^c is H, Ci-C4-alkyl, or phenyl; and m is 1 , 2 or 3.

2. The compound according to item 1 , wherein the compound is not

3. The compound according to item 1 or 2, wherein the compound according to formula (I) is present in the form of a salt, preferably in the form of a hydrochloride salt.

4. The compound according to any one of items 1 to 3, wherein

R ¹ , R ² are independently of each other selected from halogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x .

5. The compound according to any one of items 1 to 4, wherein

R ¹ is Ci-C4-alkoxy, Ci-C4-haloalkoxy or -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; and

R ² is halogen, Ci-C4-alkoxy, or Ci-C4-haloalkoxy;

R ^x is phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

6. The compound according to any one of items 1 to 5, wherein R ³ is H, or halogen; and m is 1 . 7. The compound according to any one of items 1 to 6, wherein R ⁴ , R ⁵ are H; and

R ⁶ is a 5- or 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

8. The compound according to any one of items 1 to 6, wherein R ⁴ is H; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 6- membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

9. The compound according to any one of items 1 to 8, wherein the compound according to formula (I) is selected from N-(5-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, /V-(5-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 2-(4- chloro-2-(((piperidin-4-ylmethyl)amino)methyl)phenoxy)ethan- 1 -ol hydrochloride, N-(5-chloro-2-(2- methoxyethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5-fluorobenzyl)- 1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, (S)-N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanami ne hydrochloride, (R)-N-(5-chloro-2-ethoxybenzyl)-1 -(pyrrolidin-3-yl)methanamine hydrochloride, (R)- N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-3-amine, N-(5-chloro-2-ethoxybenzyl)-1 - ethylpiperidin-4-amine, N ¹ -(5-chloro-2-ethoxybenzyl)ethane-1 ,2-diamine hydrochloride, (1r, 4r)-/V ¹ - (5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2- ethoxybenzyl)pentane-1 ,5-diamine, N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-4-amine, A/-(5- chloro-2-ethoxybenzyl)-2-(piperazin-1-yl)ethan-1 -amine hydrochloride, (R)-N-(5-chloro-2- ethoxybenzyl)pyrrolidin-3-amine hydrochloride, (1 r,3r)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclobutane- 1 ,3-diamine hydrochloride, (1 S,3S)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclopentane-1 ,3-diamine hydrochloride, (S)-N-(5-chloro-2-ethoxybenzyl)piperidin-3-amine hydrochloride, N-(5-chloro-2- ethoxybenzyl)azetidin-3-amine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan- 1 -amine hydrochloride, 2-(2-aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine hydrochloride, N ¹ -(5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2- ethoxybenzyl)-2-methylpropane-1 ,2-diamine hydrochloride, N-(4-chloro-2-ethoxybenzyl)-1 - (piperidin-4-yl)methanamine hydrochloride, N-(4,5-dichloro-2-ethoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(2-chloro-6-ethoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(3-chloro-4-ethoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2- ethoxy-5-methoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (trifluoromethyl) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, 3-(4-chloro-2- (((piperidin-4-ylmethyl)amino)methyl)phenoxy)propan-1-ol hydrochloride, N-(5-chloro-2-(3- methoxypropoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 1 -(6- chlorobenzo[d][1 ,3]dioxol-4-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, 1-(7-chloro- 2,3-dihydrobenzo[b][1 ,4]dioxin-5-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, N-(2- ethoxy-5-(trifluoromethoxy)benzyl)-1 -methylpiperidin-4-amine, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-methylpiperidin-4-amine, N ¹ -(2-ethoxy-5-(trifluoromethoxy)benzyl) cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine hydrochloride, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (1 r, 4r)-N ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, (1 s, 4s)-/V ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, N-(5-chloro-2-(2- methoxyethoxy)benzyl)-1-methylpiperidin-4-amine, N-(2-ethoxy-5-fluorobenzyl)-1-methylpiperidin- 4-amine, N-(5-chloro-2-propoxybenzyl)-1 -methylpiperidin-4-amine, N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1-methylpiperidin-4-amine, N-(5-fluoro-2-propoxybenzyl)-1-(piperidin- 4-yl) methanamine hydrochloride, N-(4-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(4-chloro-2-(2-methoxyethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-5-fluorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-4-fluorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, A/-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl ) methanamine hydrochloride, (SJ-N-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin- 3-yl)methanamine hydrochloride, N-(5-chloro-2-phenoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5- chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (R)-N-(5- chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin-3-yl)meth anamine hydrochloride, A/-(4-fluoro-2- propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(2-(cyclopropylmethoxy)-4,5- difluorobenzyl)-1 -(pi pe rid i n-4-y I) methanamine hydrochloride, (R)-N-(5-chloro-2-propoxybenzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, (R)-N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1-

(pyrrolidin-3-yl)methanamine hydrochloride, N-(4-chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-1-(1-methylpiperidin-4- yl)methanamine, N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4-yl)me thanamine hydrochloride, N-(2-(benzyloxy)-5-chlorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, and N-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1-(piperidin-4-yl )methanamine hydrochloride.

10. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of items 1 to 9 and optionally a pharmaceutically acceptable carrier, diluent or excipient.

11. A compound according to any one of items 1 to 9, or a pharmaceutical composition according to item 10 for use in medicine.

12. A compound according to any one of items 1 to 9, or a pharmaceutical composition according to item 10 for use in the treatment of an autophagy-related disease or condition.

13. The compound or the pharmaceutical composition for use according to item 12, wherein said autophagy-related disease or condition is selected from the group consisting of neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, systemic lupus erythematosus, epilepsy, cancer, liver diseases, a1 antitrypsin deficiency, Charcot Marie Tooth syndrome, Rett Syndrome, Sickle Cell disease, Wilson Disease, amyloidosis, Gaucher’s disease, lysosomal and glycogen storage disorders, cystic fibrosis; viral infection and diseases, human cytomegalovirus (HCMV) infection, hepatitis B, human immunodeficiency virus infection, Zika virus infection, coronavirus infection, HCoV-229E, HCoV-NL63, betacoronavirus infection, such as HCoV-OC43, SARS-CoV-1 , HCoV-HKU1 , MERS-CoV or SARS-CoV-2, bacterial infections, metabolic disorders, diabetes, fibrosis, silicosis, diabetic retinopathy, glaucoma, cataracts, age-related macular degeneration, glomerulonephritis, glomerulosclerosis, wound healing disorders, Niemann-Pick type C (NPC) disease, fibrinogen storage disease (FSB), inclusion body disease (IBD), muscular dystrophy, Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, myopathy, myofibrillar myopathy, hereditary myopathy, diabetic cardiomyopathy, anti-inflammatory disorders, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, irritable bowel syndrome, Crohn’s disease, vascular disorders, stroke, coronary artery diseases, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, Behcet’s syndrome, giant cell arteritis, polymyalgia rheumatic, Wegener’s granulomatosis, Churg-Strauss syndrome, vasculitis, Henoch-Schonlein pruprua, Kawasaki disease, viral infection or replication, pox virus infection, herpes virus infection, asthma, allergic rhinitis, COPD, osteoporosis, organ transplant rejection, psoriasis, hypertrophic scarring (keloid formation), adhesion formations following general or gynecological surgery, lung fibrosis, liver fibrosis, kidney fibrosis, disorders caused by intracellular parasites, malaria, tuberculosis, neuropathic pain, post-operative phantom limb pain or postherpetic neuralgia, allergies, amyotrophic lateral sclerosis (ALS), antigen induced recall response, immune response suppression, muscle degeneration and atrophy, frailty in aging, spinal cord injury, and diseases and conditions involving misfolded and/or nonfolded proteins.

14. The compound or the pharmaceutical composition for use according to item 12 or 13, wherein said treatment comprises a combination of at least one compound according to any one of items 1 to 9 with at least one additional pharmaceutically active substance for said autophagy- related disease or condition. 15. Use of a compound according to any one of items 1 to 9 for stimulating autophagy in an in- vitro assay.

In addition, the present invention relates to the following embodiments.

1 . A compound according to formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof, wherein

R ¹ , R ² are independently of each other selected from H, CN, halogen, OR ^C , Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; or

R ¹ and R ² together with the atoms to which they are attached form a 5- or 6-membered partially or fully unsaturated or aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ³ is H, CN, halogen, OR ^C , Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or -O- Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ;

R ^N is H or Ci-C ₄ -alkyl;

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, heterocyclyl, or heterocyclyl-Ci-C2- alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ^N and R ⁶ together with the atoms to which they are attached form a 4- to 6-membered saturated or partially unsaturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^x is Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ;

R ^Y is halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, NR ^a R ^b , Ci-C4-alkyl-NR ^a R ^b , or two R ^Y form cyclopropyl;

R ^a , R ^b are independently of each other selected from H, and Ci-C4-alkyl;

R ^c is H, Ci-C4-alkyl, or phenyl; and m is 1 , 2 or 3.

2. The compound according to embodiment 1 , wherein the compound is not

3. The compound according to embodiment 1 or 2, wherein the compound is not

4. The compound according to any one of embodiments 1 to 3, wherein the compound according to formula (I) is present in the form of a salt, preferably in the form of a hydrochloride salt.

5. The compound according to any one of embodiments 1 to 4, wherein

R ¹ , R ² are independently of each other selected from halogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x .

6. The compound according to any one of embodiments 1 to 5, wherein

R ¹ is Ci-C4-alkoxy, Ci-C4-haloalkoxy or -O-Ci-C4-alkylene-OR ^c , wherein each substitutable carbon atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^x ; and

R ² is halogen, Ci-C4-alkoxy, or Ci-C4-haloalkoxy;

R ^x is phenyl, or a 3- to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y . 7. The compound according to any one of embodiments 1 to 6, wherein

R ³ is H, or halogen; and m is 1 .

8. The compound according to any one of embodiments 1 to 7, wherein

R ⁴ , R ⁵ are H; and

R ⁶ is a 5- or 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

9. The compound according to any one of embodiments 1 to 7, wherein

R ⁴ is H; and

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 6- membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N and S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

10. The compound according to any one of embodiments 1 to 7, wherein

R ⁴ , R ⁵ are independently of each other selected from H, and Ci-C4-alkyl;

R ⁶ is Ci-C4-alkyl, -CH2-O-Ci-C2-alkylene-NR ^a R ^b , -Ci-Ce-alkyl-NR ^a R ^b , or a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; preferably R ⁶ is a 5- or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y ; or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a 4- to 6- membered saturated, or partially unsaturated carbocyclyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R ^Y .

11. The compound according to any one of embodiments 1 to 10, wherein the compound according to formula (I) is selected from N-(5-chloro-2-ethoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, /V-(5-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 2-(4- chloro-2-(((piperidin-4-ylmethyl)amino)methyl)phenoxy)ethan- 1-ol hydrochloride, N-(5-chloro-2-(2- methoxyethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5-fluorobenzyl)- 1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2-isopropoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, (S)-N-(5-chloro-2-ethoxybenzyl)-1-(pyrrolidin-3-yl)methanami ne hydrochloride, (R)-N-(5-chloro-2-ethoxybenzyl)-1 -(pyrrolidin-3-yl)methanamine hydrochloride, (R)- N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-3-amine, N-(5-chloro-2-ethoxybenzyl)-1 - ethylpiperidin-4-amine, N ¹ -(5-chloro-2-ethoxybenzyl)ethane-1 ,2-diamine hydrochloride, (1r, 4r)-A/ ¹ - (5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2- ethoxybenzyl)pentane-1 ,5-diamine, N-(5-chloro-2-ethoxybenzyl)-1 -methylpiperidin-4-amine, A/-(5- chloro-2-ethoxybenzyl)-2-(piperazin-1-yl)ethan-1 -amine hydrochloride, (R)-N-(5-chloro-2- ethoxybenzyl)pyrrolidin-3-amine hydrochloride, (1 r,3r)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclobutane-

1 .3-diamine hydrochloride, (1 S,3S)-N ¹ -(5-chloro-2-ethoxybenzyl)cyclopentane-1 ,3-diamine hydrochloride, (S)-N-(5-chloro-2-ethoxybenzyl)piperidin-3-amine hydrochloride, N-(5-chloro-2- ethoxybenzyl)azetidin-3-amine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-2-(piperidin-1-yl)ethan- 1 -amine hydrochloride, 2-(2-aminoethoxy)-N-(5-chloro-2-ethoxybenzyl)ethan-1 -amine hydrochloride, N ¹ -(5-chloro-2-ethoxybenzyl)cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(5-chloro-2- ethoxybenzyl)-2-methylpropane-1 ,2-diamine hydrochloride, N-(4-chloro-2-ethoxybenzyl)-1 - (piperidin-4-yl)methanamine hydrochloride, N-(4,5-dichloro-2-ethoxybenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(2-chloro-6-ethoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(3-chloro-4-ethoxybenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2- ethoxy-5-methoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(2-ethoxy-5- (trifluoromethyl) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2- (trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, 3-(4-chloro-2- (((piperidin-4-ylmethyl)amino)methyl)phenoxy)propan-1-ol hydrochloride, N-(5-chloro-2-(3- methoxypropoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, 1 -(6- chlorobenzo[d][1 ,3]dioxol-4-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, 1-(7-chloro-

2.3-dihydrobenzo[b][1 ,4]dioxin-5-yl)-N-(piperidin-4-ylmethyl) methanamine hydrochloride, N-(2- ethoxy-5-(trifluoromethoxy)benzyl)-1 -methylpiperidin-4-amine, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-methylpiperidin-4-amine, N ¹ -(2-ethoxy-5-(trifluoromethoxy)benzyl) cyclohexane-1 ,4-diamine hydrochloride, N ¹ -(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)cyclohexane-1 ,4-diamine hydrochloride, N-(2-(2-methoxyethoxy)-5-

(trifluoromethoxy)benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (1 r, 4r)-N ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, (1s, 4s)-/V ¹ -(5-chloro-2-(2- methoxyethoxy)benzyl)cyclohexane-1 ,4-di amine hydrochloride, N-(5-chloro-2-(2- methoxyethoxy)benzyl)-1-methylpiperidin-4-amine, N-(2-ethoxy-5-fluorobenzyl)-1-methylpiperidin- 4-amine, N-(5-chloro-2-propoxybenzyl)-1 -methylpiperidin-4-amine, N-(5-chloro-2- (cyclopropylmethoxy)benzyl)-1-methylpiperidin-4-amine, N-(5-fluoro-2-propoxybenzyl)-1-(piperidin- 4-yl) methanamine hydrochloride, N-(4-chloro-2-propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(4-chloro-2-(2-methoxyethoxy)benzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-5-fluorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, N-(2-(cyclopropylmethoxy)-4-fluorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, A/-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(piperidin-4-yl ) methanamine hydrochloride, S)-N-(4-chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin-3 -yl)methanamine hydrochloride, N-(5-chloro-2-phenoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, N-(5- chloro-2-(pyrimidin-2-ylmethoxy) benzyl)-1-(piperidin-4-yl)methanamine hydrochloride, (R)-N-(5- chloro-2-(cyclopropylmethoxy)benzyl)-1-(pyrrolidin-3-yl)meth anamine hydrochloride, A/-(4-fluoro-2- propoxybenzyl)-1-(piperidin-4-yl)methanamine hydrochloride, A/-(2-(cyclopropylmethoxy)-4,5- difluorobenzyl)-1 -(pi pe rid i n-4-y I) methanamine hydrochloride, (R)-N-(5-chloro-2-propoxybenzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, (R)-N-(2-ethoxy-5-(trifluoromethoxy)benzyl)-1 - (pyrrolidin-3-yl)methanamine hydrochloride, N-(4-chloro-2-ethoxy-5-fluorobenzyl)-1-(piperidin-4- yl)methanamine hydrochloride, N-(5-chloro-2-ethoxybenzyl)-1-(1-methylpiperidin-4- yl)methanamine, N-(5-chloro-2-ethoxybenzyl)-1-(3,3-difluoropiperidin-4-yl)me thanamine hydrochloride, N-(2-(benzyloxy)-5-chlorobenzyl)-1 -(piperidin-4-yl)methanamine hydrochloride, and N-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1-(piperidin-4-yl )methanamine hydrochloride.

12. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of embodiments 1 to 1 1 and optionally a pharmaceutically acceptable carrier, diluent or excipient.

13. A compound according to any one of embodiments 1 to 11 , or a pharmaceutical composition according to embodiment 12 for use in medicine.

14. A compound according to any one of embodiments 1 to 11 , or a pharmaceutical composition according to embodiment 12 for use in the treatment of an autophagy-related disease or condition.

15. The compound or the pharmaceutical composition for use according to embodiment 14, wherein said autophagy-related disease or condition is selected from the group consisting of neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, systemic lupus erythematosus, epilepsy, cancer, liver diseases (e.g. nonalcoholic fatty liver disease (NAFLD)), a1 antitrypsin deficiency, Charcot Marie Tooth syndrome, Rett Syndrome, Sickle Cell disease, Wilson Disease, amyloidosis, Gaucher’s disease, lysosomal and glycogen storage disorders (e.g., Glycogen Storage Disease type 1A (GSD1A)), cystic fibrosis; viral infection and diseases, human cytomegalovirus (HCMV) infection, hepatitis B, human immunodeficiency virus infection, Zika virus infection, coronavirus infection, HCoV-229E, HCoV-NL63, betacoronavirus infection, such as HCoV-OC43, SARS-CoV-1 , HCoV-HKU1 , MERS-CoV or SARS-CoV-2, bacterial infections, metabolic disorders, diabetes, fibrosis, silicosis, diabetic retinopathy, glaucoma, cataracts, age-related macular degeneration, glomerulonephritis, glomerulosclerosis, wound healing disorders, Niemann-Pick type C (NPC) disease, fibrinogen storage disease (FSB), inclusion body disease (IBD), muscular dystrophy, Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, myopathy, myofibrillar myopathy, hereditary myopathy, diabetic cardiomyopathy, anti-inflammatory disorders, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, irritable bowel syndrome, Crohn’s disease, vascular disorders, stroke, coronary artery diseases, myocardial infarction, unstable angina pectoris, atherosclerosis or vasculitis, Behcet’s syndrome, giant cell arteritis, polymyalgia rheumatic, Wegener’s granulomatosis, Churg-Strauss syndrome, vasculitis, Henoch-Schonlein pruprua, Kawasaki disease, viral infection or replication, pox virus infection, herpes virus infection, asthma, allergic rhinitis, COPD, osteoporosis, organ transplant rejection, psoriasis, hypertrophic scarring (keloid formation), adhesion formations following general or gynecological surgery, lung fibrosis, liver fibrosis, kidney fibrosis, disorders caused by intracellular parasites, malaria, tuberculosis, neuropathic pain, post-operative phantom limb pain or postherpetic neuralgia, allergies, amyotrophic lateral sclerosis (ALS), antigen induced recall response, immune response suppression, muscle degeneration and atrophy, frailty in aging, spinal cord injury, and diseases and conditions involving misfolded and/or nonfolded proteins.

16. The compound or the pharmaceutical composition for use according to embodiment 14 or 15, wherein said treatment comprises a combination of at least one compound according to any one of embodiments 1 to 11 with at least one additional pharmaceutically active substance for said autophagy-related disease or condition.

17. Use of a compound according to any one of embodiments 1 to 11 for stimulating autophagy in an in-vitro assay.