Modulators of intracellular chloride concentration

Abstract

The present invention relates to compounds of formula (I), to its use for the prevention or treatment of a disorder associated with depolarising GABAergic transmission, and to a pharmaceutical composition thereof.

Description

[0001] MODULATORS OF INTRACELLULAR CHLORIDE CONCENTRATION

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This Patent Application claims priority from Italian Patent Application No. 102024000000099 filed on January 4, 2024, the entire disclosure of which is incorporated herein by reference.

[0004] TECHNICAL FIELD

[0005] The present invention relates to new quinoline derivatives capable of inhibiting the sodium, potassium chloride cotransporter (NKCC1) .

[0006] BACKGROUND OF THE INVENTION

[0007] In recent years, a large body of literature has indicated that inhibitory GABAergic transmission via Cl~ permeable GABAreceptors in many other neurodevelopmental diseases, including Down syndrome, is defective (Deidda, G. et al. Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives. Front Cell Neurosci 2014, 8, 119.3; Contestabile, A. et al. The

[0008] GABAergic Hypothesis for Cognitive Disabilities in Down syndrome. Frontiers in Cellular Neurosciences 2017, 11.54) . However, the use of common GABAA receptor inhibitors to restore defective GABAergic transmission is not a viable therapeutic option. This is due to the high risk of epileptic seizures in patients.

[0009] Brain disorders characterised by altered GABAergic transmission comprise idiopathic autism, Rett syndrome, fragile X syndrome, Asperger syndrome, Di George syndrome, Angelman syndrome, 15qll.2 duplication, tuberous sclerosis complex, Down syndrome, obsessive compulsive disorder, Prader-Willi syndrome, schizophrenia, depressive-like behaviour, attention deficit hyperactivity disorder, sleep deprivation, polymicrogyria, focal cortical dysplasia, succinic semialdehyde dehydrogenase deficiency, Dravet syndrome, neonatal seizures, temporal lobe epilepsy, traumatic brain injury, spinal cord injury, peripheral nerve injury, neuropathic pain, nicotine withdrawal-induced hyperalgesia, cerebral stroke, diabetic ketoacidosis induced cerebral edema, hydrocephalus, glioma, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, post-traumatic stress disorder and fetal alcohol spectrum disorder (FASD) . The Na+, K+, Cl~ (NKCC) cotransporters encoded by the SLC12A2 (NKCC1) and SLC12A1 (NKCC2) genes belong to a family of transporters that provide electroneutral transport of sodium, potassium and chloride across the plasma membrane; by transporting two positively charged ions (sodium and potassium) together with two negatively charged ions (chloride) , a neutral balance of charges transferred within the cell is achieved. NKCC1 is widely expressed in the exocrine glands and brain; NKCC2 is found in the kidney, where it serves to extract sodium, potassium and chloride from urine so that they can be reabsorbed into the blood .

[0010] In neurons , Cl~-importing NKCC1 and Cl~-exporting KCC2 primarily control intracellular Cl~concentration .

[0011] Alterations in the NKCC1 / KCC2 expression ratio ( due to increased expression of NKCC1 and / or decreased expression of KCC2 ) have been observed in a number of brain disorders , both in animal models and in human samples . These alterations of the co-transporter lead to a pathological depolarising ( as opposed to physiological hyperpolarising and inhibitory) action of the neurotransmitter y-aminobutyric acid ( GABA) via Cl- permeable GABAA receptors in mature neurons ; targeting NKCC1 with inhibitors thus results in a therapeutic ef fect for a variety of diseases .

[0012] Inhibition of NKCC1 by the FDA-approved diuretic bumetanide has recently been shown to be a potential therapeutic strategy in several preclinical / clinical studies on neurological diseases . However, bumetanide has poor brain penetration and causes unwanted diuresis due to NKCC2 inhibition in the kidney .

[0013] To overcome these problems , an increasing number of studies have reported pro-drugs , analogues and new molecular entities that are more brain-penetrating and / or selective than bumetanide .

[0014] However, such compounds still have several drawbacks and limitations ; bumetanide derivatives are a promising first strategy for the design of more brain-penetrating NKCC1 inhibitors . However, the available data do not support the hypothesis that all these bumetanide analogues share the same mechanism of action, calling into question their main target . In addition, some of them may also share the same diuretic ef fect as bumetanide .

[0015] In recent years , several pharmacological approaches have attempted to restore [ Cl- ] i in brain disorders by acting indirectly on NKCC1 or KCC2 through upstream components of their signalling pathways . For example , the ZT- la inhibitor of proline-alanine-rich Ste2 Op-related kinase ( SPAK) , inhibitors of fms-like tyrosine kinase 3 ( FLT3 inhibitor KW- 2499 ) or glycogen synthase kinase 3 ( GSK3 p inhibitor BIO, 6- bromoindirubin-3 ' -oxime ) and activators of sirtuin 1 ( S IRT1 agonist resveratrol ) and of the transient receptor cation potential channel subfamily V member 1 ( TRPV1 agonist piperine ) , further strengthened the notion that pharmacological restoration of the physiological relationship between the NKCC1 / KCC2 transporters can attenuate the symptoms of various brain disorders . However, the compounds tested also acted on pathways involved in the regulation of several other cellular processes , raising numerous issues of tolerability and toxicity .

[0016] Finally, a new selective and more penetrating NKCC1 inhibitor in the blood-brain barrier, ARN23746 , was recently presented .

[0017] This new molecular entity belongs to a new chemical class of 4-amino-3- ( alkylsulphamoyl ) -benzoic acids . ARN23746 recovered cognitive deficits in a mouse model of DS and social / repetitive behaviour in a mouse model of VPA autism, with no diuretic ef fects and no obvious toxicity with chronic treatment in adult animals . ARN23746 is a good example of how it is possible to develop new molecules not derived from bumetanide to selectively target NKCC1 in the brain . However, ARN23746 and its derivatives still share some pharmacological characteristics with bumetanide , such as the presence of a key carboxylic acid moiety, a substituent known to be suboptimal in CNS drugs .

[0018] Therefore , there is a need for alternative therapeutic approaches for Down ' s syndrome and other brain disorders , which enable the restoration of defective GABAergic transmission through the inhibition of NKCC1 .

[0019] The aim of the present invention is therefore to provide new compounds capable of inhibiting the sodium, potassium chloride cotransporter (NKCC1 ) .

[0020] SUMMARY This purpose is achieved by a compound of formula (I) according to claims 1-7, its uses according to claims 8, 9 and 10, a pharmaceutical composition thereof according to claim 11 and methods for its use according to claims 12 and 13.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The present invention will now be described in detail with reference to the figures of the accompanying drawings, wherein :

[0023] Figure 1 illustrates the synthesis Scheme of compounds 1.11-1.15;

[0024] Figure 2 illustrates the synthesis Scheme of compounds 2.10 - 2.13;

[0025] Figure 3 illustrates the synthesis Scheme of compounds 3.8-3.10;

[0026] Figure 4 illustrates the synthesis Scheme of compounds 4.4 - 4.13;

[0027] Figure 5 shows A) the synthesis Scheme of compounds 5.32 - 5.49 and 5.54 - 5.60; B) and C) the structural formulae of compounds 5.11-5.31;

[0028] Figure 6 illustrates the synthesis Scheme of compound 6.6;

[0029] Figure 7 illustrates the synthesis Scheme of compounds 7.1 - 7.4; Figure 8 illustrates the synthesis Scheme of compound 8.4;

[0030] Figure 9 illustrates the synthesis Scheme of compound 9.4;

[0031] Figure 10 illustrates the synthesis Scheme of compounds 10.5 and 10.6;

[0032] Figure 11 illustrates the synthesis Scheme of compound 11.6;

[0033] Figure 12 illustrates the synthesis Scheme of compounds 12.7 - 12.9;

[0034] Figure 13 shows the synthesis Scheme of compounds 13.11, 13.13 - 13.17, 13.19 - 13.21, 13.23 - 13.25;

[0035] Figure 14 shows the synthesis Scheme of compounds 14.2, 14.5, 14.6, 14.8, 14.10;

[0036] Figure 15 illustrates the synthesis Scheme of compound 15.3;

[0037] Figure 16 illustrates the synthesis Scheme of compounds 16.1-16.4;

[0038] Figure 17 illustrates the synthesis Scheme of compounds 17.4 and 17.5.

[0039] DESCRIPTION OF EMBODIMENTS

[0040] In particular, according to a first aspect of the invention, a compound of formula (I) is provided: or its pharmaceutically acceptable salts, zwitterions, enantiomers, diastereoisomers, geometric isomers, solvates and tautomers .

[0041] In particular:

[0042] Ri is selected from the group consisting of Ci-Ce alkyl; Ci-Ce haloalkyl; halogen; -O-Ci-Cealkyl ; -O-C4-C10 cycloalkyl optionally substituted with a Ci-Ce alkyl; -O-Ci-Ce haloalkyl; -NH2; -NH-Ci-Ce alkyl; -NH-C4-C10 heterocycloalkyl; -N-di-Ci- C6alkyl; -NHSO2-CI-C6alkyl; -NHC (=0) Ci-C6alkyl; -NHC (=0) C3- Ce cycloalkyl;

[0043] R2 is selected from the group consisting of H, OH, halogen, -O-Ci-Ce alkyl optionally substituted with a substituent Rs,

[0044] R3 is selected from the group consisting of H, C1-C4 alkyl substituted with a substituent R7, phenyl optionally substituted with a substituent RB, monocyclic or bicyclic aromatic Ce-Cio heterocycle having 1 or 2 heteroatoms, preferably selected independently from 0, N and S; -C (=0) monocyclic aromatic C5-C10 heterocycle having 1 or 2 heteroatoms, preferably selected independently from 0, N and S; R4 is selected from the group consisting of H,

[0045] - linear or branched Ci-Ce alkyl substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl , OH, -O-Ci-Ce alkyl , halogen, COOH;

[0046] - C3-C6 cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, NH2, -NHC (=0) Ci-Ce alkyl

[0047] - monocyclic or bicyclic C3-C10 heterocycloal kyl comprising 1 or 2 heteroatoms , preferably selected independently from N, 0 and S , and optionally substituted with a substituent selected from the group consisting of linear or branched Ci-Ce alkyl

[0048] - spiro-bonded Ce-Cio heterobicycloalkyl comprising 1 or 2 heteroatoms , preferably selected independently from N, 0 and S ; or R3 and R4 taken together with the nitrogen to which they are bound form a cycle having formula where Ra, Rb , Rc , Rd, Re and Rf are independently selected from the group consisting of H, halogen, C1-C3 haloalkyl , OH, -C (=0) NH-Rg where Rg is selected from the group consisting of : - phenyl optionally substituted with a substituent selected from the group consisting of halogen, -0- Ci-C6alkyl, -SO2NH2, -SO2NH-Ci-C6alkyl , -SO2N (CI- C6alkyl)2, CN, C(=0)NH2;

[0049] - monocyclic or bicyclic aromatic C1-C10 heterocycle preferably comprising 1 or 2 heteroatoms, more preferably selected independently from N, 0 and S; provided that at least one of Ra, Rb, Rc, Rd, Re and Rf is not H;

[0050] Rs is selected from the group consisting of phenyl fluorophenyl, pyrazine;

[0051] R7 is selected from the group consisting of C3-C6 cycloalkyl, C4-C6 heterocycloalkyl comprising a heteroatom selected from N and 0, monocyclic or bicyclic aromatic C5- C10 heterocycle having 1 to 4 heteroatoms, preferably and independently selected from 0, N and S, optionally substituted with at least one substituent R9;

[0052] Rs is selected from the group consisting of CONH2, CN, halogen, OH, methoxy, CF3, C1-C4 alkyl, NH2;

[0053] R9 is selected from the group consisting of linear or branched Ci-Ce alkyl, halogen, NH2, OH, -O-Ci-C4alkyl , phenyl provided that the compound of formula I is not one of the compounds :

[0054] In an embodiment Ri is selected from the group consisting of C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -O-Ci- C3alkyl, -O-C1-C3 haloalkyl, -NH2, -NH-C1-C3 alkyl, -N-di-Ci- C3alkyl, -NHSO2-C1-C4 alkyl, -NHC (=0) C1-C3 alkyl, -NHC (=0) C3- Ce cycloalkyl.

[0055] In a further embodiment Ri is selected from the group consisting of butyl, trifluoromethyl, fluorine, methoxyl, ethoxyl, -0-CF3, -NHC (=0) CH3, -NHC (=0) ethyl , NHC (=0) cyclohexyl, -NHSO2-butyl , N(CH3)2.

[0056] According to an embodiment, R2is selected from the group consisting of H, halogen, -O-C1-C4 alkyl optionally substituted with a substituent Rs.

[0057] According to a further embodiment, R2is selected from the group consisting of H, chlorine, ethoxyl, methoxyl optionally substituted with a substituent Rs, where Rs is preferably selected from the group consisting of phenyl, fluorophenyl, pyrazine.

[0058] In an embodiment, R3 is selected from the group consisting of H, C1-C4 alkyl substituted with a substituent R7, phenyl optionally substituted with a substituent RB, monocyclic or bicyclic aromatic Ce-Cioheterocycle having 1 or 2 heteroatoms, preferably selected independently from S, 0 and N, C (=0) monocyclic aromatic C5-C6 heterocycle having 1 or 2 heteroatoms, preferably selected independently from S and N.

[0059] In an embodiment, R3 is selected from the group consisting of H, methyl substituted with a substituent R7, phenyl optionally substituted with a substituent RB, benzothiazole, benzoimidazole, benzoxazole, pyridine, pyrimidine, thiazole, thiophene, quinoxaline, quinazoline,

[0060] 2-benzoxazolinone, 3, 4-dihydro-l, 4-benzoxazin-2-one,

[0061] In a further embodiment R3 is selected from the group consisting of H, methyl optionally substituted with a substituent R7, phenyl optionally substituted with a substituent RB, benzothiazole, benzoimidazole, benzoxazole, pyridine .

[0062] In a further embodiment R4 is selected from the group consisting of H,

[0063] - linear or branched C1-C4 alkyl substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl , OH, -O-C1-C3 alkyl , halogen, COOH;

[0064] - C4-C6 cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, NH2, -NHC (=0) C1-C3 alkyl ;

[0065] - monocyclic or bicyclic C4-C10 heterocycloal kyl comprising a heteroatom, preferably selected from S , 0 and N, and optionally substituted with a linear or branched C1-C4 alkyl ;

[0066] - spiro-bonded Ce-Cio heterobicycloalkyl comprising 1 or 2 heteroatoms , preferably selected independently from N, 0 and S .

[0067] In an embodiment , R4 is selected from the group consisting of H

[0068] - linear C1-C4 alkyl substituted with at least one substituent selected from the group consisting of C3- Ce cycloalkyl , OH, -O-C1-C3 alkyl , halogen, COOH;

[0069] - C4-C6 cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, NH2, -NHC (=0) C1-C3 alkyl ;

[0070] - monocyclic or bicyclic C4-C10 heterocycloal kyl comprising a heteroatom selected between N and 0 optionally substituted with a linear or branched Ci- C4 alkyl ; - spiro-bonded Cioheterobicycloalkyl comprising a nitrogen atom.

[0071] In an embodiment, R4 is selected from the group consisting of methyl substituted with cyclopropyl; ethyl substituted with a substituent selected from the group consisting of OH, COOH, OCH3 and CF3; butyl optionally substituted with a substituent selected from the group consisting of OH, and OCH3; cyclohexyl optionally substituted with a substituent selected from the group consisting of OH, NH2 and -NHC(=O)CH3; cyclopentyl; cyclobutyl; piperidine optionally substituted with a substituent selected from the group consisting of methyl, isopropyl, isobutyl, butyl; tetrahydropyran; tetrahydrofuran; oxetane; pyrrolidine; azepane; 8-azabicyclo [ 3.2.1 ] octane ; 2-azaspiro [ 3.5 ] nonane ; aziridine; azetidine; pyrrolidine; imidazoline; pyrazoline; piperidine; azocane.

[0072] Preferably R4 is selected from the group consisting of methyl substituted with cyclohexyl; ethyl substituted with a substituent selected from the group consisting of OH, COOH, OCH3 and CF3; butyl optionally substituted with a substituent selected from the group consisting of OH, and OCH3; cyclohexyl optionally substituted with a substituent selected from the group consisting of OH, NH2 and

[0073] NHC(=O)CH3; cyclopentyl; cyclobutyl; piperidine optionally substituted with a substituent selected from the group consisting of methyl , isopropyl , isobutyl , butyl ; tetrahydropyran; tetrahydrofuran; oxetane ; pyrrolidine ; azepane ; 8-azabicyclo [ 3 . 2 . 1 ] octane ; 2-azaspiro [ 3 . 5 ] nonane .

[0074] In an embodiment , R? is selected from the group consisting of C3-C6 cycloalkyl , C4-C6 heterocycloalkyl comprising a heteroatom selected from N and 0, monocyclic or bicyclic aromatic C5-C10 heterocycle having 1 to 4 heteroatoms optionally substituted with at least one substituent R9.

[0075] In an embodiment , R7 is selected from the group consisting of monocyclic or bicyclic aromatic C5-C10 heterocycle having 1 to 3 heteroatoms , preferably selected from 0, S and N, optionally substituted with at least one substituent R9.

[0076] In an embodiment , R7 is selected from the group consisting of oxazole optionally substituted with at least one substituent R9 ; oxadiazole optionally substituted with at least one substituent R9 ; quinoline optionally substituted with at least one substituent R9 ; thiazole optionally substituted with at least one substituent R9 ; isoxazole optionally substituted with at least one substituent R9.

[0077] In an embodiment , R7 is selected from the group consisting of oxazole optionally substituted with at least one substituent R9; 1 , 3 , 4-oxadiazole optionally substituted with at least one substituent R9; 1 , 2 , 4-oxadiazole optionally substituted with at least one substituent R9; quinoline optionally substituted with at least one substituent R9; thiazole optionally substituted with at least one substituent R9.

[0078] In an embodiment, Rs is selected from the group consisting of CONH2, CN.

[0079] In an embodiment, R9 is selected from the group consisting of halogen, NH2, OH, -O-Ci-C4alkyl , phenyl; preferably R9 is selected from the group consisting of phenyl, fluorine, chlorine, NH2, OH, OCH3.

[0080] In an embodiment, when R3 and R4 are taken together with the nitrogen to which they are bound, they form a cycle having formula

[0081] Ra, Rb, Rc, Rd, Re and Rf are independently selected from the group consisting of H, fluorine, OH, C(=O)NH-Rg where Rg is selected from the group consisting of: phenyl optionally substituted with a substituent selected from the group consisting of fluorine, OCH3, SO2N(CH3)2, ON, -C(=O)NH2; pyridine; benzothiazole; benzoimidazole; benzoxazole; pyrimidine; thiazole; oxazole; thiophene; quinoxaline; quinazoline.

[0082] Preferably, Rg is selected from the group consisting of phenyl optionally substituted with a substituent selected from the group consisting of fluorine, OCH3, SO2N(CH3)2, CN, -C(=O)NH2; pyridine and benzothiazole.

[0083] In an embodiment, when R3 and R4 taken together with the nitrogen to which they are bound form a cycle, Ri is preferably selected from the group consisting of C1-C4 alkyl, C1-C3 haloalkyl, halogen, -NHSO2-C1-C4 alkyl, -NHC (=0) C1-C3 alkyl, -NHC (=0) C3-C6 cycloalkyl and R2 is selected from the group consisting of H, -O-C1-C4 alkyl optionally substituted with a substituent Rs.

[0084] In a preferred embodiment:

[0085] Ri is F ;

[0086] R2 is H;

[0087] R3 and R4 taken together with the nitrogen to which they are bound form a cycle having formula where Ra, Rb, Rc, Rd, Re and Rf are independently selected from the group consisting of H, fluorine, OH C(=O)NH-Rg where Rg is selected from the group consisting of phenyl substituted with a substituent selected from the group consisting of OCH3, SO2N(CH3)2, ON, -C(=0)NH2,- pyridine and benzothiazole.

[0088] Alternatively, in a preferred embodiment:

[0089] Ri is selected from the group consisting of F, ethoxyl;

[0090] R2 is H; R3 is selected from the group consisting of benzothiazole, benzothiazole, phenyl substituted with CONH2, pyridine, benzoimidazole substituted with CH3, -CH2- thiazole, -CH2-thiazole-NH2, -CH2-thiazole-OH, and

[0091] R4 is selected from the group consisting of cyclohexyl, cyclohexyl substituted with OH, piperidine substituted with CH3, tetrahydrofuran, oxetane, ethyl substituted with OH.

[0092] In particular, the compound of formula (I) can be selected from the group consisting of:

[0093]

[0094]

[0095] Preferably, the compound of formula (I) can be selected from the group consisting of:

[0096] A second aspect of the present invention relates to a pharmaceutical composition comprising a compound of Formula (I) or its pharmaceutically acceptable salts, zwitterions, enantiomers, diastereoisomers, geometric isomers, solvates and tautomers and at least one pharmacologically acceptable excipient. A person skilled in the art is familiar with the whole variety of such excipients such as vehicles and diluents, which are suitable for formulating a pharmaceutical composition.

[0097] The compounds of formula (I) , together with a conventionally employed adjuvant, carrier, diluent or excipient, may be formulated into pharmaceutical compositions unit dosages thereof, and in that form may be used as solids, e.g. tablets or filled capsules, or liquids, e.g. solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral administration (including subcutaneous and intravenous use) . These pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active ingredients or compounds, and these forms of dosage unit may contain any effective amount of the active ingredient commensurate with the expected daily dosage range to be used .

[0098] The pharmaceutical compositions containing a compound of this invention can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound . In general , the compounds of this invention are administered in a pharmaceutically ef fective quantity . The amount of the compound ef fectively administered will typically be determined by a physician in light of relevant circumstances , including the condition to be treated, the route of administration selected, the compound administered, the age , the weight and the response of the individual patient , the severity of the patient ' s symptoms , and the like .

[0099] The pharmaceutical compositions of the present invention can be administered through a variety of routes , including oral , rectal , transdermal , subcutaneous , intravenous , intramuscular, intranasal and pulmonary routes . The compositions for oral administration may take the form of loose liquid solutions or suspensions , or loose powders . More commonly, however, the compositions are presented in unit dosage forms to facilitate the precise dosing . The expression "unit dosage forms" refers to physically distinct units suitable as unit dosages for humans and other mammals , each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-measured, pre-filled vials or syringes in the case of liquid compositions, or pills, tablets, capsules or the like in the case of solid compositions.

[0100] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier with buffers, suspending and dispersing agents, dyes, flavours and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum, gum arable, corn starch or gelatin; an excipient such as starch, dicalcium phosphate or lactose, a disintegrating agent such as alginic acid, Primogel or maize starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose, lactose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring.

[0101] Injectable compositions are typically based on sterile saline solution or phosphate-buff ered saline solution for injection or other injectable carriers known in the art.

[0102] The pharmaceutical compositions may be in the form of tablets, pills, capsules, solutions, suspensions, emulsions, powders, suppositories and sustained release formulations.

[0103] If desired, the tablets can be coated by standard aqueous or non-aqueous techniques . The amount of active compound in such therapeutically useful compositions is such that the therapeutically active dosage will be achieved .

[0104] When a unit dosage form is a capsule , it may contain, in addition to the materials of the above type, a liquid carrier such as a fatty oil . Various other materials may be present as coatings or to modi fy the physical shape of the dosage unit . For example , the tablets may be coated with shellac, sugar, or both . To prevent the breakdown during the passage through the upper portion of the gastrointestinal tract , the composition may be a formulation with an enteric coating .

[0105] A syrup or elixir may contain, in addition to the active ingredient , sucrose as a sweetening agent , methyl and propyl parabens as preservatives , a dye and a flavouring agent such as cherry or orange flavouring .

[0106] The active compounds can also be administered intranasally, e . g . as liquid drops or sprays .

[0107] The compositions for pulmonary administration include , but are not limited to , dry powder compositions consisting of powder of a compound of the invention and the powder of a suitable carrier and / or lubricant . The compositions for pulmonary administration may be inhaled from any dry powder inhaler device known to the person skilled in the art .

[0108] The administration of the compositions is performed following a protocol and at a dosage that is suf ficient to reduce inflammation and pain in the subject. In some embodiments, in the pharmaceutical compositions of the present invention the active ingredient or the active ingredients are generally formulated in dosage units.

[0109] In some embodiments, the effective amounts for a specific formulation will depend on the severity of the disease, disorder or condition, the previous therapy, the health status of the individual and the response to the drug.

[0110] When used in combination with one or more of the other active ingredients, the compound of the present invention and the other active ingredient may be used in lower doses than when each is used individually.

[0111] Regarding formulations in relation to any variety of routes of administration, methods and formulations for drug delivery are outlined in Remington's Pharmaceutical Sciences, 17th edition, edited by Gennaro et al., Mack Publishing Co., 1985, and Remington's Pharmaceutical Sciences, edited by Gennaro AR, 20th edition, 2000, Williams & Wilkins PA, USA, and Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins Eds., 2005; and in Loyd V. Allen and Howard C. Ansel, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th edition, Lippincott Williams & Wilkins Eds., 2014.

[0112] The components described above for orally administered or injectable compositions are purely representative. The compounds of this invention can also be administered in sustained-release forms or by sustained-release drug delivery systems.

[0113] A third aspect of the present invention relates to compounds of Formula (I) as illustrated above or to the pharmaceutical composition thereof, for use as a medicament.

[0114] A fourth aspect of the present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts, solvates or isomers thereof, for use in the prevention or treatment of a disorder associated with depolarising GABAergic transmission.

[0115] The compounds of formula (I) may in particular be used in the prevention or treatment of a disorder selected from the group consisting of idiopathic autism, Rett syndrome, fragile X syndrome, Asperger syndrome, Di George syndrome, Angelman syndrome, 15qll.2 duplication, tuberous sclerosis complex, Down syndrome, obsessive compulsive disorder, Prader-Willi syndrome, schizophrenia, depressive-like behaviour, attention deficit and hyperactivity disorder, sleep deprivation, polymicrogyria, focal cortical dysplasia, succinic semialdehyde dehydrogenase deficiency, Dravet syndrome, neonatal seizures, temporal lobe epilepsy, traumatic brain injury, spinal cord injury, peripheral nerve injury, neuropathic pain, nicotine withdrawal-induced hyperalgesia, cerebral stroke, diabetic ketoacidosis induced cerebral edema, hydrocephalus, glioma, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, post-traumatic stress disorder and fetal alcohol spectrum disorder (FASD) .

[0116] In the following, the present invention will be shown by means of some examples, which are not intended to be considered limiting the scope of the invention.

[0117] Examples

[0118] Materials and methods

[0119] All the commercially available reagents and solvents were used as purchased from the suppliers without further purification. The dry solvents were purchased from Sigma- Aldrich. Automated column chromatographic purifications were performed using Teledyne ISCO (CombiFlash® Rf) or Biotage® Selekt equipment with pre-packaged silica gel or basic alumina or reversed-phase C18 silica columns of different sizes (from 4 g to 120 g) and increasing polarity mixtures of cyclohexane and ethyl acetate (EtOAc) , cyclohexane and tert-butyl methyl ether (TBME) or dichloromethane (DCM) and methanol (MeOH) or acetonitrile (MeCN) and water (H2O) . The NMR experiments were performed on a Bruker Avance III 400 system (400.13 MHz for 1H and 100.62 MHz for 13C) , equipped with a BBI probe and Z gradients. The spectra were acquired at 300 K, using deuterated dimethyl sulphoxide (DMSO-d6) or deuterated chloroform (CDCI3) as solvents. For 1H-NMR, the data are reported as follows: chemical shift, multiplicity (s= singlet, d= doublet, dd= doublet of doublets, t= triplet, q= quartet, m= multiplet) , coupling constants (Hz) and integration. UPLC / MS analyses were performed on a Waters ACQUITY UPLC / MS system consisting of an SQD (single quadrupole detector) mass spectrometer equipped with an electrospray ionisation interface and a photodiode array detector. The PDA range was 210-400 nm. The analyses were performed on an ACQUITY UPLC BEH C18 column (100x2.1 mmID, particle size 1.7 pm) with a VanGuard BEH C18 pre-column (5x2.1 mmID, particle size 1.7 pm) . The mobile phase consisted of 10 mM NH4OAC in H2O at pH 5 adjusted with CH3COOH (A) and 10 mM NH4OAC in CH3CN-H2O (95:5) at pH 5.0. Two types of gradients were applied depending on the analysis: gradient 1 (5% to 100% mobile phase B in 3 minutes) , gradient 2 (5% to 50% mobile phase B in 3 minutes) or gradient 3 (50% to 100% mobile phase B in 3 minutes) . Electrospray ionisation in positive and negative mode was applied. Electrospray ionisation in positive and negative mode was applied. ESI was applied in positive and negative modes. All the tested compounds displayed a purity of % 90 % by NMR and UPLC / MS analysis .

[0120] General processes Process A

[0121] Al: To the solution of aniline (3 g, 27 mmol, 1 eq) in toluene (0.2 M, 135 mL) at room temperature, ethyl vinyl ether (2 eq, 54 mmol, 5.170 mL) was added, followed by the catalytic addition of iodine (0.1 eq, 2.7 mmol, 685 mg) , and the reaction mixture was stirred at reflux for 5 h. The mixture was cooled to room temperature and quenched with a solution of NaHCOs (pH 8-9) . The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified on silica gel by column chromatography to obtain the desired product.

[0122] A2 : To the solution of the appropriate aniline (1 eq, 2g, 16.24 mmol) in HC1 6M (81 mL, 30 eq) a solution of crotonaldehyde (2 eq, 32.48 mmol) in toluene (0.75 M) was added and the mixture was stirred at 100°C until the reaction was complete. The reaction mixture was cooled to ambient temperature and basified with aqueous NaOH 2N to pH 10. The mixture was extracted with ethylene. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. Purification by column chromatography yielded the desired product.

[0123] Process B

[0124] To the solution of the appropriate 2-methylquinoline (1 g, 6.2 mmol, 1 eq) in acetonitrile (0.2 M, 31 mL) at room temperature, N-bromosuccinimide (0.8 eq, 4,96 mmol, 883 mg) was added, followed by the addition of benzoylperoxide (0.2 eq, 1.24 mmol, 300 mg) and the reaction mixture was stirred under reflux for 1 h and then at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCOs (pH 8-9) , extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSCh, filtered and evaporated. The crude product was purified on silica gel by column chromatography to obtain the desired product .

[0125] Process C

[0126] To the solution of the appropriate 2-methylquinoline (1 g, 6.2 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 31 mL) at room temperature, selenium dioxide (1.3 eq, 8.07 mmol, 895 mg) was added and the reaction mixture was stirred at 80°C for 2-20 h. The reaction mixture was filtered over a celite buffer and washed with ethyl acetate. The filtrate was washed with a saturated aqueous solution of Na2COs to eliminate the possible presence of the -oxide derivative of quinoline as a side product of the reaction. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was used as such for the next step or purified on silica gel by column chromatography to obtain the desired product.

[0127] Process D To the solution of the appropriate halide derivative (50 mg, 0.21 mmol, 1 eq) in tetrahydrofuran (0.1 M) at room temperature, N, -diisopropylamine (6 eq) was added followed by the addition of the appropriate amine (2 eq) . The reaction mixture was stirred at reflux overnight. Subsequently, the mixture was allowed to cool to room temperature and diluted with water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified on silica gel by column chromatography to obtain the desired product.

[0128] Process E

[0129] To the solution of amine (1-2 eq) and aldehyde (1-2 eq) in dichloromethane (0.1 - 0.3 M) , acetic acid (0.1 - 10 eq) and sodium triacetoxychlorohydride (2 - 5 eq) were added, and the mixture was stirred at room temperature for 3-20 h. The reaction mixture was quenched with saturated aqueous Na2COs. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. If necessary, the crude product was purified by column chromatography to obtain the desired product.

[0130] Process F

[0131] To the solution of 2 -methylquinolin- 6-amine (60 mg, 0.38 mmol, 1 eq) in dry dichloromethane (0.2 M, 1.9 mL) at room temperature, the appropriate acetyl or sulphonyl chloride (1.1 eq, 0.42 mmol) and triethylamine (3 eq, 1.14 mmol) were added and the mixture was stirred at room temperature for 2-20 h. The reaction mixture was diluted with ethyl acetate and washed with a solution of NaHCOs (pH 8) . The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified on silica gel by column chromatography to obtain the desired product.

[0132] Process I

[0133] To the solution of the appropriate hydroxyquinoline (50 mg, 0.28 mmol, 1 eq) in dry N, -dime thy 1 formamide, potassium carbonate (2-3 eq) was added, followed by the addition of the appropriate alkyl halide (1.2 -2 eq) . The mixture was stirred for 20 h at room temperature or heated if necessary. The reaction mixture was quenched with saturated NaHCOs and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified on silica gel by column chromatography to obtain the desired product.

[0134] Process K

[0135] KI: To the solution of aniline (0.13 mmol, 1 eq) in dry dichloromethane (0.1 M, 1.3 mL) at room temperature, trimethylaluminium (3 eq, 0.38 mmol) was added. A gas evolution was observed. The mixture was stirred for 15 minutes. Then the appropriate ester (1 eq, 0.13 mmol) was carefully added and the reaction mixture was stirred overnight at room temperature. Subsequently, the reaction mixture was carefully diluted with ethyl acetate and filtered over a celite buffer to filter out the aluminium salts. The filtrate was washed with aqueous NaHCOs. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Purification by column chromatography yielded the pure product .

[0136] K2 : To the solution of the appropriate aniline (1 eq, 0.16 mmol) in dry tetrahydrofuran (0.1 M, 1.6 mL) at room temperature, sodium hydride dispersed 60% in mineral oil (8 eq) was added and the mixture was allowed to reflux for 30 minutes. Then the ester (1 eq, 0.16 mmol) was added and the mixture was left to reflux for 30-60 minutes. The reaction mixture was allowed to cool to room temperature and cautiously quenched with water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Purification by column chromatography yielded the pure product .

[0137] Process L

[0138] To the solution of appropriate 2-methylquinoline (1 g, 6.2 mmol, 1 eq) in acetonitrile (0.25 M) at room temperature, iodine (0.75 eq, 4.65 mmol, 1.181 g) was added, followed by the addition of copper sulphate pentahydrate (0.4 eq, 2.48 mmol, 620 mg) , and the reaction mixture was stirred at 70°C for 3-20 h. The reaction mixture was allowed to cool to room temperature and diluted with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2 SO4, filtered and evaporated. The crude product was purified on silica gel by column chromatography to obtain the desired product.

[0139] Process M

[0140] To the solution of the appropriate aldehyde (1-2 eq) and amine (1-2 eq) in dry tetrahydrofuran (0.2 M) , trifluoroacetic acid (3 eq) was added and the reaction mixture was stirred at room temperature for 1 h. Then phenylsilane (3 eq) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was maintained with an aqueous solution of saturated Na2COs . The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Purification by column chromatography yielded the desired product.

[0141] Process N

[0142] To the solution of the appropriate amine (1 eq) in dry acetonitrile (0.1-0.3 M) , at room temperature, the appropriate alkyl halide (1-1.2 eq) and potassium carbonate (2.5 - 3 eq) were added; the mixture was stirred under reflux overnight. The reaction mixture was left at room temperature, diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Purification by column chromatography yielded the desired product.

[0143] Process O

[0144] 01: To the protected amine -Boc solution (230 mg, 0.47 mmol, 1 eq) in dioxane (0.1 M) a 4M HC1 solution in dioxane (8 eq) was added and the mixture was stirred at room temperature overnight. The solvent evaporated. If necessary, purification by recrystallisation or column chromatography yielded the desired product.

[0145] 02: To the protected -Boc amine solution (1 eq) in methanol (0.2 M) chlorotrimethylsilane (0.1 ml) was added and the reaction mixture was stirred at room temperature overnight. Then phenylsilane (3 eq) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated and treated with ether to form a precipitate. The precipitate was filtered to obtain the compound.

[0146] Process P

[0147] Water (100 pL) was added to the solution of the appropriate acetal-protected ketone (1 eq, 230 mg, 0.51 mmol) in TFA / DCM 1:4 (0.1 M, 5.11 mL) and the mixture was stirred at room temperature overnight. The reaction was quenched with a saturated aqueous solution of Na2COs. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2 SO4, filtered and evaporated. The product was used as such for the next step or, if necessary, purified by column chromatography to obtain the desired product.

[0148] Process Q

[0149] To the appropriate ketone solution (1 eq) in methanol / ethanol (0.2M) sodium borohydride (1.2 - 6 eq) was added and the mixture was stirred at room temperature until the starting material disappeared. The reaction mixture was cooled with water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Purification by column chromatography yielded the desired product.

[0150] Process W

[0151] To the mixture of the appropriate amine (0.33 mmol, 1.0 eq) and the appropriate carboxylic acid (1.1 eq, 0.36 mmol) in dry acetonitrile (0.1 M, 3.3 mL) at room temperature, HATU (1,1 eq, 0.36 mmol) was added, followed by the addition of N, N-diisopropylethylamine (2.0 eq, 0.66 mmol)m and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated and quenched with an aqueous solution of saturated Na2COs. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel column chromatography yielded the pure compound.

[0152] Preparation of compounds 1.4-1.15 (Scheme 1, Figure 1) 6-fluoro-2 -methylquinoline (compound 1.4, Scheme 1)

[0153] The titrated compound was synthesised according to Process Al described above, starting with 4-f luoroaniline 1.1 (3 g, 27 mmol, 1 eq) in toluene (0.2 M, 135 mL) , ethylvinylether (2 eq, 54 mmol, 5.170 mL) and iodine (0.1 eq, 2.7 mmol, 685 mg) , stirring the reaction for 5 h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10) yielded the pure titrated compound as a brownish solid in a 40% yield (1758 mg) . Characterization: Rt 1.82 min, generic method, MS (ESI) m / z = 162.1 [M+H]+. Exact mass: 161.0641. !H NMR (400 MHz, DMSO) 5 8.24 (d, J = 8.5 Hz, 1H) , 7.98 (dd, J = 9.2, 5.5 Hz, 1H) , 7.73 (dd, J = 9.5, 2.9 Hz, 1H) , 7.62 (td, J = 8.9, 2.9 Hz, 1H) , 7.46 (dd, J = 8.4, 0.9 Hz, 1H) , 2.65 (s, 3H) .

[0154] 2-methyl-6- (tri fluoromethyl) quinoline (compound 1.5, Scheme 1)

[0155] The titrated compound was synthesised according to Process Al described above, starting with 4-trif luoromethylaniline 1.2 (500 mg, 3.1 mmol, 1 eq) in toluene (0.2 M, 15.5 mL) , ethylvinylether (2 eq, 6.2 mmol, 0.59 mL) and iodine (0.1 eq, 0.31 mmol, 79 mg) , stirring the reaction for 20 h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10) yielded the pure titrated compound as a brownish solid in a 39% yield (260 mg) . Characterization: Rt 2.16 min, generic method, MS (ESI) m / z = 211.8 [M+H]+ . Exact mass: 211.0609. NMR (400 MHz, DMSO) 5 8.49 - 8.39 (m, 2H) , 8.11 (d, J = 8.8 Hz, 1H) , 7.95 (dd, J = 8.9, 2.2 Hz, 1H) , 7.58 (d, J = 8.4 Hz, 1H) , 2.71 (s, 3H) .

[0156] 6-butyl -2 -methylquinoline (compound 1.6, Scheme 1)

[0157] The titrated compound was synthesised according to Process Al described above, starting with 4-butylaniline 1.3 (300 mg, 2.01 mmol, 1 eq) in toluene (0.2 M, 9 mL) , ethylvinylether (2 eq, 4.02 mmol, 0.385 mL) and iodine (0.1 eq, 0.20 mmol, 51 mg) , stirring the reaction for 5 h. Purification by silica gel column chromatography (cyclohexane / ethyl acetate 90:10) yielded the pure titrated compound as a brownish solid in a 49% yield (200 mg) . Characterization: Rt 2.51 min, generic method, MS (ESI) m / z = 200.1 [M+H]+. Exact mass: Exact mass: 199.1361.1H NMR (400 MHz, CDC13) 5 8.00 (d, J = 8.4 Hz, 1H) , 7.96 (d, J =

[0158] 9.1 Hz, 1H) , 7.55 (dq, J = 3.9, 2.0 Hz, 2H) , 7.29 (d, J =

[0159] 3.2 Hz, 1H) , 2.2 (d, J = 3.2 Hz, 1H) .2 Hz, 1H) , 2.83 - 2.78

[0160] (m, 2H) , 2.75 (s, 3H) , 1.72 (tt, J = 9.1, 6.8 Hz, 2H) , 1.42

[0161] (h, J = 7.4 Hz, 2H) , 0.98 (t, J = 7.3 Hz, 3H) .

[0162] 2- (bromomethyl) -6-fluoroquinoline (compound 1.7, Scheme 1)

[0163] The titrated compound was synthesised according to Process B described above, starting with 6-f luoro-2-methylquinoline 1.4 (1 g, 6.2 mmol, 1 eq) in acetonitrile (0.2 M, 31 mL) , N- bromosuccinimide (0.8 eq, 4.96 mmol, 883 mg) and benzoylperoxide (0.2 eq, 1.24 mmol, 300 mg) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 95:05) yielded the pure product titrated in a 46% yield (550 mg) . Characterization: Rt 2.07 min, generic method, MS (ESI) m / z = 239.8 [M+H]+. Exact mass: 238.9746.) .TH NMR (400 MHz, CDC13_3mm) 5 8.13 (d, J = 8.5 Hz, 1H) , 8.07 (dd, J = 9.2,

[0164] 5.3 Hz, 1H) , 7.59 (dd, J = 8.6, 0.9 Hz, 1H) .6, 0.9 Hz, 1H) , 7.50 (ddd, J = 9,3, 8,3, 2,8 Hz, 1H) , 7.43 (dd, J = 8.7, 2.8 Hz, 1H) , 4.70 (s, 2H) .

[0165] 2- (bromomethyl) -6- (trifluoromethyl) quinoline (compound 1.8,

[0166] Scheme 1)

[0167] The titrated compound was synthesised according to Process B described above, starting with 6-trif luoromethyl-2- methylquinoline 1.5 (180 mg, 0.85 mmol, 1 eq) in acetonitrile (0.2 M, 5 mL) , N-bromosuccinimide (0.8 eq, 0.68 mmol, 121 mg) and benzoylperoxide (0.2 eq, 0.17 mmol, 41 mg) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 95:05) yielded the pure product titrated in a 54% yield (107 mg) . Characterization: Rt 1.13 min, apolar method, MS (ESI) m / z = 289.9 [M+H]+. Exact mass Exact mass: 288.9714. NMR (400 MHz, CDC13) 5 8.27 (d, J = 8.5 Hz, 1H) , 8.18 (d, J = 8.9 Hz, 1H) , 8.14 (s, 1H) , 7.90 (dd, J = 8.8, 2.1 Hz, 1H) , 7.68 (d, J = 8.5 Hz, 1H) , 4.72 (s, 2H) .

[0168] 6-fluoroquinolin-2-carbaldehyde (compound 1.9, Scheme 1)

[0169] The titrated compound was synthesised according to Process C described above, starting with 6-f luoro-2-methylquinoline 1.4 (1 g, 6.2 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 31.0 mL) , selenium dioxide (1.3 eq, 8.07 mmol, 895 mg) . The reaction mixture was stirred at 80°C for 2h. The compound was obtained pure without column chromatographic purification (94% yield, 1.036 g, light brown solid) . Characterization: Rt 1.82 min, generic method, MS (ESI) m / z = 175.9 [M+H]+ . Exact mass: 175.0433. iH NMR (400 MHz, DMSO) 5 10.12 (d, J = 0.8 Hz, 1H) , 8.60 (d, J = 8.5 Hz, 1H) , 8.32 (dd, J = 9.3, 5.5 Hz, 1H) , 8.04 (dd, J = 8.5, 0.9 Hz, 1H) , 7.97 (dd, J = 9.3, 2.9 Hz, 1H) , 7.85 (td, J = 8.9, 2.9 Hz, 1H) .

[0170] 6-butylquinolin-2-carbaldehyde (compound 1.10, Scheme 1)

[0171] The titrated compound was synthesised according to Process C described above, starting with 6-butyl-2-methylquinoline 1.6 (200 mg, 1.00 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 5.0 mL) , selenium dioxide (1.3 eq, 1.30 mmol, 145 mg) . The reaction mixture was stirred at 80°C for 2h. The titrated product was obtained pure without purification by column chromatography (quantitative yield, 220 mg, light brown solid) . Characterization: Rt 2.62 min, generic method, MS (ESI) m / z = 214.1 [M+H]+ . Exact mass: 213.1154. NMR (400 MHz, CDC13) 5 10.21 (d, J = 0.8 Hz, 1H) , 8.23 (d, J = 8.4 Hz, 1H) , 8.16 (d, J = 8.5 Hz, 1H) , 8.00 (d, J = 8.4 Hz, 1H) , 7.71 - 7.60 (m, 2H) , 2.89 - 2.78 (m, 2H) , 1.79 - 1.65 (m, 2H) , 1.40 (dt, J = 14.7, 7.4 Hz, 2H) , 0.96 (t, J = 7.4 Hz, 3H) .

[0172] 2- ( (3, 3 -di fluoropiper idin-l-yl) methyl) -6 -fluoroquinoline (Compound 1.11, Scheme 1)

[0173] The titrated compound was synthesised according to Process D described above, starting with 2- (bromomethyl) -6- f luoroquinoline 1.7 (50 mg, 0.21 mmol, 1 eq) in THF (0.1 M, 2.1 mmol) , N, N-diisopropylamine (6 eq, 1.25 mmol, 0.21 mL) and 3, 3-dif luoropiperidin-l-ium chloride (2 eq, 66 mg) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 60:40) yielded the pure titrated compound as a white solid in a yield of 78% (46 mg) . Characterization: Rt 2.16 min, generic method, MS (ESI) m / z = 281.1 [M+H]+, exact mass: 280.1187. iH NMR (400 MHz, DMSO) 5 8.34 (d, J = 8.5 Hz, 1H) , 8.03 (dd, J = 9.2, 5.4 Hz, 1H) , 7.75 (dt, J = 9.5, 2.7 Hz, 1H) , 7.68-7.59 (m, 2H) , 3.84 (s, 2H) , 2.72 (t, J = 11.5 Hz, 2H) , 2.47 (t, J = 5.3 Hz, 2H) , 1.88 (tt, J = 13.9, 6.4 Hz, 2H) , 1.71 - 1.61 (m, 2H) .

[0174] 2- ( (4 ,4-difluoropiperidin-l-yl)methyl) -6-fluoroquinoline (Compound 1.12, Scheme 1)

[0175] The titrated compound was synthesised according to Process D described above, starting with 2- (bromomethyl) -6- f luoroquinoline 1.7 (50 mg, 0.21 mmol, 1 eq) in THF (0.1 M, 2.1 mL) , N, N-diisopropylethylamine (6 eq, 1.25 mmol, 0.21 mL) and 3, 3-dif luoropiperidin-l-ium chloride (2 eq, 66 mg) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 60:40) yielded the compound titrated pure as a white solid in a yield of 75% (44 mg) . Characterization: Rt 2.10 min, generic method, MS (ESI) m / z = 281.1 [M+H]+, exact mass: 280.1187. NMR (400 MHz, DMSO) 5 8.35 (d, J = 8.5 Hz, 1H) , 8.04 (dd, J = 9.2, 5.5 Hz, 1H) , 7.78 (dd, J = 9.4, 2.9 Hz, 1H) , 7.70 (dd, J = 8.5, 0.9 Hz, 1H) .5, 0.9 Hz, 1H) , 7.65 (td, J = 8.9, 2,9 Hz, 1H) , 3,83 (s, 2H) , 2.58 (t, J = 5.7 Hz, 4H) , 1.99 (tt, J = 14.1, 5.7 Hz, 4H) .

[0176] 1- ( (6- (tri fluoromethyl) quinolin-2-yl) methyl) piperidin-3-ol (compound 1.13, Scheme 1)

[0177] The titrated compound was synthesised according to Process D described above, starting with 2- (bromomethyl) -6- trif luoromethylquinoline 1.8 (50 mg, 0.17 mmol, 1 eq) in THE (0.1 M, 1.7 mL) , N, N-diisopropylamine (6 eq, 1.25 mmol, 0.15 mL) and 3, 3-dif luoropiperidin-l-ium chloride (2 eq, 47 mg) . Purification by silica gel column chromatography (ethyl acetate / methanol 95:05) yielded the pure titrated compound as a yellowish oil in a yield of 89% (48 mg) . Characterization: Rt 1.63 min, generic method, MS (ESI) m / z = 311.1 [M+H]+. Exact mass: 310.1293. iH NMR (400 MHz, DMSO) 5 8.52 (dd, J = 8.7, 2.2 Hz, 1H) , 8.47 (s, 1H) , 8.16 (d, J = 8.8 Hz, 1H) , 7.96 (dt, J = 8.9, 2.1 Hz, 1H) .9, 2.1 Hz, 1H) , 7.77 (dd, J = 8.6, 1.9 Hz, 1H) , 4.66 (q, J = 5.1 Hz, 1H) , 3.78 (qd, J = 14.1, 1.7 Hz, 2H) , 3.52 (dt, J = 9.1, 1.7 Hz, 2H) .52 (dt, J = 9.5, 4.8 Hz, 1H) , 2.80 (dd, J = 10.8, 4.0 Hz, 1H) , 2.65 (d, J = 11.3 Hz, 1H) , 2.08 - 1.92 (m, 1H) , 1.91 - 1.73 (m, 1H) .91 - 1.73 (m, 2H) , 1.63 (dt, J = 12.6, 3.9 Hz, 1H) , 1.45 (q, J = 12.2 Hz, 1H) , 1.14 - 0.94 (m, 1H) .

[0178] 1- ( (6-butylquinolin-2-yl) methyl ) piperidin-3-ol (compound 1.14, Scheme 1)

[0179] To the solution of 3-hydroxypiperidin-l-ium chloride (39 mg

[0180] 0.28 mmol, 1.2 eq) in dry dichloromethane (0.1 M, 2.3 mL) at room temperature, triethylamine (6.6 eq, 1.55 mmol, 0.22 mL) was added. A gas evolution was observed. The mixture was stirred for 5 min to obtain the free amine, which was reacted with 6-butylquinolin-2-carbaldehyde 1.10 (1 eq, 0.23 mmol, 50 mg) , acetic acid (10 eq, 2.34 mmol, 0.1 mL) and sodium triacetoxyborohydride (4 eq, 0.94 mmol, 199 mg) , according to Process E described above. Purification by silica gel column chromatography (dichloromethane / methanol 95:05) yielded the compound as a yellow oil in a yield of 74% (52 mg) . Characterization: Rt 2.00 min generic method, MS (ESI) m / z = 299.5 [M+H]+. Exact mass: 298.2045.TH NMR (400 MHz, DMSO) 5 8.22 (d, J = 8.5 Hz, 1H) , 7.88 (d, J = 8.6 Hz, 1H) , 7.70 (d, J = 2.0 Hz, 1H) , 7.60 - 7. 55 (m, 2H) , 7.5 (m, 2H) .55 (m, 2H) , 4.61 (dd, J = 5.0, 2.2 Hz, 1H) , 3.75 (d, J = 13.6 Hz, 1H) , 3.67 (d, J = 13.6 Hz, 1H) , 3.49 (tt, J = 9.0, 4.5 Hz, 1H) , 2.5 (tt, J = 9.0, 4.5 Hz, 1H) .5 Hz, 1H) , 2.84 - 2.72 (m, 3H) , 2.69 - 2.62 (m, 1H) , 1.97 (td, J = 11.2, 2.8 Hz, 1H) , 1.87 - 1.77 (m, 2H) , 1.68 - 1.57 (m, 2H) , 2H, 2H, 2H.68 - 1.57 (m, 3H) , 1.51 - 1.38 (m, 1H) , 1.38 (s, 1H) , 1.08 (tdd, J = 12.1, 10.1, 4.2 Hz, 1H) , 0.91 (t, J = 7.3 Hz, 3H) .

[0181] N- ( ( 6-fluoroquinolin-2-yl) methyl ) cyclohexanamine (compound 1.15, Scheme 1)

[0182] The titrated compound was synthesised according to

[0183] Process E described above, starting with cyclohexylamine (391 pL, 1.2 eq, 3.43 mmol) in dry dichloromethane (0.2 M, 2.3 mL) , 6-f luoroquinolin-2-carbaldehyde 1.9 (1 eq, 2.85 mmol, 500 mg) , acetic acid (10 eq, 28.55 mmol, 326 pL) and sodium triacetoxyborohydride (4 eq, 11.42 mmol, 2.419 g) , stirring the reaction mixture for 18 h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 40:60 to 0:100) yielded the pure titrated compound as a beige solid in a yield of 63% (472 mg) . Characterization: Rt 1.71 min, generic method. MS (ESI) m / z = 259.7 [M+H]+. Exact mass: 258.1532. !H NMR (400 MHz, DMSO) 5 8.29 (d, J = 8.5 Hz, 1H) , 8.01 (dd, J = 9.2, 5.5 Hz, 1H) , 7.74 (dd, J = 9.4, 2.9 Hz, 1H) , 7.69-7.59 (m, 2H) , 3.98 (s, 2H) , 2.44 - 2.34 (m, 1H) , 1.84 (d, J = 11.7 Hz, 2H) , 1.65 (t, J = 6.3 Hz, 2H) , 1.53 (s, 1H) , 1.23 - 0.99 (m, 5H) .

[0184] N- (2-methylquinolin-6-yl) acetamide (compound 2.2, Scheme 2)

[0185] The titrated compound was synthesised according to Process F described above, starting with 2-methylquinolin-6-amine 2.1 (60 mg, 0.38 mmol, 1 eq) in dichloromethane (0.2 M, 1.9 mL) , acetyl chloride (30 pL, 1.1 eq, 0.42 mmol) and triethylamine (158 pL, 3 eq, 1.14 mmol) , stirring for 2 h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 60:40) yielded the pure titrated compound as a yellow solid in quantitative yield (76 mg) . Characterization: Rt = 1.24 min, MS (ESI) m / z = 201.2 [M+H]+. Exact mass: 200.0950. iH NMR (400 MHz, CDC13) 5 8.32 (d, J = 2.4 Hz, 1H) , 8.00 (d, J = 8.8 Hz, 2H) , 7.94 (d, J = 9.0 Hz, 1H) , 7.53 (dd, J = 9.0, 2.5 Hz, 1H) , 7.28 (d, J = 1.9 Hz, 1H) , 2.73 (s, 3H) , 2.24 (s, 3H) .

[0186] N- (2-methylquinolin-6-yl) propionamide (compound 2.3, Scheme 2)

[0187] The titrated compound was synthesised according to Process F described above, starting with 2-methylquinolin-6-amine 2.1 (50 mg, 0.32 mmol, 1 eq) in dichloromethane (0.2 M, 1.6 mL) , propionyl chloride (30 pL, 1.1 eq, 0.35 mmol) and triethylamine (132 pL, 3 eq, 0.95 mmol) , stirring for 18 h. Purification by silica gel column chromatography (dichloromethane / methanol 95:05) yielded the pure titrated compound as a white solid in quantitative yield (70 mg) . Characterization: Rt = 1.41 min, MS (ESI) m / z = 213.1 [M-H]~ . Exact mass: 214.1106. NMR (400 MHz, CDC13) 5 8.33 (d, J = 2.4 Hz, 1H) , 7.99 (d, J = 8.4 Hz, 1H) , 7.93 (d, J = 9.0 Hz, 1H) , 7.58 - 7.45 (m, J = 9.0 Hz, 1H) .58 - 7.45 (m, 2H) , 7.29 - 7.22 (m, 1H) , 2.71 (s, 3H) , 2.45 (q, J = 7.6 Hz, 2H) , 1.28 (t, J = 7.5 Hz, 3H) .

[0188] N- (2-methylquinolin-6-yl) cyclohexanecarboxamide (compound 2.4, Scheme 2)

[0189] The titrated compound was synthesised according to Process F described above, starting with 2-methylquinolin-6-amine 2.1 (50 mg, 0.32 mmol, 1 eq) in dichloromethane (0.2 M, 1.6 mL) , cyclohexanecarbonylchloride (47 pL, 1.1 eq, 0.35 mmol) and triethylamine (132 pL, 3 eq, 0.95 mmol) , stirring for 18 h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 60:40) yielded the pure titrated compound as a white solid in a yield of 93% (80 mg) . Characterization: Rt = 1.96 min, MS (ESI) m / z = 267.2 [M-H] . Exact mass: 268.1576. iH NMR (400 MHz, CDC13) 5 8.38 (d,

[0190] J = 2.4 Hz, 1H) , 8.00 (d, J = 8.5 Hz, 1H) , 7.95 (d, J = 9.0

[0191] Hz, 1H) , 7.57 - 7.48 (m, 2H) , 7.28 (d, J = 1.0 Hz, 1H) , 2.73

[0192] (s, 3H) , 2.31 (tt, J = 11.0 Hz, 2H) .31 (tt, J = 11.7, 3.5

[0193] Hz, 1H) , 2.01 (d, J = 12.9 Hz, 2H) , 1.92 - 1.83 (m, 2H) ,

[0194] 1.77 (d, J = 13.8 Hz, 2H) , 1.60 (q, J = 12.5 Hz, 2H) , 1.32

[0195] (q, J = 12.8 Hz, 4H) .

[0196] N- (2-methylquinolin-6-yl) butan-l-sulphonamide (compound

[0197] 2.5, Scheme 2)

[0198] To the solution of 2 -methylquinolin- 6-amine 2.1 (50 mg, 0.32 mmol, 1 eq) in dry dichloromethane (0.2 M, 1.6 mL) at 0°C, butyl sulphonyl chloride (1.5 eq, 0.47 mmol, 61 pL) and triethylamine (3 eq, 0.95 mmol, 132 pL) were added and the mixture was stirred at room temperature overnight. Then aqueous NaOH 2M (4.5 eq, 0.72 mL) and methanol (1.3 mL) were added to destroy the bisulphonamide derivative. The resulting mixture was stirred at room temperature for 3 h. The mixture was diluted with ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2 SO4, filtered and evaporated. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 70:30) yielded the pure titrated compound as transparent oil in a yield of 83% (74 mg) . Characterization: Rt = 1.79 min, MS (ESI) m / z = 277.1 [M-H] . Exact mass: 278.1089. iH NMR (400

[0199] MHz, CDCI3 ) 5 8.00 (dd, J = 8.7, 2.1 Hz, 2H) , 7.67 (d, J =

[0200] 2.5 Hz, 1H) , 7.46 (dd, J = 9.0, 2.5 Hz, 1H) , 7.30 (d, J =

[0201] 8.5 Hz, 1H) , 6.5 (d, J = 8.5 Hz, 1H) .5 Hz, 1H) , 6.92 (s, 1H) , 3.19 - 3.10 (m, 2H) , 2.73 (s, 3H) , 1.89 - 1.77 (m, 2H) , 1.41 (h, J = 7.4 Hz, 2H) , 0.88 (t, J = 7.4 Hz, 3H) .

[0202] N- (2-formylquinolin-6-yl) acetamide (compound 2.6, Scheme 2)

[0203] The titrated compound was synthesised according to Process C described above, starting with N- (2-methylquinolin-6- yl)acetamide 2.2 (75 mg, 0.379 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 1.9 mL) , selenium dioxide (1.3 eq, 0.49 mmol, 54 mg) . The reaction mixture was stirred at 80°C for 2h. The titrated product was obtained pure without column chromatographic purification. Yield: 95% (76 mg) . Characterization: Rt 1.37 min, generic method, MS (ESI) m / z = 215.0 [M+H]+. Exact mass: 214.0742. NMR (400 MHz, CDC13) 5 10.19 (d, J = 0.9 Hz, 1H) , 8.45 (s, 1H) , 8.26 (d, J = 8.5 Hz, 1H) , 8.19 (d, J = 9.0 Hz, 1H) , 8.02 (d, J = 8.5 Hz, 1H) , 7.65 (dd, J = 9.1, 2.4 Hz, 1H) , 7.45 (s, 1H) , 2.29 (s, 3H) .

[0204] N- (2-formylquinolin-6-yl) propionamide (compound 2.7, Scheme

[0205] 2)

[0206] The titrated compound was synthesised according to Process

[0207] C described above, starting with N- (2-methylquinolin-6- yl ) propionamide 2.3 (65 mg, 0.30 mmol, 1 eq) in dry 1,4- di oxane ( 0.2 M, 1.5 mL) , selenium dioxide (1.3 eq, 0.39 mmol, 44 mg) . The reaction mixture was stirred at 80°C for 2h. The titrated product was obtained pure without column chromatographic purification. Yield: 61% (43 mg) . Characterization: Rt 1.56 min, generic method, MS (ESI) m / z = 227.0 [M+H]+. Exact mass: Exact mass: 228.0899.1H NMR (400 MHz, CDC13_3mm) 5 10.19 (s, 1H) , 8.48 (d, J = 2.3 Hz, 1H) , 8.25 (d, J = 8.5 Hz, 1H) , 8.18 (d, J = 9.1 Hz, 1H) , 8.01 (d, J = 8.1 Hz, 1H) .O1 (d, J = 8.4 Hz, 1H) , 7.66 (dd, J = 9.1, 2.4 Hz, 1H) , 7.45 (s, 1H) , 2.48 (dq, J = 14.8, 7,5 Hz, 3H) , 1.31 (t, J = 7.5 Hz, 3H) .

[0208] N- (2-f ormylquinolin-6-yl) cyclohexanecarboxamide (compound 2.8, Scheme 2)

[0209] The titrated compound was synthesised according to Process C described above, starting with N- (2-methylquinolin-6- yl ) cyclohexanecarboxamide 2.4 (75 mg, 0.28 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 1.4 mL) , selenium dioxide (1.3 eq, 0.49 mmol, 54 mg) . The reaction mixture was stirred at 80°C for 2h. The titrated product was obtained pure without column chromatographic purification. Yield: 98% (76 mg) . Characterization: Rt 2.13 min, generic method, MS (ESI) m / z = 283.0 [M+H]+. Exact mass: 282.1368. NMR (400 MHz, CDC13) 5 10,21 (d, J = 0,9 Hz, 1H) , 8,53 (d, J = 2,4 Hz, 1H) , 8,26 (d, J = 8,3 Hz, 1H) , 8,20 (d, J = 9,1 Hz, 1H) , 8,02 (d, J = 8,5 Hz, 1H) , 7, 68 (dd, J = 9,1, 2.4 Hz, 1H) , 7.56 - 7.47 (m, 1H) , 2.35 (tt, J = 11.7, 3.5 Hz, 1H) , 2.04 (d, J = 13.0 Hz, 2H) , 1.95 - 1.86 (m, 3H) , 1.76 (d, J = 9.7 Hz, 1H) , 1.72- 1.58 (m, 1H) , 1.44 - 1.24 (m, 3H) .

[0210] N- (2-formylquinolin-6-yl) butan-l-sulphonamide (compound 2.9, Scheme 2)

[0211] The titrated compound was synthesised according to Process C described above, starting with N- (2-methylquinolin-6- yl ) butane-l-sulphonamide 2.5 (70 mg, 0.26 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 1.3 mL) , selenium dioxide (1.3 eq, 0.33 mmol, 36 mg) . The reaction mixture was stirred at 80°C for 2h. The titrated product was obtained pure without column chromatographic purification. Yield: 73% (55 mg) . Characterization: Rt 1.89 min, generic method, MS (ESI) m / z = 293.0 [M+H]+. Exact mass: 292.0882. iH NMR (400 MHz, CDCI3 3mm) 5 10.20 (d, J = 0.9 Hz, 1H) , 8.24 (dd, J = 8.8, 6.0 Hz, 2H) , 8.04 (d, J = 8.5 Hz, 1H) , 7.75 (d, J = 2.6 Hz,

[0212] 1H) , 7.58 (dd, J = 9.6 Hz, 1H) .58 (dd, J = 9.1, 2.5 Hz, 1H) ,

[0213] 6.97 (s, 1H) , 3.27 - 3.19 (m, 2H) , 1.92 - 1.80 (m, 2H) , 1.44

[0214] (h, J = 7.3 Hz, 2H) , 0.91 (t, J = 7.3 Hz, 3H) .

[0215] N- (2- ( (3-hydroxypiperidin-l-yl)methyl) quinolin-6- yl) acetamide (Compound 2.10, Scheme 2)

[0216] To the solution of 3-hydroxypiperidin-l-ium chloride (31 mg,

[0217] 0.22 mmol, 1.2 eq) in dry dichloromethane (0.1 M, 1.9 mL) at room temperature, triethylamine (6.6 eq, 1.23 mmol, 0.17 mL) was added. A gas evolution was observed. The mixture was shaken for 5 min to obtain the free amine, which was reacted with N- (2-formylquinolin-6-yl) acetamide 2.6 (1 eq, 0.19 mmol, 40 mg) , acetic acid (10 eq, 1.9 mmol, 0.1 mL) and sodium triacetoxyborohydride (4 eq, 0.75 mmol, 158 mg) , according to Process E described above. Purification by silica gel column chromatography (ethylacetate / methanol 95:05) yielded the compound as a white foamy solid in a yield of 85% (48 mg) . Characterization: Rt 0.87 min generic method, MS (ESI) m / z = 300.1 [M+H]+. Exact mass: 299.1634. iH NMR (400 MHz, DMSO) 5 10.24 (s, 1H) , 8.32 (d, J = 2.3 Hz, 1H) , 8.22 (d, J = 8.5 Hz, 1H) , 7.90 (d, J = 9.0 Hz, 1H) , 7.74 (dd, J = 9.0 Hz, 1H) .74 (dd, J = 9.1, 2.4 Hz, 1H) , 7.55 (d, J = 8.5 Hz, 1H) , 4.59 (s, 1H) , 3.74 (d, J = 13.6 Hz, 1H) , 3.66 (d, J = 13.6 Hz, 1H) , 3.66 (d, J = 13.6 Hz, 1H) .6 Hz, 1H) , 3.48 (dt, J = 9.5, 4.7 Hz, 1H) , 2.80 (dd, J = 10.5, 4.0 Hz, 1H) , 2.71 - 2.61 (m, 1H) , 2.12 (s, 3H) , 2.03 - 1.93 (m, 1H) , 3H (s, 1H) .93 (m, 1H) , 1.87 - 1.77 (m, 2H) , 1.63 (dt, J = 13.4, 3.6 Hz, 1H) , 1.45 (q, J = 12.3 Hz, 1H) , 1.13 - 1.03 (m, 1H) .

[0218] N- (2- ( (3-hydroxypiperidin-l-yl)methyl) quinolin-6- yl) propionamide (compound 2.11, Scheme 2)

[0219] To the solution of 3-hydroxypiperidin-l-ium chloride (29 mg, 0.21 mmol, 1.2 eq) in dry dichloromethane (0.1 M, 1.8 mL) at room temperature, triethylamine (6.6 eq, 1.16 mmol, 0.16 mL) was added. A gas evolution was observed. The mixture was shaken for 5 min to obtain the free amine, which was reacted with N- (2-formylquinolin-6-yl) propionamide 2.7 (1 eq, 0.18 mmol, 40 mg) , acetic acid (10 eq, 1.75 mmol, 0.10 mL) and sodium triacetoxyborohydride (4 eq, 0.70 mmol, 149 mg) , according to Process F described above. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 90:10) yielded the compound as a white solid in a yield of 58% (32 mg) . Characterization: Rt 1.16 min, generic method, MS (ESI) m / z = 312.1 [M+H]+. Exact mass: Exact mass: 313.1790. iH NMR (400 MHz, DMSO) 5 10.18 (s, 1H) , 8.34 (d, J = 2.3 Hz, 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.89 (d, J = 9.0 Hz, 1H) , 7.75 (dd, J = 9.0 Hz, 1H) .75 (dd, J = 9.1, 2.4 Hz, 1H) , 7.56 (d, J = 8.5 Hz, 1H) , 4.62 (d, J = 4.9 Hz, 1H) , 3.74 (d, J = 13.6 Hz, 1H) , 3.65 (d, J = 13.6 Hz, 1H) , 3.65 (d, J = 13.6 Hz, 1H) .6 Hz, 1H) , 3.53 - 3.43 (m, 1H) , 2.80 (d, J = 10.4 Hz, 1H) , 2.66 (d, J = 11.1 Hz, 1H) , 2.39 (q, J = 7.5 Hz, 2H) , 2.02 - 1.92 (m, J = 4.9 Hz, 1H) .02 - 1.92 (m, 1H) , 1.82 (t, J = 9.8 Hz, 2H) , 1.70 - 1.57 (m, 1H) , 1.45 (q, J = 12.2 Hz, 1H) , 1.12 (t, J = 7.5 Hz, 4H) .

[0220] N- (2- ( (3-hydroxypiperidin-l-yl)methyl) quinolin-6- yl) cyclohexanecarboxamide (compound 2.12, Scheme 2)

[0221] To the solution of 3-hydroxypiperidin-l-ium chloride (41 mg,

[0222] 0.30 mmol, 1.2 eq) in dry dichloromethane (0.1 M, 2.5 mL) at room temperature, triethylamine (6.6 eq, 1.64 mmol, 0.23 mL) was added. A gas evolution was observed. The mixture was shaken for 5 min to obtain the free amine, which was reacted with N- (2-formylquinolin-6-yl) cyclohexanecarboxamide 2.8 (1 eq, 0.25 mmol, 70 mg) , acetic acid (10 eq, 2.5 mmol, 0.14 mL) and sodium triacetoxyborohydride (4 eq, 0.99 mmol, 210 mg) , according to Process E described above. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 95:05) yielded the compound as a white solid in a yield of 46% (42 mg) . Characterization: Rt 1.69 min, generic method, MS (ESI) m / z = 368.1 [M+H]+. Exact mass: 367.2260. !H NMR (400 MHz, DMSO) 5 10.11 (s, 1H) , 8.36 (d, J = 2.3 Hz, 1H) , 8.20 (d, J = 8.5 Hz, 1H) , 7.88 (d, J = 9.0 Hz, 1H) , 7.76 (dd, J = 9.0 Hz, 1H) .1, 2.4 Hz, 1H) , 7.55 (d, J = 8.5 Hz, 1H) , 4.61 (d, J = 4.9 Hz, 1H) , 3.74 (d, J = 13.6 Hz, 1H) , 3.65 (d, J = 13.6 Hz, 1H) , 3.54 - 3.42 (m, 1H) , 3.5 - 3.5 (m, 1H) .42 (m, 1H) , 2.80 (dd, J = 10.7, 4.0 Hz, 1H) , 2.66 (d, J = 11.0 Hz, OH) , 2.40 (tt, J = 11.6, 3.5 Hz, 1H) , 2.01 - 1.92 (m, 1H) , 1.88 - 1.73 (m, 1H) .88 - 1.73 (m, 6H) , 1.72 - 1.59 (m, 2H) , 1.45 (q, J = 12.3 Hz, 3H) , 1.27 (dq, J = 23.9, 12.2 Hz, 3H) , 1.08 (qd, J = 12.2, 4.2 Hz, 1H) .

[0223] N- (2- ( ( 3 -hydroxypiper idin-l-yl) methyl) quinol in- 6 -yl) butan- 1 -sulphonamide (compound 2.13, Scheme 2)

[0224] To the solution of 3-hydroxypiperidin-l-ium chloride (40 mg, 0.29 mmol, 1.2 eq) in dry dichloromethane (0.1 M, 2.4 mL) at room temperature, triethylamine (6.6 eq, 1.58 mmol, 0.22 mL) was added. A gas evolution was observed. The mixture was shaken for 5 min to obtain the free amine, which was reacted with N- (2-formylquinolin-6-yl) butan-l-sulphonamide 2.9 (1 eq, 0.24 mmol, 70 mg) , acetic acid (10 eq, 2.39 mmol, 0.14 mL) and sodium triacetoxyborohydride (4 eq, 0.96 mmol, 203 mg) , according to Process E described above. Purification by silica gel column chromatography (dichloromethane / methanol

[0225] 100:0 to 90:10) yielded the compound as a white solid in a yield of 57% (52 mg) . Characterization: Rt 1.47 min, generic method, MS (ESI) m / z = 378.9 [M+H]+. Exact mass: 377.1773. iH NMR (400 MHz, DMSO) 5 8.24 (d, J = 8.5 Hz, 1H) , 7.92 (d, J = 9.0 Hz, 1H) , 7.67 (s, 1H) , 7.57 (d, J = 8.5 Hz, 1H) , 4.60 (d, J = 5.5 Hz, 1H) .60 (d, J = 5.0 Hz, 1H) , 3.74 (d, J = 13.6 Hz, 1H) , 3.66 (d, J = 13.7 Hz, 1H) , 3.23 - 3.11 (m, 2H) , 2.80 (d, J = 10.5 Hz, 1H) , 2.80 (d, J = 10.5 Hz, 1H) .5 Hz, 1H) , 2.69 - 2.66 (m, 1H) , 1.97 (t, J = 9.4 Hz, 1H) , 1.83

[0226] (t, J = 9.8 Hz, 1H) , 1.65 (td, J = 14.5, 6.5 Hz, 3H) , 1.53 - 1.38 (m, 1H) , 1.33 (dt, J = 14.4, 7.2 Hz, 2H) , 1.09 (d, J = 10.7 Hz, 1H) , 0.81 (t, J = 7.4 Hz, 3H) .

[0227] 6-fluoro-2-methylquinolin-4-ol (compound 3.1, Scheme 3)

[0228] 4-f luoroaniline 1.1 (4000 mg, 36 mmol, 1 eq) was stirred in polyphosphoric acid (20 g) at 80°C for 10 min. Then ethyl acetoacetate (4556 pL, 1 eq, 36 mmol) was slowly added and the mixture was stirred at 130°C for 4 h. The resulting black oil was allowed to cool to room temperature. Then water and ammonia were added and the resulting mixture was stirred for 15 minutes. The formation of a solid was observed. The solid was filtered and washed with water. The residue was dried and purified by silica gel column chromatography using 100% to 80% DCM / MeOH as an eluent to obtain the compound as a white solid with a yield of 51%. (3295 mg) . Characterization: Rt 1.08 min, generic method, MS (ESI) m / z = 177.8 [M+H]+. Exact mass: 177.0590. iH NMR (400 MHz, DMSO) 5 7.68 (dd, J = 9.4, 2.9 Hz, 1H) , 7.62 - 7.48 (m, 2H) , 5.94 (s, 1H) , 2.35 (s, 3H) .

[0229] 4- (benzyloxy) -6-fluoro-2-methylquinoline (compound 3.2,

[0230] Scheme 3)

[0231] The titrated compound was synthesised according to Process I described above, starting with 4-f luoro-2-hydroxyquinoline

[0232] 3.1 (50 mg, 0.28 mmol, 1 eq) , potassium carbonate (2 eq, 0.56 mmol, 79 mg) and benzylbromide (1.2 eq, 0.34 mmol, 40 pL) in dry N, N-dime thy 1 formamide (0.3 M, 0.9 mL) . The reaction mixture was stirred at room temperature for 20 h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 70:30) yielded the compound as a white solid in a yield of 85% (65 mg) . Characterization: Rt 2.39 min, generic method. MS (ESI) m / z = 268.0 [M+H]+. Exact mass: 267.1059. NMR (400 MHz, CDC13) 5 7.94 (dd, J = 9.2,

[0233] 5.2 Hz, 1H) , 7.79 (dd, J = 9.5, 2.9 Hz, 1H) , 7.49 (ddd, J = 10.1, 7.8, 1.6 Hz, 3H) , 7.46 - 7.36 (m, 3H) , 6.72 (s, 1H) , 5.26 (s, 2H) , 2.68 (s, 3H) .

[0234] 6-fluoro-4- ( (4 -fluorobenzyl) oxy) -2 -methylquinoline

[0235] (compound 3.3, Scheme 3)

[0236] The titrated compound was synthesised according to Process

[0237] I described above, starting with 4-f luoro-2-hydroxyquinoline 3.1 (60 mg, 1 eq, 0.34 mmol) in N, N-dime thy 1 formamide dry (0.3 M, 1.1 mL) , potassium carbonate (2 eq, 0.68 mmol, 94 mg) and 4-f luoro-benzylbromide (1.2 eq, 0.41 mmol, 51 pL) . The reaction mixture was stirred at room temperature for 20 h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10 to 60:40) yielded the compound as a grey solid in a yield of 88% (85 mg) .

[0238] Characterization: Rt 2.44 min, generic method. MS (ESI) m / z = 285.6, 287.0 [M+H]+. Exact mass: 285.0965.1H NMR (400 MHz, CDC13_3mm) 5 7.96 (dd, J = 9.2, 5.2 Hz, 1H) , 7.77 (dd, J = 9.4, 2.9 Hz, 1H) , 7.53 - 7.40 (m, 3H) , 7.21 - 7.10 (m, 2H) , 5.24 (s, 2H) , 2.70 (s, 3H) .

[0239] Pyrazine -2 -methyl methanesulphonate (compound 3.4a, Scheme

[0240] To the solution of pyrazin-2-ylmethanol (100 mg, 0.91 mmol, 1 eq) in dry dichloromethane (IM, 0.9 mL) at 0°C, methanesulphonylchloride (1.8 eq, 1.63 mmol, 126 pL) and triethylamine (1.8 eq, 1.63 mmol, 227 pL) were added and the mixture was stirred at room temperature for 18 h. The solvents were evaporated and the intermediate was used as such for the next step.

[0241] 6-fluoro-2 -methyl -4- (pyrazine-2 -methoxy) quinoline (compound 3.4, Scheme 3)

[0242] The titrated compound was synthesised according to Process

[0243] I described above, starting with 4-f luoro-2-hydroxyquinoline 3.1 (50 mg, 1 eq, 0.28 mmol) in dry N, -dime thy 1 formamide (0.15 M, 1.9 mL) , potassium carbonate (3 eq, 0.85 mmol, 117 mg, and pyrazin-2-methyl methanesulphonate 3.4a (1 eq, 0.85 mmol) .15 M, 1.9 mL) , potassium carbonate (3 eq, 0.85 mmol, 117 mg) and pyrazin-2-methyl methanesulphonate 3.4a (1.2 eq, 0.34 mmol, 63 mg) , adding catalytic sodium iodide (0.2 eq, 0.06 mmol, 8 mg) . The reaction mixture was stirred at room temperature for 20 h, then heated to 70°C for 5 h. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 90:10) yielded the compound as a white solid in a yield of 43% (33 mg) .

[0244] Characterization: Rt 1.74 min, generic method. MS (ESI) m / z = 270.0 [M+H]+. Exact mass: 269.0964. iH NMR (400 MHz, DMSO) 5 9.00 (d, J = 1.5 Hz, 1H) , 8.72 (dd, J = 2.6, 1.5 Hz, 1H) , 8.70 (d, J = 2.5 Hz, 1H) , 7.94 (dd, J = 9.2, 5.4 Hz, 1H) .2, 5.4 Hz, 1H) , 7.82 (dd, J = 9.7, 2.9 Hz, 1H) , 7.62 (td, J = 8.8, 3.0 Hz, 1H) , 7.18 (s, 1H) , 5.55 (s, 2H) , 2.61 (s, 3H) .

[0245] 4- (benzyloxy) -6-fluoroquinolin-2-carbaldehyde (compound

[0246] 3.5, Scheme 3)

[0247] The titrated compound was synthesised according to Process C described above, starting with 4- (benzyloxy) -6-fluoro-2- methylquinoline 3.2 (65 mg, 0.24 mmol, 1 eq) in dry 1,4- dioxane (0.2 M, 1.2 mL) , selenium dioxide (1.3 eq, 0.32 mmol, 35 mg) . The reaction mixture was stirred at 80°C for 2h. The titrated product was obtained pure without column chromatographic purification. Yield: 95% (67 mg) . Characterization: Rt 1.56 min, generic method, MS (ESI) m / z = 281.9 [M+H]+, 280.0 [M-H] . Exact mass: 281.0852. iH NMR (400 MHz, CDC13) 5 10.13 (s, 1H) , 8.20 (dd, J = 9.2, 5.3 Hz, 1H) , 7.90 (dd, J = 9.3, 2.9 Hz, 1H) , 7.56 (ddd, J = 9.3, 8.0, 2.9 Hz, 1H) , 7.53 - 7.38 (m, 6H) , 5.36 (s, 2H) .

[0248] 6-fluoro-4- ( (4 -fluorobenzyl) oxy) quinolin-2-carbaldehyde (compound 3.6, Scheme 3)

[0249] The titrated compound was synthesised according to Process C described above, starting with 6-f luoro-4- ( ( 4- f luorobenzyl ) oxy ) -2-methylquinoline 3.3 (70 mg, 0.25 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 1.2 mL) , selenium dioxide (1.3 eq, 0.32 mmol, 35 mg) , stirred at 80°C for 2 h. The titrated product was obtained pure without purification by column chromatography (quantitative yield, 74 mg) . Characterization: Rt 2.55 min, MS (ESI) m / z = 300.0 [M+H]+. Exact mass: 299.0758.1H NMR (400 MHz, CDC13_3mm) 5 10.15 (s, 1H) , 8.22 (dd, J = 9.2, 5.3 Hz, 1H) , 7.89 (dd, J = 9.2, 2.9 Hz, 1H) , 7.64 - 7.52 (m, 2H) , 7.52 (s, 1H) , 7.22 - 7.12 (m, 2H) , 5.35 ( s , 2H) .

[0250] 6-fluoro-4- (pyrazin-2-ylmethoxy) quinolin-2-carbaldehyde (compound 3.7, Scheme 3)

[0251] The titrated compound was synthesised according to the previously described Process C, starting with 6-fluoro-2- methyl-4- (pyrazin-2-ylmethoxy) quinoline 3.4 (42 mg, 0.16 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 0.8 mL) , selenium dioxide (1.3 eq, 0.32 mmol, 22 mg) , stirred at 80°C for 2 h. Purification of the product by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 90:10) yielded the pure titrated compound in a yield of 29% (13 mg) . Characterization: Rt 1.84 min, MS (ESI) m / z = 283.9 [M+H]+. Exact mass: 283.0757. iH NMR (400 MHz, CDC13) 5 10,16 (s, 1H) , 8,92 (d, J = 1,5 Hz, 1H) , 8,71 - 8, 64 (m, 2H) , 8,25 (dd, J = 9,2, 5.3 Hz, 1H) , 7.94 (dd, J = 9.2, 2.9 Hz, 1H) , 7.62 (ddd, J = 9.2, 8.0, 2.9 Hz, 1H) , 7.55 (s, 1H) , 5.57 (s

[0252] 2H) .

[0253] I- ( (4- (benzyloxy) -6-fluoroquinolin-2-yl)methyl)piperidin-3- ol (compound 3.8, Scheme 3)

[0254] To the solution of 3-hydroxypiperidin-l-ium chloride (38 mg, 0.28 mmol, 1.2 eq) in dry dichloromethane (0.1 M, 2.3 mL) at room temperature, triethylamine (6.6 eq, 1.58 mmol, 0.22 mL) was added. A gas evolution was observed. The mixture was shaken for 5 min to obtain the free amine, which was reacted with 4- (benzyloxy) -6-f luoroquinolin-2-carbaldehyde 3.5 (1 eq, 0.23 mmol, 65 mg) , acetic acid (10 eq, 2.31 mmol, 0.13 mL) and sodium triacetoxyborhydrochloride (4 eq, 0.92 mmol, 196 mg) , according to Process E described above. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 90:10) yielded the compound as a white solid in a yield of 57% (49 mg) . Characterization: Rt 2.05 min, generic method, MS (ESI) m / z = 367.0 [M+H]+. Exact mass: 366.1744. iH NMR (400 MHz, DMSO) 5 7.97 (dd, J = 9.2, 5.3 Hz, 1H) , 7.76 (dd, J = 9.6, 2.9 Hz, 1H) , 7.63 (td, J = 8.8, 3.0 Hz, 1H) , 7.60 - 7.55 (m, J = 8.0 Hz, 1H) .60 - 7.55 (m, 2H) , 7.48 - 7.42 (m, 2H) , 7.41 - 7.35 (m, 1H) , 7.25 (s, 1H) , 5.41 (s, 2H) , 4.61 (s, 1H) , 3.74 -

[0255] 3.60 (m, 2H) , 7.60 (td, J = 9.8, 3.0 Hz, 1H) .60 (m, 2H) ,

[0256] 3.50 (bs, 1H, superimposed on solvent signal) , 2.78 (dd, J

[0257] = 10.4, 3.9 Hz, 1H) , 2.60 (d, J = 11.2 Hz, 1H) , 2.02 - 1.90

[0258] (m, 1H) , 1.90 - 1.74 (m, 2H) , 1.62 (dd, J = 13.4, 3.9 Hz, 1H) , 1.43 (q, J = 11.8 Hz, 1H) , 1.09 (qd, J = 12.1, 4.0 Hz, 1H) .

[0259] 1- ( (6-fluoro-4- ( (4 -fluorobenzyl) oxy) quinolin-2-yl) methyl) piperidin-3-ol (compound 3.9, Scheme 3)

[0260] To the solution of piperidin-3-ol hydrochloride (41 mg, 0.3 mmol, 1.2 eq) in dry dichloromethane (0.1 M, 2.5 mL) at room temperature, triethylamine (6.6 eq, 1.65 mmol, 230 pL) was added. A gas evolution was observed. The mixture was stirred for 5 min to obtain the free amine, which was reacted with 6-fluoro-4- ( ( 4- fluorobenzyl ) oxy) quinolin-2-carbaldehyde 3.6 (1 eq, 0.25 mmol 75 mg) , acetic acid (10 eq, 2.51 mmol, 143 pL) and sodium triacetoxyborohydride (4 eq, 1 mmol, 212 mg) according to Process E described above. Purification by silica gel column chromatography (dichloromethane / methanol 95:05) yielded the compound as a pale yellow solid in a yield of 58% (56 mg) . Characterization: Rt 2.16 min, generic method, MS (ESI) m / z = 385.0 [M+H]+, 443.1 [M+CH3COO]~ . Exact mass: 384.1649. iH NMR (400 MHz, DMSO) 5 7.96 (dd, J = 9.2, 5.3 Hz, 1H) , 7.74 (dd, J = 9.6, 2.9 Hz, 1H) , 7.61 (dddd, J = 10.3, 7.0, 4.9 Hz, 1H) .3, 7.0, 4.1, 2.2 Hz, 3H) , 7.30 - 7.20 (m, 3H) , 5.38 (s, 2H) , 4.69 (s, 1H) , 3.72 - 3.60 (m, 2H) , 2.7 (dd, J = 10.6, 2.9 Hz, 1H) , 2.7 (dd, J = 10.3 Hz, 2H) .77 (dd, J = 10.7, 4.0 Hz, 1H) , 2.58 (d, J = 11.1 Hz, 1H) , 1.96 (td, J = 11.1, 2.8 Hz, 1H) , 1.91 - 1.82 (m, 1H) , 1.82 - 1.74 (m, 1H) , 1.61 (dt, J = 13.1, 3.8 Hz, 1H) , 1.43 (qd, J = 12.3, 7.5 Hz, 1H) , 1.16 - 1.03 (m, 1H) .

[0261] 1- ( (6-fluoro-4- (pyrazin-2-ylmethoxy) quinolin-2- yl) methyl ) piperidin-3-ol (compound 3.10, Scheme 3)

[0262] To the solution of piperidin-3-ol hydrochloride (7 mg, 0.05 mmol, 1.2 eq) in dry dichloromethane (1 mL) at room temperature, triethylamine (6.6 eq, 0.28 mmol, 39 pL) was added. A gas evolution was observed. The mixture was shaken for 5 min to obtain the free amine, which was reacted with 6-f luoro-4- (pyrazin-2-ylmethoxy ) quinolin-2-carbaldehyde 3.7 (1 eq, 0.04 mmol, 12 mg) , acetic acid (10 eq, 0.42 mmol, 24 pL) and sodium triacetoxyborohydride (4 eq, 0.17 mmol, 36 mg) according to Process E described above. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 90:10) yielded the compound as a white solid in a yield of 63% (10 mg) . Characterization: Rt 1.51 min, generic method, MS (ESI) m / z = 369.0 [M+H]+. Exact mass: 368.1649. !H NMR (400 MHz, DMSO) 5 8.97 (d, J = 1.5 Hz, 1H) , 8.74 - 8.66 (m, 2H) , 7.99 (dd, J = 9.2, 5.3 Hz, 1H) , 7.85 (dd, J = 9.6, 3.0 Hz, 1H) , 7.65 (td, J = 8.8, 3.0 Hz, 1H) , 7.26 (s, 1H) , 5.58 (s, 2H) , 4.61 (d, J = 5.1 Hz, 1H) , 3.76 - 3.57 (m, 3H) .76 - 3.57 (m, 2H) , 3.54 - 3.47 (m, 1H) , 2.76 (d, J = 10.5 Hz, 1H) , 2.57 (s, 1H) , 1.96 (t, J = 11.6 Hz, 1H) , 1.82 (dt, J = 19.5 Hz, 1H) .82 (dt, J = 19.3, 10.5 Hz, 2H) , 1.61 (d, J = 12.9 Hz, 1H) , 1.41 (d, J = 12.6 Hz, 1H) , 1.13 - 1.03 (m, 1H) .

[0263] 2- (ethoxycarbonyl) piperidin-l-ium chloride (compound 4.2, Scheme 4 )

[0264] To the solution of pipecolinic acid 4.1 (1 g, 7.74 mmol, 1 eq) in absolute ethanol (0.5 M, 16 mL) thionyl chloride (1.2 eq, 9.3 mmol, 0.67 mL) was added. A gas evolution was observed. The reaction mixture was stirred at room temperature overnight. The solvents and excess thionyl chloride were evaporated to obtain the product. The product was obtained pure without any purification. Characterization: Rt = 0.86 min, generic method. MS (ESI) m / z = 158.1 [M+H] . Exact mass: 157.1103. NMR (400 MHz, DMSO) 5 9.50 (s, 1H) , 4.23 (q, J = 7.1 Hz, 2H) , 4.06 (d, J = 10.9 Hz, 1H) , 3,24 (d, J = 12.7 Hz, 1H) , 2.89 (t, J = 11.5 Hz, 1H) , 2.12 - 2.01 (m, 1H) , 1.80 - 1.46 (m, 3H) , 1.25 (t, J = 7.1 Hz, 3H) . ethyl l-( (6-fluoroquinolin-2-yl) methyl ) piperidin-2- carboxylate (compound 4.3, Scheme 4)

[0265] To the solution of 2- (ethoxycarbonyl) piperidin-l-ium chloride 4.2 (850 mg, 4.3 mmol, 1.2 eq) in dry dichloromethane (18.3 mL, 0.2 M) at room temperature, triethylamine (6.6 eq, 24.11 mmol, 3.36 mL) was added. A gas evolution was observed. The mixture was stirred for 5 min to obtain the free amine, which was reacted with 6- f luoroquinolin-2-carbaldehyde 1.9 (1 eq, 3.65 mmol, 640 mg) , acetic acid (10 eq, 36.54 mmol, 2.09 mL) and sodium triacetoxyborohydride (4 eq, 14.62 mmol, 3.097 g) , stirring the reaction overnight, according to Process E described above. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 95:05) yielded the product as a yellow solid in quantitative yield (1.215 g) . Characterization: Rt 2.43 min, generic method. MS (ESI) m / z = 317.1 [M+H. Exact mass: 316.1587. iH NMR (400 MHz, CDC13) 5 8.09 - 8.01 (m, 2H) , 7.78 (dd, J = 8.5, 0.9 Hz, 1H) , 7.47 - 7.36 (m, 2H) , 4.20 (qd, J = 7.5, 0.9 Hz, 1H) .2O (qd, J = 7.1, 1.7 Hz, 2H) , 4.06 (d, J = 14.1 Hz, 1H) , 3.69 (d, J =

[0266] 14.1 Hz, 1H) , 3.26 (dd, J = 8.3, 4.0 Hz, 1H) .3, 4, 0 Hz, 1H) ,

[0267] 2.94 (dt, J = 11, 6, 4,8 Hz, 1H) , 2,27 (dt, J = 12.0, 6.2 Hz,

[0268] 1H) , 1.98 - 1.77 (m, 2H) , 1.71 - 1.63 (m, OH) , 1.56 (qd, J = 6.3, 4.3 Hz, 2H) , 1.49 - 1.34 (m, 1H) , 1.28 (t, J = 7.1 Hz, 3H) .

[0269] 1- ( (6-fluoroquinolin-2-yl) methyl) -N-phenylpiperidin-2- carboxamide (compound 4.4, Scheme 4)

[0270] The titrated compound was synthesised according to Process KI, starting with ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) piperidin-2-carboxylate 4.3 (40 mg, 0.13 mmol, 1 eq) , aniline (1 eq, 0.13 mmol, 11 pL) and trimethylaluminium 2M in toluene (3 eq, 0.38 mmol, 0.19 mL) , stirring the reaction at room temperature overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 60:40) yielded the pure titrated compound as a white solid in a yield of 88% (41 mg) . Characterization: Rt 2.40 min, generic method, MS (ESI) m / z = 364.1 [M+H]+. Exact mass: 363.1747. !H NMR (400 MHz, DMSO) 5 9.95 (s, 1H) , 8.35 (d, J = 8.5 Hz, 1H) , 8.02 (dd, J = 9.3, 5.4 Hz, 1H) , 7.84 (d, J = 8.6 Hz, 1H) , 7.84 (d, J = 8.6 Hz, 1H) .6 Hz, 1H) , 7.76 (dd, J = 9.4, 2.9 Hz, 1H) , 7.70 - 7.60 (m, 3H) , 7.34 - 7.25 (m, 2H) , 7.06 (tt, J = 7.4, 1.2 Hz, 1H) , 3.99 (d, J = 13.9 Hz, 1H) , 3.55 (d, J = 13.9 Hz, 1H) , 3.11 (dd, J = 9.6, 3.4 Hz, 1H) , 2.84 (d, J = 11.6 Hz, OH) , 2.23 - 2.13 (m, 2H) .23 - 2.13 (m, 1H) , 1.93 - 1.82 (m, 1H) , 1.75 (q, J = 10.1 Hz, 2H) , 1.59 - 1.41 (m, 2H) , 1.33 (d, J = 11.8 Hz, 1H) . l-( (6-fluoroquinolin-2-yl) methyl) -N- (pyridin-3- yl) piperidin-2 -carboxamide (compound 4.5, Scheme 4)

[0271] The titrated compound was synthesised according to Process KI, starting with ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) piperidin-2-carboxylate 4.3 (50 mg, 0.16 mmol, 1 eq) , 3-aminopyrin (1 eq, 0.16 mmol, 15 mg) and trimethylaluminium 2M in toluene (3 eq, 0.47 mmol, 0.24 mL) , stirring the reaction at room temperature overnight. Purification by silica gel column chromatography (ethyl acetate / methanol from 100:0 to 90:10) yielded the pure titrated compound as a white solid in a yield of 62% (36 mg) . Characterization: Rt 2.00 min, generic method, MS (ESI) m / z = 363.1 [M-H]~. Exact mass: 364.1699.TH NMR (400 MHz, DMSO) 5 10.17 (s, 1H) , 8.80 (dd J = 2.6 0.8 Hz, 1H) 8.35

[0272] (d, J = 8.5 Hz, 1H) , 8.25 (dd, J = 4.7, 1.5 Hz, 1H) , 8.10

[0273] (ddd, J = 8.5 Hz, 1H) .1O (ddd, J = 8.4, 2.6, 1.5 Hz, 1H) ,

[0274] 8.00 (dd, J = 9.2, 5.4 Hz, 1H) , 7.83 (d, J = 8.5 Hz, 1H) , 7.76 (dd, J = 9.4, 2.9 Hz, 1H) , 7.64 (td, J = 8.5 Hz, 1H) .64

[0275] (td, J = 8.9, 2.9 Hz, 1H) , 3.99 (d, J = 13.9 Hz, 1H) , 3.57

[0276] (d, J = 13.9 Hz, 1H) , 3.13 (dd, J = 9.6, 3.6 Hz, 1H) , 2.89- 2.82 (m, 1H) , 2.24 - 2.14 (m, 1H) , 1.93 - 1.84 (m, 1H) , 1.75 (q, J = 10.3 Hz, 2H) , 1.61 - 1.44 (m, 2H) , 1.35 (t, J = 11.8 Hz, 1H) .

[0277] N- (benzo [d] thiazol-6-yl) -1- ( (6-fluoroquinolin-2- yl) methyl) piperidin-2 -carboxamide (compound 4.6, Scheme 4)

[0278] The titrated compound was synthesised according to Process KI, starting with ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) piperidin-2-carboxylate 4.3 (50 mg, 0.16 mmol, 1 eq) , benzo [d] thiazol- 6-amine (1 eq, 0.16 mmol, 24 mg) and trimethylaluminium 2M in toluene (3 eq, 0.47 mmol, 0.24 mL) , stirring the reaction at room temperature overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 80:20 to 70:30) yielded the pure titrated compound as a white solid in a yield of 55% (36 mg) . Characterization: Rt 2.27 min, generic method, MS (ESI) m / z = 421.0 [M+H]+. Exact mass: 420.1420. iH NMR (400 MHz, DMSO) 5 10.24 (s, 1H) , 9.25 (s, 1H) , 8.56 (d, J = 2.1 Hz, 1H) , 8.35 (d, J = 8.5 Hz, 1H) , 8.00 (dd, J = 9.0, 4.4 Hz, 2H) .O, 4.4 Hz, 2H) , 7.84 (d, J = 8.6 Hz, 1H) , 7.75 (dd, J = 9.4, 2.9 Hz, 1H) , 7.67 (dd, J = 8.8, 2.1 Hz, 1H) , 7.62 (td,

[0279] J = 8.9, 2.9 Hz, 1H) , 4.5 (td, J = 8.9, 2.9 Hz, 1H) .9 Hz,

[0280] 1H) , 4.00 (d, J = 13.9 Hz, 1H) , 3.59 (d, J = 13.9 Hz, 1H) ,

[0281] 3.15 (dd, J = 9.5, 3.4 Hz, 1H) , 2.86 (d, J = 11.5 Hz, 1H) ,

[0282] 2.21 (t, J = 9.8, 2.1 Hz, 1H) .21 (t, J = 9.3 Hz, 1H) , 1.90 (d, J = 12,5 Hz, 1H) , 1.82 - 1.69 (m, 2H) , 1.58 - 1.44 (m, 2H) , 1.36 (t, J = 11.6 Hz, 1H) .

[0283] N- (3-fluorophenyl) -1- ( (6-fluoroquinolin-2- yl) methyl) piperidin-2 -carboxamide (compound 4.7, Scheme 4)

[0284] The titrated compound was synthesised according to Process KI, starting with ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) piperidin-2-carboxylate 4.3 (50 mg, 0.16 mmol, 1 eq) , 3-f luoroaniline (1 eq, 0.16 mmol, 15 pL) and trimethylaluminium 2M in toluene (3 eq, 0.47 mmol, 0.24 mL) , stirring the reaction at room temperature overnight.

[0285] Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 70:30) yielded the pure titrated compound as a white foamy solid in a yield of 33% (20 mg) . Characterization: Rt 2.50 min, generic method, MS (ESI) m / z = 380.1 [M-H] . Exact mass: 381.1653. NMR (400 MHz, DMSO) 5 10.17 (s, 1H) , 8.35 (d, J = 8.5 Hz, 1H) , 8.00 (dd, J = 9.2, 5.4 Hz, 1H) , 7.82 (d, J = 8.5 Hz, 1H) , 7.75 (dd, J = 9.5 Hz, 1H) .75 (dd, J = 9.4, 2.9 Hz, 1H) , 7.68 - 7.58 (m, 2H) , 7.41 (dt, J = 8.3, 1.2 Hz, 1H) , 7.33 (td, J = 8.2, 6.7 Hz, 1H) , 6.92 - 6.82 (m, 1H) , 7.9 (dt, J = 8.5 Hz, 1H) , 7.9

[0286] (dt, J = 8.5 Hz, 1H) .82 (m, 1H) , 3.96 (d, J = 13.9 Hz, 1H) ,

[0287] 3.62 - 3.53 (m, 1H) , 3.10 (dd, J = 9.6, 3.4 Hz, 1H) , 2.87 - 2.78 (m, 1H) , 2.24 - 2.13 (m, 1H) .24 - 2.13 (m, 1H) , 1.87

[0288] (d, J = 12.6 Hz, 1H) , 1.73 (q, J = 9.9 Hz, 2H) , 1.50 (d, J

[0289] = 23.0 Hz, 2H) , 1.35 (t, J = 15.5 Hz, 1H) .

[0290] 1- ( (6-fluoroquinolin-2-yl) methyl) -N- (3- methoxyphenyl) piperidin-2 -carboxamide (compound 4.8, Scheme 4)

[0291] The titrated compound was synthesised according to Process

[0292] KI, starting with ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) piperidin-2-carboxylate 4.3 (50 mg, 0.16 mmol, 1 eq) , 3-methoxyaniline (1 eq, 0.16 mmol, 17 pL) and trimethylaluminium 2M in toluene (3 eq, 0.47 mmol, 0.24 mL) , stirring the reaction at room temperature overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 80:20 to 60:40) yielded the pure titrated compound as a white solid in a yield of 32% (20 mg) . Characterization: Rt 2.45 min, generic method, MS (ESI) m / z = 394.0 [M+H]+. Exact mass: 393.1853.1H NMR (400 MHz, DMSO) 5 9.93 (s, 1H) , 8.35 (d, J = 8.5 Hz, 1H) , 8.01 (dd, J = 9.3, 5.4 Hz, 1H) , 7.83 (d, J = 8.5 Hz, 1H) , 7.77 - 7.71 (m, J = 8.5 Hz, 1H) .77 - 7.71 (m, 1H) , 7.63 (td, J = 8.9, 2.9 Hz, 1H) , 7.36 (t, J = 2.2 Hz, 1H) , 7.21 (dt, J = 15.9, 8.1 Hz, 2H) , 6.62 (dd, J = 7.7, 2.3 Hz, 1H) , 3.98 (d, J = 14.0 Hz, 1H) , 3.72 (s, 3H) , 3.55 (d, J = 13.8 Hz, 1H) , 3.10 (d, J = 9.3 Hz, 1H) , 2.84 (d, J = 11.4 Hz, 1H) , 2.16 (d, J = 11.4 Hz, 1H) , 2.5 (d, J = 11.5 Hz, 1H) , 2.6 (d, J = 11.5 Hz, 2H) .16 (d, J = 11.7 Hz, 1H) , 1.88 (d, J = 12.4 Hz, 1H) , 1.74 (d, J = 10.4 Hz, 2H) , 1.64 - 1.40 (m, 2H) , 1.38 - 1.16 (m, 1H) .

[0293] 1- ( (6-fluoroquinolin-2-yl) methyl) -N- (pyridineyl) piperidin-2 -carboxamide (compound 4.9, Scheme 4)

[0294] The titrated compound was synthesised according to Process K2, starting with 2-aminopyridine (15 mg, 0.16 mmol, 1 eq) in dry tetrahydrofuran (0.1 M, 1.6 mL) , sodium hydride dispersed 60% in mineral oil (8 eq, 1.26 mmol, 50 mg) , and ethyl 1- ( ( 6-f luoroquinolin-2-yl ) methyl ) piperidin-2- carboxylate 4.3 (1 eq, 0.16 mmol, 50 mg) . Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 95:05) yielded the product as a foamy yellow solid in a 62% yield (36 mg) . Characterization: Rt 2.34 min, generic method. MS (ESI) m / z = 363.1 [M-H]~, 364.9 [M+H]+. Exact mass: 364.1699. NMR (400 MHz, DMSO) 5 10.43 (s, 1H) , 8.38 - 8.31 (m, 2H) , 8.16 - 8.07 (m, 2H) , 7.82 - 7.72 (m, 3H) , 7.64 (td, J = 8.9, 2.9 Hz, 1H) , 7.11 (ddd, J = 7.3, 4.9, 1.1 Hz, 1H) , 4.02 (d, J = 14.1 Hz, 1H) , 3.2 (d, J = 14.1 Hz, 1H) .1 Hz, 1H) , 3.66 (d, J = 14.1 Hz, 1H) , 3.28 (dd, J = 8.8, 3.8 Hz, 1H) , 2.90 - 2.82 (m, 1H) , 2.32 - 2.22 (m, 1H) , 1.93 - 1.86 (m, 1H) , 1.80 - 1.65 (m, 2H) , 1.54 (s, 1H) , 1.51 - 1.33 (m, 2H) .

[0295] N- 2- (N,N-dimethylsulphamoyl) phenyl) -1- ( (6-fluoroquinolin- 2 -yl) methyl) piperidin-2 -carboxamide (compound 4.10, Scheme 4)

[0296] The titrated compound was synthesised according to Process K2, starting with 2-amino-N, N-dimethylbenzenesulphonamide (22 mg, 0.11 mmol, 1 eq) in dry tetrahydrofuran (0.1 M, 1.1 mL) , sodium hydride dispersed 60% in mineral oil (8 eq, 0.89 mmol, 35 mg) , and ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) piperidin-2-carboxylate 4.3 (1 eq, 0.11 mmol, 35 mg) . Purification by silica gel column chromatography (dichloromethane / methanol 95:05) yielded the product as a white solid in a yield of 29% (15 mg) . Characterization: Rt 2.53 min, generic method. MS (ESI) m / z = 471.1 [M+H]+.

[0297] 470.1788. !H NMR (400 MHz, DMSO) 5 10.53 (s, 1H) , 8.50 (d, J = 8.4 Hz, 1H) , 8.34 (d, J = 8.6 Hz, 1H) , 8.00 (dd, J = 9.2,

[0298] 5.4 Hz, 1H) .2, 5,4 Hz, 1H) , 7.85 (d, J = 8.6 Hz, 1H) , 7.78

[0299] - 7.70 (m, 2H) , 7.70 - 7.56 (m, 2H) , 7.35 - 7.27 (m, 1H) , 4. (d, J = 13.5 Hz, 1H) .12 (d, J = 13.9 Hz, 1H) , 3.78 (d, J =

[0300] 14,0 Hz, 1H) , 3.21 (dd, J = 8, 6, 3,9 Hz, 1H) , 2.83 (d, J =

[0301] 11.9 Hz, 1H) , 2.70 (s, 5H) , 2.30 (t, J = 10.5 Hz, 1H) , 1.93 (d, J = 12.9 Hz, 1H) , 1.70 (d, J = 45.5 Hz, 2H) , 1.47 - 1.29 (m, 2H) .

[0302] N- (3-cyanophenyl) -1- ( (6-fluoroquinolin-2- yl) methyl) piperidin-2 -carboxamide (compound 4.11, Scheme 4)

[0303] The titrated compound was synthesised according to Process KI starting with ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) piperidin-2-carboxylate 4.3 (50 mg, 0.16 mmol, 1 eq) , 3-aminobenzonitrile (1 eq, 0.16 mmol, 18 mg) and trimethylaluminium 2M in toluene (3 eq, 0.47 mmol, 0.24 mL) , stirring the reaction at room temperature overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 80:20 to 60:40) yielded the product as a white in a 40% yield (25 mg) . Characterization: Rt 2.40 min, generic method. MS (ESI) m / z = 389, 0 [M+H]+. Exact mass: 388.1699. NMR (400 MHz, DMSO) 5 10.27 (s, 1H) , 8.34 (d, J = 8.5 Hz, 1H) , 8.14 (q, J = 1.3 Hz, 1H) , 7.98 (dd, J = 9.2, 5.4 Hz, 1H) , 7.90 (dt, J = 7.5 Hz, 1H) .90 (dt, J = 7.0, 2.4 Hz, 1H) , 7.82 (d, J = 8.5 Hz, 1H) , 7.74 (dd, J = 9.5, 2.9 Hz, 1H) , 7.61 (td, J = 8.9, 2.9 Hz, 1H) , 7.55 - 7.45 (m, 2H) , 3.98 (d, J = 13.9 Hz, 1H) , 3.58 (d, J = 13.9 Hz, 1H) , 3.12 (dd, J = 9.5, 3.5 Hz, 1H) , 2.87 (dt, J = 11.6, 4.1 Hz, 1H) , 2.25 - 2.14 (m, J = 8.9, 2.9 Hz, 1H) .25 - 2.14 (m, 1H) , 1.88 (dd, J = 13.2, 4.2 Hz, 1H) , 1.81 - 1.67 (m, 2H) , 1.58 - 1.43 (m, 2H) , 1.34 (t, J = 11.7 Hz, 1H) .

[0304] N-(4- N , N-dimethylsulphamoyl) phenyl) -1- ( (6-fluoroquinolin- 2 -yl) methyl) piperidin-2 -carboxamide (compound 4.12, Scheme

[0305] 4)

[0306]

[0307] The titrated compound was synthesised according to Process K2, starting with 4-amino-N, N-dimethylbenzenesulphonamide (32 mg, 0.16 mmol, 1 eq) in dry tetrahydrofuran (0.1 M, 1.6 mL) , sodium hydride dispersed 60% in mineral oil (8 eq, 1.26 mmol, 51 mg) , and ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) pyrolysed .6 mL) , sodium hydride in 60% dispersion in mineral oil (8 eq, 1.26 mmol, 51 mg) , and ethyl l— ( (6— f luoroquinolin-2-yl ) methyl ) piperidin-2-carboxylate 4.3 (1 eq, 0.16 mmol, 50 mg) . Purification by silica gel column chromatography (dichloromethane / methanol from 100:0 to 96:04) yielded the product as a white foamy solid in a yield of 27% (20 mg) . Characterization: Rt 2.35 min, generic method. MS (ESI) m / z = 469.2 [M-H] . 470.1788. NMR (400 MHz, DMSO) 5 10.37 (s, 1H) , 8.34 (d, J = 8.5 Hz, 1H) , 8.00 (dd, J = 9.2, 5.4 Hz, 1H) , 7.92 (d, J = 8.8 Hz, 2H) , 7.82 (d, J = 8.8 Hz, 2H) .82 (d, J = 8.5 Hz, 1H) , 7.75 (dd, J = 9.4, 2.9 Hz, 1H) , 7.68 (d, J = 8.8 Hz, 2H) , 7.63 (td, J = 8,9, 2.9 Hz, 1H) , 3.98 (d, J = 14. .0 Hz, 1H) , 3.59 (d, J = 13.9 Hz, 1H) , 3.16 (dd, J = 9.2, 3.5 Hz, 1H) , 2.87 (d, J = 11.7 Hz, 1H) , 2.57 (s, 6H) , 2.21 (t, J = 10.5 Hz, 1H) , 1H) .5 Hz, 1H) , 1.89 (d, J = 12.5 Hz, 1H) , 1.75 (q, J = 11.3 Hz,

[0308] 2H) , 1.53 (d, J = 11.5 Hz, 2H) , 1.34 (d, J = 11.6 Hz, 1H) .

[0309] N- (3-carbamophenyl) -1- ( (6-fluoroquinolin-2- yl) methyl) piperidin-2 -carboxamide (compound 4.13, Scheme 4)

[0310] The titrated compound was synthesised according to Process KI, starting with ethyl 1- ( ( 6-f luoroquinolin-2- yl ) methyl ) piperidin-2-carboxylate 4.3 (50 mg, 0.16 mmol, 1 eq) , 3-aminobenzamide (1 eq, 0.16 mmol, 22 mg) and trimethylaluminium 2M in toluene (3 eq, 0.47 mmol, 0.24 mL) , stirring the reaction at room temperature overnight. The crude product was purified by silica gel column chromatography, using 100:0 to 80:20 dichloromethane / methanol as an eluent. A second column chromatography on silica gel, using 60:40 to 0:100 cyclohexane / ethyl acetate as an eluent, yielded the pure titrated compound as a white foamy solid in a yield of 31% (20 mg) . Characterization: Rt 1.88 min, generic method. MS (ESI) m / z = 405.1 [M-H] . Exact mass: 406.1805. iH NMR (400 MHz, DMSO) 5 10,10 (s, 1H) , 8,35 (d, J = 8,5 Hz, 1H) , 8,14 (t, J = 1,9 Hz, 1H) , 8,04 (dd, J = 9,2, 5,4 Hz, 1H) , 7.93 (s, 1H) , 7.86 - 7.79 (m, 2H) , 7.76 (dd, J = 9.4, 2.9 Hz, 1H) , 7.63 (td, J = 8.9, 2.9 Hz, 1H) , 7.54 (dt, J = 8.0, 1.3

[0311] Hz, 1H) , 7.41 - 7.29 (m, 1H) , 7.29 (s, 1H) .41 - 7.29 (m,

[0312] 2H) , 4.00 (d, J = 13.9 Hz, 1H) , 3.63 - 3.53 (m, 1H) , 3.17 (dd, J = 33.2, 11.9 Hz, 1H) , 2.84 (d, J = 11.6 Hz, 1H) , 2.19 (t, J = 10.2 Hz, 1H) .19 (t, J = 10.7 Hz, 1H) , 1.90 (d, J =

[0313] 14.0 Hz, 1H) , 1.75 (q, J = 10.9 Hz, 2H) , 1.65 - 1.41 (m,

[0314] 2H) , 1.34 (d, J = 11.9 Hz, 1H) .

[0315] 6-methoxy-2 -methylquinoline (compound 5.3, Scheme 5)

[0316] The titration compound was synthesised according to Process A2, starting with 4-methoxyaniline 5.1 (1 eq, 2g, 16.24 mmol) dissolved in 6M HC1 (81 mL, 30 eq) , and a solution of crotonaldehyde (2 eq, 32.48 mmol, 2.69 mL) in toluene (0.75 M, 21.7 mL) , stirring the reaction at 100°C for 48h. Purification of the crude product by silica gel column chromatography yielded the pure titration compound as a brownish solid in a yield of 74% (2.1 g) . Characterization: Rt 1.69 min, generic method, MS (ESI) m / z = 173.8 [M+H]+. Exact mass 173.0841. iH NMR (400 MHz, DMSO) 5 8.14 (d, J = 8.4 Hz, 1H) , 7.82 (d, J = 9.0 Hz, 1H) , 7.39 - 7.29 (m, 3H) , 3.88 (s, 3H) , 2.61 (s, 3H) .

[0317] 2 -methyl-6- (tri fluoromethoxy) quinoline (compound 5.4,

[0318] Scheme 5) The titrated compound was synthesised according to Process

[0319] Al, starting with 4-trif luoromethoxyaniline 5.2 (500 mg, 2.82 mmol, 1 eq) in toluene (0.2 M, 14 mL) , ethylvinyl ether (2 eq, 5.65 mmol, 540 pL) and catalytic iodine (0.1 eq, 0.28 mmol, 72 mg) , stirring the reaction mixture at 80°C for 6 h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 100:0 to 90:10) yielded the pure titrated product as brownish oil in a yield of 47% (307 mg) . Characterization: Rt 2.24 min, generic method, MS (ESI) m / z = 227.8 [M+H]+. Exact mass: 227.0558. NMR (400 MHz, CDC13) 5 8.04 (dd, J = 8.8, 3.7 Hz, 2H) , 7.60 (s, 1H) , 7.53 (dd, J = 9.1, 2.7 Hz, 1H) , 7.34 (d, J = 8.4 Hz, 1H) , 2.75 (s, 3H) . 6-fluoro-2- (iodomethyl) quinoline (compound 5.6, Scheme 5)

[0320] The titrated compound was synthesised according to Process L, starting with 6-f luoro-2-methylquinoline 1.4 (1 g, 6.2 mmol, 1 eq) in acetonitrile (0.25 M, 25 mL) , iodine (0.75 eq, 4.65 mmol, 1.181 g) , copper sulphate pentahydrate (0.4 eq, 2.48 mmol, 620 mg) , stirring the reaction at 70°C for 5h. Purification by silica gel column chromatography (cyclohexane / ethyl acetate 100:0 to 90:10) yielded the pure titrated product as a light brown solid in a yield of 64% (870 mg) . Characterization: Rt 2.20 min, generic method. MS (ESI) m / z = 287.9 [M+H]+. Exact mass: 286.9607. iH NMR (400 MHz, DMSO) 5 8.33 (d, J = 8.5 Hz, 1H) , 8.03 (dd, J = 9.3, 5.4 Hz, 1H) , 7.78 (dd, J = 9.4, 2.9 Hz, 1H) , 7.72 - 7.64 (m, 2H) , 4.76 (s, 2H) .

[0321] 6- (tri fluoromethyl) quinolin-2-carbaldehyde (compound 5.7, Scheme 5)

[0322] The titrated compound was synthesised according to Process C, starting with the solution of 6-trif luoromethyl-2- methylquinoline 1.5 (100 mg, 0.47 mmol, 1 eq) in dry 1,4- di oxane ( 0.3 M, 1.6 mL) , selenium dioxide (1.3 eq, 0.62 mmol, 68 mg) , stirring the reaction mixture at 80°C for 2 h. The titrated product was obtained pure without purification by column chromatography as a brown solid. Yield: 91%, 98 mg. Characterization: Rt 2.25 min, generic method, MS (ESI) m / z = 225.7 [M+H] + . iH NMR (400 MHz, DMSO) 5 10.16 (d, J = 0.8 Hz, 1H) , 8.83 (d, J = 8.5 Hz, 1H) , 8.69 (d, J = 2.1 Hz, 1H) , 8.43 (d, J = 8.8 Hz, 1H) , 8.19 - 8.11 (m, 2H) .

[0323] 2- (iodomethyl) -6- (tri luoromethoxy) quinoline (compound 5.8,

[0324] Scheme 5)

[0325] The titrated compound was synthesised according to Process

[0326] L, starting with 2-methyl-6-trif luoromethoxyquinoline 5.4 (150 mg, 0.66 mmol, 1 eq) in acetonitrile (0.25 M, 2.6 mL) , iodine (0.75 eq, 0.5 mmol, 126 mg) , copper sulphate pentahydrate (0.4 eq, 0.26 mmol, 66 mg) , stirring the reaction mixture at 70°C overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 80:20) yielded the pure titrated product as a brownish solid in a 50% yield (92 mg) . Characterization: Rt 2.52 min, generic method, MS (ESI) m / z = 353.7 [M+H]+. Exact mass: 352.9524. NMR (400 MHz, DMSO) 5 8.44 (d, J = 8.5 Hz, 1H) , 8.09 (d, J = 9.2 Hz, 1H) , 8.06 - 7.99 (m, 1H) , 7.77 - 7.72 (m, 2H) , 4.77 (s, 2H) .

[0327] 6-methoxyquinolin-2-carbaldehyde (compound 5.9, Scheme 5)

[0328] The titrated compound was synthesised according to Process C, starting with 6-methoxy-2-methylquinoline 5.3 (100 mg, 0.58 mmol, 1 eq) in dry 1,4-dioxane (0.3 M, 1.9 mL) , selenium dioxide (1.3 eq, 0.75 mmol, 83 mg) , stirring the reaction mixture at 80°C for 2h. The compound was obtained pure without column chromatographic purification (92% yield, 100 mg) . Characterization: Rt 1.86 min, generic method, MS (ESI) m / z = 188.0 [M+H]+. Exact mass: 187.0633. 1H NMR (400 MHz, DMSO) 5 10.08 (s, 1H) , 8.41 (dd, J = 9.3, 5.4 Hz, 1H) , 8.03 (dd, J = 9.5, 2.8 Hz, 1H) , 7.97 (ddd, J = 9.2, 8.3, 2.8 Hz, 1H) .

[0329] 6-ethoxyquinolin-2-carbaldehyde (compound 5.10, Scheme 5)

[0330] The product was synthesised according to Process C, starting with 6-ethoxy-2-methylquinoline 5.5 (500 mg, 2.67 mmol, 1 eq) in dry 1,4-dioxane (0.3 M, 8.9 mL) , selenium dioxide (1.3 eq, 3.47 mmol, 358 mg) , stirring the reaction mixture at 80°C for 2h. The compound was obtained pure without purification by column chromatography as a brownish solid in a yield of 97%. Characterization: Rt 2.06 min, generic method, MS = 201.8 [M+H]+. Exact mass: 201.0790.1H NMR (400 MHz, DMSO) 5 10.08 (d, J = 0.8 Hz, 1H) , 8.50 - 8.41 (m, 1H) , 8.12 (d, J = 9.1 Hz, 1H) , 7.95 (d, J = 8.4 Hz, 1H) , 7.54

[0331] (dd, J = 9.1, 2.8 Hz, 1H) , 7.51 (d, J = 2.7 Hz, 1H) , 4.23

[0332] (q, J = 7.0 Hz, 2H) , 1.43 (t, J = 7.0 Hz, 3H) .

[0333] N-cyclohexylaniline (compound 5.11, Scheme 5) H aN

[0334] The titrated compound was synthesised according to Process E, starting with cyclohexanone (105 pL, 1.02 mmol, 1 eq) in dry dichloromethane (0.2 M, 5 mL) , aniline (1.2 eq, 1.22 mmol, 111 pL) , acetic acid (10 eq, 10.2 mmol, 583 pL) and sodium triacetoxyborohydride (4 eq, 4.08 mmol, 583 pL) .22 mmol, 111 pL) , acetic acid (10 eq, 10.2 mmol, 583 pL) and sodium triacetoxyborohydride (4 eq, 4.08 mmol, 863 mg) , stirring the reaction mixture at room temperature overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 99:01) yielded the pure titrated compound as a white solid in a yield of 85% (155 mg) . Characterization: Rt 2.60 min, generic method, MS (ESI) m / z = 176.1 [M+H]+. Exact mass: 175.1361. NMR (400 MHz, CDC13) 5 7.11 - 7.03 (m, 2H) , 6.58 (tt, J = 7.3, 1.1 Hz, 1H) , 6.53 - 6.49 (m, 2H) , 3.42 (s, 1H) , 3.18 (tt, J = 10.1, 3.7 Hz, 1H) , 1.98 (dt, J = 12.7, 3.8 Hz, 2H) , 1.69 (dp, J = 11.6, 4.0 Hz, 2H) , 1.61 - 1.50 (m, 1H) , 1.36 - 1.21 (m, 2H) , 1.21 - 1.00 (m, 3H) .

[0335] N-cyclohexylbenzo [d] thiazol-6-amine (compound 5.12, Scheme 5)

[0336] The titrated compound was synthesised according to Process E, starting with cyclohexanone (1 eq, 2.27 mmol, 234 pL) , benzo [d] thiazol- 6-amine 6.1 (1 eq, 2.27 mmol, 340 mg) , acetic acid (10 eq, 22.67 mmol, 1.3 mL) and sodium triacetoxyborohydride (4 eq, 9.07 mmol, 1.92 g) in dry dichloromethane, stirring the reaction mixture at room temperature overnight. Purification by silica gel column chromatography (cyclohexane / ethyl acetate from 100:0 to 90:10) yielded the pure titrated compound as a white solid in a yield of 94% (500 mg) . Characterization: Rt 2.36 min, generic method, MS (ESI) m / z = 232.9 [M+H]+. Exact mass: 232.1034. !H NMR (400 MHz, DMSO) 5 8.86 (s, 1H) , 7.72 (d, J = 8.8 Hz, 1H) , 7.11 (d, J = 2.2 Hz, 1H) , 6.84 (dd, J = 8.9, 2.3 Hz, 1H) , 5.80 - 5.74 (m, 1H) , 4.41 (d, J = 4.2 Hz, 1H) , 3.31 - 3.19 (m, 1H) , 2.02 - 1.92 (m, 2H) , 1.67 (ddt, J = 46.4, 12.2, 3.9 Hz, 6H) , 1.44 - 1.28 (m, 2H) .

[0337] 4- (cydohexyl ami no) benzamide (compound 5.13, Scheme 5)

[0338] The titrated compound was synthesised according to Process

[0339] E, starting with cyclohexanone (263 pL, 2.55 mmol, 1 eq) in dry dichloromethane (0.8 M, 3.2 mL) , 4-aminobenzamide (1 eq, 2.55 mmol, 347 mg) , acetic acid (10 eq, 25.47 mmol, 1.46 mL) , sodium triacetoxyborhydride (4 eq, 10.19 mmol, 1.46 mL) .55 mmol, 347 mg) , acetic acid (10 eq, 25.47 mmol, 1.46 mL) , sodium triacetoxiborhydride (4 eq, 10.19 mmol, 2.16 g) , stirring the reaction at room temperature overnight. The compound was obtained pure without column chromatographic purification (100% yield, 565 mg, white solid) . Characterization: Rt 1.88 min, generic method, MS = 219.0 [M+H]+. Exact mass: 218.1419. iH NMR (400 MHz, DMSO) 5 7.68 - 7.57 (m, 2H) , 7.53 (s, 1H) , 6.80 (s, 1H) , 6.57 - 6.49 (m, 2H) , 5.97 (d, J = 7.9 Hz, 1H) , 3.26 - 3.14 (m, 1H) , 3.5 (m, 1H) .14 (m, 1H) , 1.95 - 1.86 (m, 2H) , 1.71 (dt, J = 13.0, 3.7 Hz, 2H) , 1.64 - 1.54 (m, 1H) , 1.34 (qd, J = 12.3, 3.3 Hz, 2H) , 1.24 - 1.05 (m, 3H) . N-cyclohexylpyridine-3-amine (compound 5.14, Scheme 5)

[0340] The titrated compound was synthesised according to Process E, starting with cyclohexanone (317 pL, 3.06 mmol, 1 eq) in dry dichloromethane (0.3 M, 10.2 mL) , 3-aminopyridine (1 eq, 3.06 mmol, 288 mg) , acetic acid (10 eq, 30.57 mmol, 1.750 mL) and sodium triacetoxyborohydride (4 eq, 12.23 mmol, 2.591 g) . Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 98:02) yielded the pure titrated compound as white crystals in a yield of 62% (336 mg) . Characterization: Rt 1.84 min, generic method, MS (ESI) m / z = 177.9 [M+H]+. Exact mass: 176.1313. NMR (400 MHz, CDC13) 5 7.99 (d, J = 2.9 Hz, 1H) , 7.90 (dd, J = 4.7, 1.4 Hz, 1H) , 7.05 (dd, J = 8.3, 4.7 Hz, 1H) , 6.84 (ddd, J = 8.3, 2.9, 1.4 Hz, 1H) , 3.55 (s, 1H) , 3.24 (s, 1H) , 3.5 (s, 1H) .24 (s, 1H) , 2.04 (dd, J = 12.1, 4.5 Hz, 2H) , 1.78 (dq, J = 13.2, 4.1 Hz, 3H) , 1.66 (dt, J = 12.6, 3.8 Hz, 1H) , 1.43 - 1.31 (m, 2H) , 1.29 - 1.07 (m, 3H) .

[0341] 4- (cyclohexylamino) benzonitrile (compound 5.15, Scheme 5)

[0342] The titrated compound was synthesised according to Process E, starting with cyclohexanone (1 eq, 2.04 mmol, 211 pL) in dry dichloromethane (0.3 M, 6.8 mL) , 4-amino benzonitrile (1 eq, 2.04 mmol, 241 mg) , acetic acid (10 eq, 20.4 mmol, 1.166 mL) and sodium triacetoxyborhydrochloride (4 eq, 8.15 mmol, 1.166 mL) .O4 mmol, 241 mg) , acetic acid (10 eq, 20.4 mmol, 1.166 mL) and sodium triacetoxiborhydride (4 eq, 8.15 mmol, 1.727 g) , stirring the reaction mixture overnight. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 98:02) yielded the pure titrated compound as white crystals in a yield of 59% (243 mg) . Characterization: Rt 2.48 min, generic method, MS = 200.9 [M+H]+. Exact mass: 200.1313. NMR (400 MHz, CDC13) 5 7.43 - 7.35 (m, 2H) , 6.56 - 6.48 (m, 2H) , 4.10 (dd, J = 13.9, 7.4 Hz, 1H) , 3.29 (tdt, J = 10.9, 7.8, 3.8 Hz, 1H) , 2.01 (d, J = 4.2 Hz, 2H) , 1.81 - 1.75 (m, 2H) , 1.67 (dt, J = 12.8, 3.8 Hz, 1H) , 1.45 - 1.31 (m, 2H) , 1.29 - 1.11 (m, 3H) .

[0343] N-cyclohexyl-1 -methyl -lH-benzo [d] imidazol-6-amine (compound 5.16, Scheme 5)

[0344] The titrated compound was synthesised according to Process E, starting with cyclohexanone (140 pL, 1.36 mmol, 1 eq) in dry dichloromethane (4.5 mL, 0.3 M) , 1-methyl-lH- benzo [d] imidazol- 6-amine (1 eq, 1.36 mmol, 200 mg) , acetic acid (10 eq, 13.6 mmol, 775 pL) and sodium triacetoxiborhydride (4 eq, 5.42 mmol, 775 pL) .36 mmol, 200 mg) , acetic acid (10 eq, 13.6 mmol, 775 pL) and sodium triacetoxiborhydride (4 eq, 5.42 mmol, 1.148 g) , stirring the reaction mixture at room temperature overnight. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 95:05) yielded the pure titrated compound as a purple foamy solid in a yield of 68% (212 mg) . Characterization: Rt 1.90 min, generic method, MS = 230.0 [M+H]+. Exact mass: 229.1579. NMR (400 MHz, DMSO) 5 7.80 (s, 1H) , 7.29 (d, J = 8.6 Hz, 1H) , 6.57 (dd, J = 8.6, 2.1 Hz, 1H) , 6.53 (d, J = 2.0 Hz, 1H) , 3. (s, 3H) , 3. (s, 3H) , 3. (s, 3H) .68 (s, 3H) , 3.29 - 3.16 (m, 1H) , 2.00 - 1.92 (m, 2H) , 1.76 - 1.67 (m, 4H) , 1.67 - 1.55 (m, 2H) , 1.39 - 1.25 (m, 2H) .

[0345] N-cyclohexy Ibenzo [d] oxazol-6-amine (compound 5.17, Scheme 5)

[0346] The titrated compound was synthesised according to Process E, starting with cyclohexanone (153 pL, 1.48 mmol, 1 eq) in dry dichloromethane (4.9 mL, 0.2 M) , benzo [d] oxazole- 6-amine (1 eq, 1.48 mmol, 198 mg) , (10 eq, 14.77 mmol, 845 pL) and sodium triacetoxiborhydride (4 eq, 5.91 mmol, 1.25 mg) .48 mmol, 198 mg) , (10 eq, 14.77 mmol, 845 pL) and sodium triacetoxiborhydride (4 eq, 5.91 mmol, 1.252 g) , stirring the reaction at room temperature overnight. Purification by silica gel column chromatography (petroleum ether / ethyl acetate 90:10) yielded the pure titrated compound as violet oil in a yield of 53% (171 mg) . Characterization: Rt 2.31 min, generic method, MS (ESI) m / z = 216.9 [M+H]+. Exact mass: 216.1263. iH NMR (400 MHz, CDC13) 5 7.88 (s, 1H) , 7.51 (d, J = 8.6 Hz, 1H) , 6.75 (d, J = 2.2 Hz, 1H) , 6.63 (dd, J = 8.6, 2.2 Hz, 1H) , 3.76 (s, 1H) , 3.29 (tt, J = 10.2, 3.8 Hz, 1H) .2, 3.8 Hz, 1H) , 2.11 (dd, J = 11.5, 4.3 Hz, 2H) , 1.81 (dt, J = 13.2, 3.9 Hz, 2H) , 1.74 - 1.56 (m, 1H) , 1.50 - 1.34 (m, 2H) , 1.34 - 1.14 (m, 2H) .

[0347] N- ( (3 -phenyl -1 , 2 , 4-oxadiazol-5-yl) methyl) cyclohexanamine (compound 5.18, Scheme 5)

[0348] The titrated compound was synthesised according to Process F, starting with cyclohexanone (263 pL, 2.55 mmol, 1 eq) in dry dichloromethane (0.8 M, 3.2 mL) , ( 3-phenyl-l , 2 , 4- oxadiazole-5-yl ) methanamine (1 eq, 2.55 mmol, 446.73 mg) , acetic acid (10 eq, 25.47 mmol, 1.46 mL) , sodium triacetoxyborohydride (4 eq, 10.47 mmol, 1.46 mL) .55 mmol, 446.73 mg) , acetic acid (10 eq, 25.47 mmol, 1.46 mL) , sodium triacetoxyborohydride (4 eq, 10.19 mmol, 2.16 g) , stirring the reaction at room temperature overnight. The compound was obtained pure without purification by column chromatography

[0349] (100% yield, white solid, 655 mg) . Characterization: Rt 1.93 min, generic method, MS = 258.1 [M+H]+. Exact mass: 257.15.

[0350] N- ( (5-phenyl-l , 3 , 4 -oxadiazol -2 -yl) methyl) cyclohexanamine

[0351] (compound 5.19, Scheme 5)

[0352] The titrated compound was synthesised according to Process

[0353] E, starting with cyclohexanone (263 pL, 2.55 mmol, 1 eq) in dry dichloromethane (0.8 M, 3.2 mL) , (5-phenyl-l, 3, 4- oxadiazole-2-yl ) methanamine (1 eq, 2.55 mmol, 446 mg) , acetic acid (10 eq, 25.47 mmol, 1.46 mL) , sodium triacetoxyborohydride (4 eq, 10.19 mmol, 1.46 mL) .55 mmol, 446 mg) , acetic acid (10 eq, 25.47 mmol, 1.46 mL) , sodium triacetoxyborohydride (4 eq, 10.19 mmol, 2.16 g) , stirring the reaction at room temperature overnight. The compound was obtained pure without column chromatographic purification (87% yield, 388 mg, white solid) . Characterization: Rt 1.88 min, generic method, MS = 176.0 [M+H]+. Exact mass: 175.19.

[0354] N- ( (2-phenyloxazol-5-yl)methyl) cyclohexanamine (compound 5.20, Scheme 5)

[0355] The titrated compound was synthesised according to Process

[0356] E, starting with cyclohexanone (263 pL, 2.55 mmol, 1 eq) in dry dichloromethane (0.8 M, 3.2 mL) , (2-phenyloxazol-5- yl ) methanamine (1 eq, 2.55 mmol, 445 mg) , acetic acid (10 eq, 25.47 mmol, 1.46 mL) , sodium triacetoxiborhydride (4 eq, 10.19 mmol, 1.46 mL) .55 mmol, 445 mg) , acetic acid (10 eq, 25.47 mmol, 1.46 mL) , sodium triacetoxiborhydride (4 eq, 10.19 mmol, 2.16 g) , stirring the reaction at room temperature overnight. The compound was obtained pure without purification by column chromatography (90% yield, 587 mg, white solid) . Characterization: Rt 1.88 min, generic method, MS = 257.0 [M+H]+. Exact mass: 256.16.

[0357] N- (pyridin-S-ylmethyl) cyclohexanamine (compound 5.21, Scheme 5)

[0358] The titrated compound was synthesised according to Process E, starting with cyclohexanone (263 pL, 2.55 mmol, 1 eq) in dry dichloromethane (0.8 M, 3.2 mL) , pyridin-3-ylmethanamine (1 eq, 2.55 mmol, 275.75 mg) , acetic acid (10 eq, 25.47 mmol,

[0359] 1.46 mL) , sodium triacetoxiborhydride (4 eq, 10.19 mmol,

[0360] 1.46 mL) .55 mmol, 275.75 mg) , acetic acid (10 eq, 25.47 mmol,

[0361] 1.46 mL) , sodium triacetoxiborhydride (4 eq, 10.19 mmol, 2.16 g) , stirring the reaction at room temperature overnight. The compound was obtained pure without column chromatographic purification (100% yield, 484 mg, white solid) . Characterization: Rt 1.88 min, generic method, MS = 191.0 [M+H]+. Exact mass: 190.15. N- (tetrahydrofuran-3-yl) benzo [d] thiazol-6-amine (compound

[0362] 5.22, Scheme 5)

[0363] The titrated compound was synthesised according to Process E previously described, starting with benzo [d] thiazol-6- amine 6.1 (431 mg, 2.87 mmol, 1 eq) in DCM (0.3 M, 10 mL) , dihydrofuran-3 ( 2H) -one (1 eq, 2.87 mmol, 247.87 mg) acetic acid (10 eq, 28.7 mmol, 1.67 mL) and sodium triacetoxyborohydride (4 eq, 11.48 mmol, 2.43 g) stirring the reaction overnight at room temperature. The reaction was quenched by adding sodium bicarbonate, extracted with ethyl acetate, washed with brine and dried over Na2SO4. The solvent was evaporated by rotavapor and the crude product obtained was purified by silica gel column chromatography ( cyclohexane / ethylacetate 90:10) to obtain the pure titrated compound as a white solid in 90% yield (569 mg) . Characterization: Rt 1.5 min, generic method, MS (ESI) m / z = 220.9 [M+H]+. Exact mass: 220,07;! H NMR (400 MHz, DMSO) 5 8.91 (s, 1H) , 7.76 (d, J = 8.8 Hz, 1H) , 7.13 (d, J = 2.3 Hz, 1H) , 6.87 (dd, J = 8.9, 2.3 Hz, 1H) , 6.20 (d, J = 6.3 Hz, 1H) , 4.03 (ddt, J = 10.0, 6.7, 3.3 Hz, 1H) , 3.92 (dd, J = 8.8, 5.8 Hz, 1H) , 3.84 (dt, J = 8.4, 7.3 Hz, 1H) , 3.74 (td, J = 8.2, 5.4 Hz, 1H) , 3.56 (dd, J = 8.2, 5.4 Hz, 1H) .56 (dd, J = 8.8, 3.6 Hz, 1H) , 2.28 - 2.15 (m, 1H) , 1.79 (dddd, J = 12.6, 7.3, 5.5, 3.6 Hz, 1H) .

[0364] N- (oxetan-3-yl) benzo [d] thiazol-6-amine (compound 5.23,

[0365] Scheme 5)

[0366] The titrated compound was synthesised according to Process E previously described, starting with benzo [d] thiazol-6- amine 6.1 (431 mg, 2.87 mmol, 1 eq) in DCM (0.3 M, 10 mL) , oxetan-3-one (1 eq, 2.87 mmol, 206.8 mg) acetic acid (10 eq, 28.7 mmol, 1.67 mL) and sodium triacetoxyborohydride (4 eq, 11.48 mmol, 2.43 g) stirring the reaction overnight at room temperature. The reaction was quenched by adding sodium bicarbonate, extracted with ethyl acetate, washed with brine and dried over Na2SO4. The solvent was evaporated by rotavapor and the crude product obtained was purified by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10) to obtain the pure titrated compound as a white solid in 95% yield (561 mg) . Characterization: Rt 1.36 min, generic method, MS (ESI) m / z = 206.9 [M+H] + . Exact mass: 206.05;1H NMR (400 MHz, DMSO) 5 8.93 (s, 1H) , 7.78 (d, J = 8.8 Hz, 1H) , 6.98 (d, J = 2.4 Hz, 1H) , 6.82 (dd, J = 8.8, 2.3 Hz, 1H) , 6.71 (d, J = 6.3 Hz, 1H) , 4.88 (t, J = 6.5 Hz, 2H) , 4.58 (h, J = 6.4 Hz, 1H) , 4.43 (t, J = 6.0 Hz, 2H) .

[0367] N- ( cycl opr opylme thy 1) benzo [d] thiazol-6-amine (compound 5.24, Scheme 5)

[0368] The titrated compound was synthesised according to general Process E from benzo [d] thiazol- 6-amine 6.1 (60 mg, 0.40 mmol, 1.0 eq) in dry DCM (0.3 M, 1.3 mL) , cyclopropane carbaldehyde (30 pL, 0.40 mmol, 1 eq) , acetic acid (10 eq, 4.00 mmol, 228 pL) and sodium triacetoxyborohydride (4 eq, 1.60 mmol, 338 mg) . Purification by flash chromatography on silica gel ( cyclohexane / EtOAc 85:15) yielded the pure titrated compound as a white solid (39.3 mg, yield 48%) . Characterization: Rt = 2.02 min; MS (ESI) m / z : 205.3 [M+H]+. Exact mass: 204, 0721.1H NMR (400 MHz, CDC13) 5 8.64 (s, 1H) , 7.87 (d, J = 8.8 Hz, 1H) , 7.01 (d, J = 2.0 Hz, 1H) , 6.81 (ddd, J = 8.9, 2.4, 1.0 Hz, 1H) , 4.04 (s, 1H) , 3.00 (dd, J = 7.0, 1.1 Hz, 2H) , 1.17 - 1.07 (m, 1H) , 0.63 - 0.52 (m, 2H) , 0.27 (qd, J = 4.8, 2.5 Hz, 2H) . tert-butyl 4-( (benzo [d] thiazol -6-ylamino) methyl )piperidin- 1-carboxylate (compound 5.25, Scheme 5)

[0369] The titrated compound was synthesised according to general process E from benzo [d] thiazol- 6-amine 6.1 (100 mg, 0.67 mmol) in dry DCM (0.3 M, 2 mL) , l-Boc-piperidin-4- carboxaldehyde (142 mg, 0.67 mmol) , acetic acid (10 eq, 6.66 mmol, 380 pL) and sodium triacetoxyborohydride (4 eq, 2.66 mmol, 565 mg) . Purification by flash chromatography on silica gel ( cyclohexane / EtOAc 85:15) yielded the pure titrated compound as white foam (134.6 mg, yield 58 %) .

[0370] Characterization: Rt = 2.33 min; MS (ESI) m / z : 348.0 [M+H]+. Exact mass: 347.1667. iH NMR (400 MHz, CDC13) 5 8.65 (s, 1H) , 7.87 (d, J = 8.8 Hz, 1H) , 7.02 (d, J = 2.4 Hz, 1H) ,

[0371] 6.79 (dd, J = 8.8, 2.4 Hz, 1H) , 4.21 - 4.07 (m, 1H) , 3.96

[0372] (bs, 1H) , 3.09 (d, J = 6.3 Hz, 2H) , 2.82 - 2.41 (m, 2H) ,

[0373] 1.87 - 1.73 (m, 3H) , 1.46 (s, 9H) , 1.29 - 1.13 (m, 2H) . tert-butyl 3- (benzo [d] thiazol-6-ylamino) pyrrolidin-1- carboxylate (compound 5.26, Scheme 5)

[0374] Boc

[0375] The titrated compound was synthesised according to general

[0376] Process E starting with benzo [d] thiazol- 6-amine 6.1 (100 mg, 0.67 mmol) in dry DCM (0.3 M, 2 mL) , tert-butyl-3- oxopyrrolidin-l-carboxylate (112 pL, 0.67 mmol) , acetic acid (10 eq, 6.66 mmol) and sodium triacetoxyborohydrate (4 eq, 2.66 mmol, 565 mg) . Purification by flash chromatography on silica gel ( cyclohexane / EtOAc 80:20) yielded the pure titrated compound as white oil (143.8 mg, yield 68 %) . Characterization: Rt = 2.09 min; MS (ESI) m / z : 320.0 [M+H]+. Exact mass: 319.1354. iH NMR (400 MHz, CDCI3 ) 5 8.68 (s, 1H) , 7.89 (d, J = 8.8 Hz, 1H) , 7.05 (d, J = 2.4 Hz, 1H) , 6.80 (dd, J = 8.8, 2.4 Hz, 1H) , 4.29 - 3.96 (m, 1H) , 3.9 (m, 1H) .96 (m, 1H) , 3.83 - 3.64 (m, 1H) , 3.58-3.38 (m, 1H) , 3.34- 3.15 (m, 1H) , 2.23 (dtd, J = 13.2, 7.7, 5.6 Hz, 1H) , 1.99-

[0377] 1.86 (m, 1H) , 1.47 (s, 9H) . tert-butyl 4- (benzo [d] thiazol-6-ylamino) azepane-1- carboxylate (compound 5.27, Scheme 5)

[0378] The titrated compound was synthesised according to the general Process E from benzo [d] thiazol- 6-amine 6.1 (100 mg, 0.67 mmol) in dry DCM (0.3 M, 2 mL) , tert-butyl 4-oxoazepane- 1-carboxylate (142 mg, 0.67 mmol) , acetic acid (10 eq, 6.66 mmol, 380 pL) and sodium triacetoxyborohydride (4 eq, 2.66 mmol, 565 mg) . Purification by flash chromatography on silica gel ( cyclohexane / EtOAc 75:25) yielded the pure titrated compound as white foam (171.4 mg, yield 74 %) .

[0379] Characterization: Rt = 2.32 min; MS (ESI) m / z : 347.9 [M+H]+. Exact mass: 347.1667. iH NMR (400 MHz, DMSO-d6) 5 8.87 (s, 1H) , 7.73 (d, J = 8.8 Hz, 1H) , 7.05 (d, J = 2.3 Hz, 1H) ,

[0380] 6.81 (dt, J = 9.0, 2.2 Hz, 1H) , 5.90 (t, J = 6.5 Hz, 1H) ,

[0381] 3.59 - 3.44 (m, 3H) .59 - 3.44 (m, 1H) , 3.41 - 3.34 (m, 3H) ,

[0382] 3.22 (dt, J = 8.7, 4.9 Hz, 1H) , 2.09 - 1.92 (m, 2H) , 1.94 -

[0383] 1.71 (m, 2H) , 1.70 - 1.49 (m, 2H) , 1.42 (s, 9H) . tert-butyl 4- (benzo [d] thiazol -6-ylamino) piperidin-1- carboxylate (compound 5.28, Scheme 5)

[0384] The titrated compound was synthesised according to Process E, starting with benzo [d] thiazol- 6-amine 6.1 (528 mg, 1 eq, 3.52 mmol) in dry dichloromethane (0.3 M, 11.7 mL) , 1-boc- 4-piperidone (1 eq, 3.52 mmol, 700 mg, acetic acid (10 eq, 35.2 mmol, 2.01 mL) and sodium triacetoxyborohydride (4 eq, 14.08 mmol, 2.98 g) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate) yielded the pure titrated compound as a yellowish oil in a yield of 67% (800 mg) . Characterization: Rt 2.24 min, generic method, MS (ESI) m / z = 333.9 M+H]+; 392.2 [M+CH3COO-]~ . Exact mass: 333.1511. !H NMR (400 MHz, DMSO) 5 8.89 (s, 1H) , 7.74 (d, J = 8.9 Hz, 1H) , 7.18 (d, J = 2.3 Hz, 1H) , 6.85 (dd, J = 8.9, 2.3 Hz, 1H) , 5.87 (d, J = 8.1 Hz, 1H) , 3.2 (d, J = 8.1 Hz, 1H) .1 Hz, 1H) , 3.89 (d, J = 13.2 Hz, 2H) , 3.56 - 3.42 (m, 1H) , 2.93 (s, 2H) , 1.93 (dd, J = 12.3, 3.7 Hz, 2H) , 1.41 (s, 9H) , 1.30 - 1.16 (m, 2H) .

[0385] N- (tetrahydro-2H-pyran-4-yl) benzo [d] thiazol-6-amine (compound 5.29, Scheme

[0386] The titrated compound was synthesised according to Process E, starting with tetrahydro-4H-pyran-4-one (200 mg, 2 mmol, 1 eq) in dry dichloromethane (5 mL, 0.3 M) , benzo [d] thiazol- 6-amine (1 eq, 2 mmol, 300 mg) , acetic acid (10 eq, 20 mmol, 1.144 mL) and sodium triacetoxiborohydride (4 eq, 8 mmol, 1.693 g) , stirring the reaction at room temperature overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 50:50) yielded the pure titrated product as white crystals in a yield of 30%

[0387] (140 mg) . Characterization: Rt 1.60 min, generic method, MS (ESI) m / z = 234.9 [M+H]+. Exact mass: 234.0827. NMR (400

[0388] MHz, DMSO) 5 8.88 (s, 1H) , 7.74 (d, J = 8.8 Hz, 1H) , 7.19 (d, J = 2.2 Hz, 1H) , 6.86 (dd, J = 8.9, 2.4 Hz, 1H) , 5.89 (d, J = 8.0 Hz, 1H) , 3.0.1 (d, J = 8.0 Hz, 1H) .O Hz, 1H) , 3.89 (dt, J = 11.6, 3.6 Hz, 2H) , 3.56 - 3.40 (m, 3H) , 1.93 (d, J = 12.5 Hz, 2H) , 1.40 (qd, J = 11.1, 4.4 Hz, 2H) .

[0389] N- (thiazol-5-ylmethyl) cyclopentanamine (compound 5.30, Scheme 5)

[0390] The titrated compound was synthesised according to Process E, starting with cyclopentamine (1 eq, 26 pL, 0.265 mmol) in dry dichloromethane (900 pL) , aldehyde 13.12 (1 eq, 20 pL, 0.265 mmol) , sodium triacetoxiborhydride (4 eq, 225 mg, 1.06 mmol) , stirring the reaction at room temperature overnight. The crude product was subjected directly to the subsequent reaction without further purification.

[0391] N- (4- (benzo [d] thiazol-6-ylamino) cyclohexyl) acetamide (compound 5.31, Scheme

[0392] The titrated compound was synthesised according to Process E, starting with N- ( 4-oxocyclohexyl ) acetamide (155 mg, 1 mmol, 1 eq) , benzo [d] thiazol- 6-amine 6.1 (1 eq, 150 mg, 1.0 mmol) , glacial acetic acid (1 eq, 1 mmol, 59 pL) and sodium triacetoxyborohydride (2 eq, 424 mg, 2 mmol) in dry dichloromethane (0.3 M, 3 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. Purification by silica gel column chromatography (hexane / i- PrOH 99:01 to 80:20) yielded the pure titrated product in a yield of 87% (250 mg) . Characterisation: LCMS only, MS (ESI) : m / z = 290.1 [M+H]+. Exact mass: 289.1249.

[0393] N-cyclohexyl-N- ( (6-fluoroquinolin-2-yl) methyl) aniline (compound 5.32, Scheme 5)

[0394] The titrated compound was synthesised according to Process E, starting with N- 6-f luoroquinolin-2-carbaldehyde 1.9 (50 mg, 0.29 mmol, 1 eq) in dry dichloromethane (0.1 M, 2.9 mL) , N-cyclohexylaniline 5.11 (1.2 eq, 0.34 mmol, 60 mg) , acetic acid (10 eq, 2.85 mmol, 163 pL) and sodium triacetoxyborohydride (4 eq, 2.85 mmol) , stirring the reaction mixture at room temperature overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 95:05) yielded the pure titrated compound as a white solid in a yield of 20% (20 mg) .

[0395] Characterization: Rt 2.40 min, apolar method, MS (ESI) m / z = 335.0 [M+H]+. Exact mass: 334.1845. NMR (400 MHz, DMSO) 5 8.25 (d, J = 8.6 Hz, 1H) , 8.05 (dd, J = 9.2, 5.4 Hz, 1H) ,

[0396] 7.73 (dd, J = 9.3, 2.9 Hz, 1H) , 7.66 (td, J = 8.9, 2.9 Hz,

[0397] 1H) , 7.44 (d, J = 8.6 Hz, 1H) , 7.10 (dd, J = 8.6, 7.1 Hz,

[0398] 2H) , 6.71 (d, J = 8.2, 5.4 Hz, 1H) .71 (d, J = 8.3 Hz, 2H) ,

[0399] 6.59 (t, J = 7.2 Hz, 1H) , 4.65 (s, 2H) , 3.85 (s, 1H) , 1.79 (dd, J = 28.3, 10.3 Hz, 4H) , 1.61 (d, J = 13.0 Hz, 1H) , 1.44 (h, J = 12.5 Hz, 4H) , 1.15 (dd, J = 21.3, 9.5 Hz, 1H) .

[0400] N-cyclohexyl-N- ( (6-fluoroquinolin-2- yl) methyl) benzo [d] thiazol-6-amine (compound 5.33, Scheme 5)

[0401] The titrated compound was synthesised according to Process N, starting with N-cyclohexylbenzo [d] thiazol- 6-amine 5.12 (70 mg, 0.30 mmol, 1 eq) in dry acetonitrile (0.1 M, 3 mL) , potassium carbonate (3 eq, 0.90 mmol, 125 mg) and 6-fluoro- 2- ( iodomethyl ) quinoline 5.6 (1.1 eq, 0.33 mmol, 95 mg) .

[0402] Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 95:05) yielded the pure titrated compound as a white solid in a yield of 55% (70 mg) . Characterization: Rt 1.99 min, generic method, MS (ESI) m / z = 392.3 [M+H]+. Exact mass: 391.1518. iH NMR (400

[0403] MHz, DMSO) 5 8.94 (s, 1H) , 8.25 (d, J = 8.6 Hz, 1H) , 8.06

[0404] (dd, J = 9.2, 5.4 Hz, 1H) , 7.79 (d, J = 9.1 Hz, 1H) , 7.73

[0405] (dd, J = 9.4, 2.9 Hz, 1H) , 7.66 (td, J = 8.9, 2.9 Hz, 1H) ,

[0406] 7.49 - 7.41 (m, 2H) , 6.97 (dd, J = 9.2, 2.6 Hz, 1H) , 4.76 (s, 2H) , 4.02 - 3.89 (m, 1H) , 1.86 (d, J = 9.6 Hz, 2H) , 1.76 (d, J = 10.9 Hz, 2H) .76 (d, J = 10.1 Hz, 2H) , 1, 61 (d, J = 12,8 Hz, 1H) , 1.47 (q, J = 11.7 Hz, 4H) , 1.26 - 1.04 (m, 2H) .

[0407] 4- (cyclohexyl ( (6-fluoroquinolin-2-yl) methyl) amino) benzamide (compound 5.34, Scheme 5)

[0408] The titrated compound was synthesised according to Process M, starting with f luoroquinolin-2-carbaldehyde 1.9 (64 mg, 0.37 mmol, 2 eq) , 4- ( cyclohexylamino ) benzamide 5.13 (1 eq, 0.18 mmol, 40 mg) in dry THE (0.2 M, 0.9 mL) , trifluoroacetic acid (3 eq, 0.55 mmol, 42 pL) , phenylsilane (3 eq, 0.55 mmol, 69 pL) . The crude product was purified on silica gel by column chromatography using 100:0 to 90:10 dichloromethane / methanol as an eluent to obtain the insufficiently pure compound. The compound was further purified by silica gel column chromatography using 100:0 to 90:10 dichloromethane / ethyl acetate as an eluent to obtain the pure titrated compound as a white solid in a yield of 16% (11 mg) . Characterization: Rt 2.39 min, generic method, MS (ESI) m / z = 378.0 [M+H]+ . Exact mass: 377.1903. NMR (400 MHz, DMSO) 5 8.27 (d, J = 8.6 Hz, 1H) , 8.04 (dd, J = 9.3, 5.4 Hz, 1H) , 7.73 (dd, J = 9.4, 2.9 Hz, 1H) , 7.70 - 7.53 (m, 3H) , 7.38 (d, J = 8.6 Hz, 1H) , 6.88 (s, 1H) , 6H (s, 1H) .88 (s, 1H) , 6.70 (d, J = 9.1 Hz, 2H) , 4.73 (s, 2H) , 3.95 (s, 2H) , 1.85 - 1.69 (m, 4H) , 1.60 (d, J = 12.8 Hz, 1H) , 1.45 (q, J = 11.7 Hz, 4H) , 1.27 - 1.09 (m, 1H) .

[0409] N-cyclohexyl-N- ( (6-fluoroquinolin-2-yl) methyl )pyridin-3- amine (compound 5.35, Scheme 5)

[0410] The titrated compound was synthesised according to Process M, starting with f luoroquinolin-2-carbaldehyde 1.9 (80 mg, 0.45 mmol, 2 eq) and N-cyclohexylpyridin-3-amine 5.14 (1 eq, 0.23 mmol, 40 mg) in dry tetrahydrofuran (0.2 M, 1.1 mL) , trifluoroacetic acid (3 eq, 0.68 mmol, 52 pL) , phenylsilane (3 eq, 0.68 mmol, 85 pL) . The crude product was purified on silica gel by column chromatography using 100:0 to 90:10 dichloromethane / methanol as an eluent to obtain the insufficiently pure compound. The compound was further purified by a second silica gel column chromatography using 100:0 to 90:10 cyclohexane / isopropanol as an eluent to obtain the compound as a white foamy solid in a yield of 23% (18 mg) . Characterization: Rt 2.57 min, generic method, MS = 335.8 [M+H]+. Exact mass: 335.1798. NMR (400 MHz, DMSO) 5 8.28 (d, J = 8.6 Hz, 1H) , 8.07 - 8.00 (m, 2H) , 7.80 (dd, J = 3.9, 1.8 Hz, 1H) , 7.73 (dd, J = 9.4, 2.9 Hz, 1H) , 7.66 (td, J = 8.9, 2.9 Hz, 1H) , 7.44 (d, J = 8.6 Hz, 1H) , 7.15 -

[0411] 7.05 (m, 1H) .15 - 7.05 (m, 2H) , 4.69 (s, 2H) , 3.88 (d, J =

[0412] 9.5 Hz, 1H) , 1.82 (d, J = 10.5 Hz, 2H) , 1.75 (d, J = 11.5

[0413] Hz, 2H) , 1.60 (d, J = 13.1 Hz, 1H) , 1.45 (h, J = 12.7 Hz,

[0414] 4H) , 1.14 (t, J = 12.3 Hz, 1H) .

[0415] 4- (cyclohexyl ( (6-fluoroquinolin-2-yl) methyl) amino) benzonitrile (compound 5.36, Scheme 5)

[0416] The titrated compound was synthesised according to Process M, starting with f luoroquinolin-2-carbaldehyde 1.9 (87 mg, 0.5 mmol, 2 eq) and 4- ( cyclohexylamino ) benzonitrile 5.15 (1 eq, 0.25 mmol, 50 mg) in dry tetrahydrofuran (0.2 M) , trifluoroacetic acid (3 eq, 0.75 mmol, 57 pL) , phenylsilane (3 eq, 0.75 mmol, 94 pL) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 90:10) yielded the pure titrated compound as a beige solid in a yield of 45% (41 mg) . Characterization: Rt 2.06 min, apolar method, MS (ESI) m / z = 358.1 [M-H]~. Exact mass: 359.1798. iH NMR (400 MHz, DMSO) 5 8.29 (d, J = 8.6 Hz, 1H) , 8.03 (dd, J = 9.2, 5.4 Hz, 1H) , 7.76 (dd, J = 9.4, 2.9 Hz, 1H) , 7.66 (td, J = 8.9, 2.9 Hz, 1H) , 7.56-7.48 (m, 2H) , 7.39 (d, J = 8.6 Hz, 1H) , 6.85 - 6.76 (m, 2H) , 4.79 (s, 2H) , 4.05 - 3.90 (m, 1H) , 1.86 - 1.70 (m, 4H) , 1.64 - 1.36 (m, 5H) , 1.19 - 1.03 (m, 1H) .

[0417] N-cyclohexyl -N- ( (6-fluoroquinolin-2-yl) methyl) -1-methyl-lH- benzo [d] imidazol-6-amine (compound 5.37, Scheme 5)

[0418] The titrated compound was synthesised according to Process

[0419] M, starting with f luoroquinolin-2-carbaldehyde 1.9 (2 eq, 0.44 mmol, 76 mg) and N-cyclohexyl-l-methyl-lH- benzo [d] imidazol- 6-amine 5.16 (50 mg, 0.22 mmol, 1 eq) in dry tetrahydrofuran (0.2 M, 1.1 mL) , trifluoroacetic acid (3 eq, 0.65 mmol, 50 pL) , phenylsilane (3 eq, 0.65 mmol, 82 pL) . Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 90:10) yielded the pure titrated product as a foamy yellow solid in a yield of 46% (39 mg) . Characterization: Rt 2.59 min, generic method, MS = 389.0 [M+H]+. Exact mass: 388.2063. iH NMR (400 MHz, DMSO) 5 8.22 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.2, 5.4 Hz, 1H) , 7.87 (s, 1H) , 7.71 (dd, J = 9.4, 2.9 Hz, 1H) .4, 2.9 Hz, 1H) , 7.65 (td, J = 8.9, 2.9 Hz, 1H) , 7,50 (d, J = 8, 6 Hz, 1H) , 7.37 (d, J = 8.9 Hz, 1H) , 6.87 (d, J = 2. .4 Hz, 1H) , 6.76 (dd, J = 8.9, 2.4 Hz, 1H) , 4.70 (s, 2H) , 3.95 - 3.77 (m,

[0420] 1H) , 3.64 (s, 3H) , 1.89 (d, J = 10.6 Hz, 2H) , 1.89 (d, J =

[0421] 10.6 Hz, 2H) , 1.5 (d, 2H) .6 Hz, 2H) , 1.77 (d, J = 11.6 Hz,

[0422] 2H) , 1.61 (d, J = 13.0 Hz, 1H) , 1.55 - 1.34 (m, 4H) , 1.20 -

[0423] 1.01 (m, 1H) .

[0424] N-cyclohexyl -N- ( (6-fluoroquinolin-2- yl) methyl) benzo [d] oxazol-6-amine (compound 5.38, Scheme 5)

[0425] The titrated compound was synthesised according to Process

[0426] M, starting with N-cyclohexylbenzo [d] oxazol- 6-amine 5.17 (50 mg, 0.23 mmol, 1 eq) , f luoroquinolin-2-carbaldehyde 1.9 (2 eq, 0.46 mmol, 81 mg) in dry tetrahydrofuran (0.2M, 1.2 mL) , trifluoroacetic acid (3 eq, 0.69 mmol, 53 pL) , phenylsilane (3 eq, 0.69 mmol, 53 pL) . The crude product was purified on silica gel by column chromatography using 80:20 to 50:50 cyclohexane / ethyl acetate as an eluent to obtain the insufficiently pure product. The compound was further purified by a second column chromatography on silica gel using 100:0 to 90:10 dichloromethane / ethyl acetate as an eluent to obtain the pure titrated compound as a yellow foamy solid in a 40% yield. Characterization: Rt 1.95 min, apolar method, MS (ESI) m / z = 376.0 [M+H]+. iH NMR (400 MHz, DMSO) 5 8.38 (s, 1H) , 8.26 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.2, 5.4 Hz, 1H) , 7.74 (dd, J = 9.2, 5.4 Hz, 1H) .74 (dd, J = 9,4, 2,9 Hz, 1H) , 7, 67 (td, J = 8,9, 2,9 Hz, 1H) , 7,47 (dd, J = 11,2, 8,7 Hz, 2H) , 7,03 (d, J = 2.4 Hz, 1H) , 6.83 (dd, J = 9.0, 2.5 Hz, 1H) , 4.73 (s, 2H) , 3.92 (t, J = 9.8 Hz, 1H) , 1.87 (d, J = 9.9 Hz, 2H) , 1.76 (d, J = 10.2 Hz, 2H) .76 (d, J = 10.7 Hz, 2H) , 1.62 (d, J = 13.0 Hz, 1H) , 1.48 (q, J = 12.1 Hz, 4H) , 1.21 - 1.08 (m, 1H) .

[0427] N- ( (6-fluoroquinolin-2-yl) methyl) -N- ( (5-phenyl-l ,3,4- oxadiazol -2 -yl) methyl ) cyclohexanamine (Compound 5.39,

[0428] Scheme 5)

[0429] The titrated compound was synthesised according to Process

[0430] M described above. 6-f luoroquinolin-2-carbaldehyde 1.9 (350 mg, 2 mmol) is dissolved in 14 mL of THF, TFA (3 mmol, 235 gL) and N- ( (5-phenyl-l, 3, 4-oxadiazol-2- yl ) methyl ) cyclohexanamine 5.19 (1 mmol, 258 mg) are added and the mixture is stirred for 1 h. Phenyl silane (2.25 mmol, 273 gL) is added dropwise and the mixture is stirred overnight. The reaction is quenched with sodium carbonate, extracted with ethyl acetate, washed with brine and dried over sodium sulphate. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10) yielded the pure titrated compound as a white solid with a yield of 45% (187 mg) . Characterization: Rt 2.41 min, generic method, MS (ESI) m / z = 417 [M+H] +. Exact mass: 416.50. iH NMR (400 MHz, DMSO) 5 8.26 (d, J = 8.5 Hz, 1H) , 7.98 (dd, J = 9.2, 5.4 Hz, 1H) , 7.86 - 7.82 (m, 2H) , 7.73 (d, J = 8.5 Hz, 1H) , 7.66 (dd, J = 9.4, 2.9 Hz, 1H) , 7.62 - 7.47 (m, 4H) , 4. (s, 2H) , 4. (s, 2H) , 4. (s, 2H) , 4. (s, 2H) .18 (s, 2H) , 4.12 (s, 2H) , 2.72 - 2.59 (m, 1H) , 1.88 (d, J = 12.0 Hz, 2H) , 1.74 (d, J = 12.1 Hz, 2H) , 1.55 (d, J = 11.6 Hz, 1H) , 1.33 (q, J = 11.8 Hz, 2H) , 1.14 (dq, J = 26.0, 12.4 Hz, 3H) .

[0431] N- ( (6-fluoroquinolin-2-yl) methyl) -N- ( (2-phenyloxazol-5- yl) methyl) cyclohexanamine (Compound 5.40, Scheme 5)

[0432]

[0433] The titrated compound was synthesised according to Process

[0434] M described above. 6-f luoroquinolin-2-carbaldehyde 1.9 (350 mg, 2 mmol) is dissolved in 14 mL THF, TFA (3 mmol 235 pL) and N- ( ( 2-phenyloxyazol-5-yl ) methyl ) cyclohexanamine 5.20 (1 mmol, 2.56 mg) are added and the reaction is pre-stirred for 1 h. Phenyl silane (2.25 mmol, 273 pL) is added dropwise and the mixture is stirred overnight. The reaction is quenched with sodium carbonate, extracted with ethyl acetate, washed with brine and dried over sodium sulphate. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10) yielded the pure titrated compound as a white solid in a yield of 74% (307 mg) . Characterization: Rt 2.28 min, generic method, MS (ESI) m / z = 416 [M+H]+. Exact mass: 415.21. iH NMR (400 MHz, DMSO) 5 8.25 (d, J = 8.6 Hz, 1H) , 8.03 (s, 1H) , 7.99 (dd, J = 9.2, 5.5 Hz, 1H) , 7.92 - 7.87 (m, 2H) , 7.80 (d, J = 8.6 Hz, 1H) , 7.69 (dd, J = 9.5, 2.9 Hz, 1H) , 7.59 (td, J = 8.9, 2.9 Hz, 1H) .9, 2.9 Hz, 1H) , 7.51 - 7.46 (m, 3H) , 3.97 (s, 2H) , 3.70 (s, 2H) , 2.62 - 2.53 (m, 1H) , 1.88 (d, J = 12.0 Hz, 2H) , 1.72 (d, J = 11.4 Hz, 2H) , 1.54 (d, J = 10.5 Hz, 1H) , 1.42 - 1.00 (m, 5H) . N- ( (6-fluoroquinolin-2-yl) methyl) -N- ( (3-phenyl-l ,2,4- oxadiazol -5 -yl) methyl) cyclohexanamine (Compound 5.41,

[0435] Scheme 5)

[0436] The titrated compound was synthesised according to Process M described above. 6-f luoroquinolin-2-carbaldehyde 1.9 (350 mg, 2 mmol) was dissolved in 14 mL of THF, TFA (3 mmol 235 pL) and N- ( ( 3-phenyl-l , 2 , 4-oxadiazol-5- yl ) methyl ) cyclohexanamine 5.18 (1 mmol, 2.57 mg) are added and the mixture was stirred for 1 h. Phenyl silane (2.25 mmol, 273 pL) is added dropwise and the mixture was stirred overnight. The reaction is quenched with sodium carbonate, extracted with ethyl acetate, washed with brine and dried over sodium sulphate. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10) yielded the pure titrated compound as a white solid in a yield of 52% (216 mg) . Characterization: Rt 2.44 min, generic method, MS (ESI) m / z = 417 [M+H] +. Exact mass: 416.20. iH NMR (400 MHz, DMSO) 5 8.26 (d, J = 8.5 Hz, 1H) , 7.98 (dd, J = 9.2, 5.4 Hz, 1H) , 7.87 - 7.82 (m, 2H) , 7.73 (d, J = 8.5 Hz, 1H) , 7.66 (dd, J = 9.4, 2.9 Hz, 1H) , 7.62 - 7.47 (m, 2H) .62 - 7.47 (m, 4H) , 4.18 (s, 2H) , 4.12 (s, 2H) , 2.74 - 2.60 (m, 1H) , 1.88

[0437] (d, J = 12.0 Hz, 2H) , 1.74 (d, J = 12.1 Hz, 2H) , 1.55 (d, J

[0438] = 11.6 Hz, 1H) , 1.42 - 1.01 (m, 5H) .

[0439] N,N-bis ( (6-fluoroquinolin-2-yl) methyl) cyclohexanamine

[0440] (compound 5.42, Scheme 5)

[0441] The titrated compound was synthesised according to Process M described above; 6-f luoroquinolin-2-carbaldehyde 1.9 (350 mg, 2 mmol) was dissolved in 14 mL THF, TFA (3 mmol 235 pL) and N- (pyridin-3-ylmethyl ) cyclohexanamine 5.21 (1 mmol, 190 mg) were added and the reaction was pre-stirred for 1 hr.

[0442] Phenyl silane (2.25 mmol, 273 pL) is added dropwise and the mixture is stirred overnight. The reaction is quenched with sodium carbonate, extracted with ethyl acetate, washed with brine and dried over sodium sulphate. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10) yielded the pure titrated compound as a white solid in a yield of 57% (238 mg) . Characterization: Rt 2.12 min, generic method, MS (ESI) m / z = 418 [M+H] +. Exact mass: 417.20.TH NMR (400 MHz, CDC1 _33 mm) 5 8.02 - 7.93 (m, 4H) , 7.75 - 7.68 (m, 2H) , 7.44 - 7.37 (m, 2H) , 7.34 (dd, J = 8.9, 2.8 Hz, 2H) , 4.04 (s, 4H) , 2.54 (tt, J = 11.8 Hz, 2H) .54 (tt, J = 11.7, 3.4 Hz, 1H) , 2.02 (d, J = 12.3 Hz, 2H) , 1.79 (d, J =

[0443] 11.6 Hz, 2H) , 1.63 (s, 2H) , 1.47 - 1.34 (m, 2H) , 1.20 - 1.09 (m, 2H) .

[0444] N-cyclohexyl -N- ( (6-methoxyquinolin-2-yl) methyl) benzo [d] thiazol-6-amine (compound 5.43, Scheme 5)

[0445] The titrated compound was synthesised according to Process

[0446] M, starting with N-cyclohexylbenzo [d] thiazol- 6-amine 5.12 (62 mg, 0.27 mmol, 1 eq) and 6-methoxyquinolin-2- carbaldehyde 5.9 (2 eq, 0.54 mmol, 100 mg) in dry tetrahydrofuran (0.2 M, 1.3 mL) , trifluoroacetic acid (3 eq, 0.8 mmol, 61 pL) , phenylsilane (3 eq, 0.8 mmol, 100 pL) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 90:10) yielded the pure titrated product as a white solid with a yield of 49%. Characterization: Rt 1.92 min, generic method, MS (ESI) m / z = 403.9 [M+H] + . !H NMR (400 MHz, DMSO) 5 8.94 (s, 1H) , 8.15

[0447] (d, J = 8.5 Hz, 1H) , 7.90 (d, J = 9.2 Hz, 1H) , 7.78 (d, J = 9.1 Hz, 1H) , 7.45 - 7.34 (m, 3H) , 7.32 (d, J = 2.8 Hz, 1H) , 6.98 (dd, J = 9.2, 2.6 Hz, 1H) , 4.73 (s, 2H) , 3.94 (d, J = 11.0 Hz, 1H) , 3.88 (s, 3H) , 1.87 (d, J = 9.9 Hz, 2H) , 1.77 (d, J = 10.9 Hz, 2H) , 1.62 (d, J = 13.0 Hz, 1H) , 1.48 (q, J = 13.0 Hz, 4H) , 1.19 - 1.11 (m, 1H) .

[0448] N-cyclohexyl-N- ( (6-ethoxyquinolin-2- yl) methyl) benzo [d] thiazol-6-amine (compound 5.44, Scheme 5)

[0449] The product was synthesised according to Process M, starting with cyclohexylbenzo [d] thiazol- 6-amine 5.12 (1 eq, 43 mg, 0.19 mmol) and 6-ethoxyquinolin-2-carbaldehyde 5.10 (2 eq, 0.37 mmol, 74 mg) , trifluoroacetic acid (3 eq, 0.56 mmol, 42 pL) , phenylsilane (3 eq, 0.56 mmol, 70 pL) in dry tetrahydrofuran (0.2 M, 0.9 mL) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 80:20) yielded the pure product titrated as a white solid in a yield of 45% (35 mg) . Characterization: Rt 2.19 min, generic method, MS (ESI) m / z = 418.0 [M+H]+. Exact mass: 417.1875. iH NMR (400 MHz, DMSO) 5 8,94 (s, 1H) , 8,13 (d, J = 8, 6 Hz, 1H) , 7,89 (d, J = 9,2 Hz, 1H) , 7,78 (d, J = 9.1 Hz, 1H) , 7.42 (d, J = 2.6 Hz, 1H) , 7.41 - 7.33 (m, 2H) , 7.30 (d, J = 2.8 Hz, 1H) , 6.98 (dd, J = 9.2, 2.6 Hz, 1H) , 6.98

[0450] (d, J = 9.2, 2.6 Hz, 1H) .2, 2, 6 Hz, 1H) , 4.72 (s, 2H) , 4.14

[0451] (q, J = 6,9 Hz, 2H) , 3.91 (d, J = 28.3 Hz, 1H) , 1.87 (d, J

[0452] = 9.7 Hz, 2H) , 1.77 (d, J = 10.7 Hz, 2H) , 1.62 (d, J = 12.9

[0453] Hz, 1H) , 1.59 - 1.33 (m, 7H) , 1.22 - 1.07 (m, 1H) . N-cyclohexyl -N- ( (6- (tri fluoromethyl) quinolin-2- yl) methyl) benzo [d] thiazol-6-amine (compound 5.45, Scheme 5)

[0454] The titrated compound was synthesised according to Process

[0455] M, starting with cyclohexylbenzo [d] thiazol- 6-amine 5.12 (50 mg, 0.22 mmol, 1 eq) and 6- (trifluoromethyl) quinolin-2- carbaldehyde 5.7 (2 eq, 0.43 mmol, 97 mg) in dry tetrahydrofuran (0.2 M, 1.1 mL) , trifluoroacetic acid (3 eq, 0.65 mmol, 49 pL) , phenylsilane (3 eq, 0.65 mmol, 81 pL) . The crude product was purified on silica gel by column chromatography using 100:0 to 90:10 cyclohexane / ethyl acetate as an eluent. The product was further purified by a second column chromatography on silica gel using 100:0 to 90:10 cyclohexane / dichloromethane as an eluent. The product was further triturated with t-butyl methylether to obtain the pure titration product as a pale yellow solid in a 10% yield (10 mg) . Characterization: Rt 2.41 min, generic method, MS (ESI) m / z = 441.9 [M+H]+ . iH NMR (400 MHz, DMSO) 5 8.95 (s, 1H) , 8.50 - 8.45 (m, 2H) , 8.19 (d, J = 8.8 Hz, 1H) , 8.04 - 7.97 (m, 1H) , 7.79 (d, J = 9.0 Hz, 1H) , 7.58 (d, J = 8.6 Hz, 1H) , 7.45 (d, J = 2.6 Hz, 1H) , 6.99 (dd, J = 9.0 Hz, 1H) .99 (dd, J = 9.2, 2.6 Hz, 1H) , 4.83 (s, 2H) , 3.97 (s, 1H) , 1.88 (d, J = 9.6 Hz, 2H) , 1.77 (d, J = 10.8 Hz, 2H) , 1.63 (d, J = 12.8 Hz, 1H) , 1.49 (q, J = 12.0 Hz, 4H) , 1.21 - 1.09 (m, 1H) .

[0456] N-cyclohexyl -N- ( (6- ( tri fluoromethoxy) quinolin-2- yl) methyl) benzo [d] thiazol-6-amine (compound 5.46, Scheme 5)

[0457] The titrated compound was synthesised according to Process

[0458] N, starting with cyclohexylbenzo [d] thiazol- 6-amine 5.12 (53 mg, 0.23 mmol, 1 eq) in dry ACN (0.1 M, 2.3 mL) , potassium carbonate (3 eq, 0.69 mmol, 95 mg) and 2- (iodomethyl) -6- ( trifluoromethoxy) quinoline 5.8 (1.15 eq, 0.26 mmol, 93 mg) , stirring the reaction mixture at reflux overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 95:05) yielded the pure titrate as a pale yellow solid in a yield of 68% (72 mg) . Characterization: Rt 2.46 min, apolar method, MS (ESI) m / z = 457.9 [M+H]+, 456.0 [M-H] ; 515.9 [M+CH3COO ] . Exact mass: 457.1436. iH NMR (400 MHz, DMSO) 5 8.95 (s, 1H) , 8.37 (d, J = 8.6 Hz, 1H) , 8.12 (d, J = 9.2 Hz, 1H) , 8.00 (s, 1H) , 7.79 (d, J = 9.1 Hz, 1H) , 7.77 - 7.71 (m, 1H) , 7.51 (d, J =

[0459] 8.6 Hz, 1H) , 7.44 (d, J = 2. .5 Hz, 1H) , 6.98 (dd, J = 9.2,

[0460] 2.6 Hz, 1H) , 4.79 (s, 2H) , 3.96 (s, 1H) , 1.87 (d, J = 9.6 Hz, 2H) , 1.77 (d, J = 10.6 Hz, 2H) , 2H (d, J = 10.6 Hz, 2H) .77 (d, J = 10.7 Hz, 2H) , 1.63 (d, J = 12.9 Hz, 1H) , 1.48 (q, J = 11.5 Hz, 4H) , 1.15 (d, J = 12.6 Hz, 1H) .

[0461] N- ( (6-fluoroquinolin-2-yl) methyl) -N- ( tetridrofuran-3- yl) benzo [d] thiazol-6-amine (compound 5.47, Scheme 5)

[0462] The titrated compound was synthesised according to Process N, starting with 6-fluoro-2- ( iodomethyl ) quinoline 5.6 (350 mg, 2 mmol) in 20 mL ACN, potassium carbonate (3 mmol, 414 mg) and N- ( tetrahydrofuran-3-yl ) benzo [d] thiazol- 6-amine 5.22 (1.6 mmol, 352.4 mg) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10-10:90) yielded the pure titrated compound as a white solid in a yield of 53% (314 mg) . Characterization: Rt 0.93 min, generic method, MS (ESI) m / z = 394 [M+H]+. Exact mass: 393.13.1H NMR (400 MHz, DMSO) 5 8.98 (s, 1H) , 8.29 (d, J = 8.6 Hz, 1H) , 8.04 (dd, J = 9.3, 5.4 Hz, 1H) , 7.83 - 7.71 (m, 2H) , 7.66 (td, J = 9.0, 2.9 Hz, 1H) , 7.51 - 7.43 (m, 2H) , 6.99 (dd, J = 9.0, 2H) .99 (dd, J = 9.1, 2.6 Hz, 1H) , 4.79 (q, J = 18.3 Hz, 3H) , 4.01 - 3.85 (m, 2H) , 3.78 (dd, J = 9.7, 4.1 Hz, 1H) , 3.66 (q, J = 8.0 Hz, 1H) , 2.40 (h, J = 7.9 Hz, 1H) , 1.94 (dq, J = 13.1, 7.7 Hz, 1H) .

[0463] N- ( (6-fluoroquinolin-2-yl) methyl) -N- (oxe tan-3- yl) benzo [d] thiazol-6-amine (Compound 5.48, Scheme 5)

[0464] The titrated compound was synthesised according to Process N, starting with 6-fluoro-2- ( iodomethyl ) quinoline 5.6 (350 mg, 2 mmol) in 20 mL ACN, potassium carbonate (3 mmol, 414 mg) and N- (oxetan-3-yl ) benzo [d] thiazol- 6-amine 5.23 (1.6 mmol, 343.7 mg) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10-10:90) yielded the pure titrated compound as a white solid in a yield of 57% (345 mg) . Characterization: Rt 1.00 min, generic method, MS (ESI) m / z = 380 [M+H]+. Exact mass: 379.12.1H NMR (400 MHz, CDC13) 5 8.73 (s, 1H) , 8.12 - 7.99 (m, 2H) , 7.94 (d, J = 9.0 Hz, 1H) , 7.55 - 7.45 (m, 2H) , 7.42 (dd, J = 8.7, 2.8 Hz, 1H) .7, 2.8 Hz, 1H) , 7,02 (d, J = 2.5 Hz, 1H) , 6.89 (dd, J = 9.0, 2.5 Hz, 1H) , 5.05 - 4.91 (m, 3H) , 4.86 (s, 2H) , 4.83 - 4.73 (m, 2H) .

[0465] N- (cyclopropYlmethyl) -N- ( (6-fluoroquinolin-2- yl) methyl) benzo [d] thiazol-6-amine (compound 5.49, Scheme 5)

[0466] The titrated compound was synthesised according to general

[0467] Process M, starting with the intermediate 5.24 (39 mg, 0.19 mmol) , f luoroquinolin-2-carbaldehyde 1.9 (67 mg, 0.38 mmol) in dry THF (0.2 M, 1 mL) , trifluoroacetic acid (3 eq, 0.57 mmol, 44 qL) and phenylsilane (3 eq, 0.57 mmol, 71 qL) . Purification by reversed-phase flash chromatography (H2O / MeCN 35:65) yielded the pure titrated compound as a brown solid (9.1 mg, yield 13%) . Characterization: Rt = 1.50 min; MS (ESI) m / z: 364.1 [M+H]+. Exact mass: 363.1205. NMR (400 MHz, DMSO-d6) 5 8.93 (s, 1H) , 8.26 (d, J = 8.6 Hz, 1H) , 8.05 (dd, J = 9.2, 5.4 Hz, 1H) , 7.79 (d, J = 9.2, 5.4 Hz,

[0468] 1H) .79 (d, J = 9.1 Hz, 1H) , 7.74 (dd, J = 9.4, 2.9 Hz, 1H) ,

[0469] 7.66 (td, J = 8.9, 2.9 Hz, 1H) , 7.45 (d, J = 8.6 Hz, 1H) ,

[0470] 7.45 (d, J = 8.6 Hz, 1H) .6 Hz, 1H) , 7.42 (d, J = 2.5 Hz,

[0471] 1H) , 7.02 (dd, J = 9.1, 2.6 Hz, 1H) , 4.94 (s, 2H) , 3.53 (d, J = 6.6 Hz, 2H) , 1.20 (dq, J = 13.2, 6.2 Hz, 1H) , 0.59 - 0.39 (m, 2H) , 0.29 (dd, J = 4.9, 1.6 Hz, 2H) . tert-butyl 4- ( (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl)methyl) amino)methyl)piperidin-l-carboxylate (compound 5.50, Scheme 5)

[0472] The titrated compound was synthesised according to general Process N, starting with the intermediate 5.25 (134 mg, 0.39 mmol) , 6-fluoro-2- ( iodomethyl ) quinoline 5.6 (121 mg, 0.42 mmol) and potassium carbonate (3 eq, 1.16 mmol, 160 mg) in dry acetonitrile (0.1 M, 4 mL) . Purification by reversed- phase flash chromatography (H2O / MeCN 30:70) yielded the pure titrated compound as yellow foam (104.9 mg, yield 54%) . Characterization: Rt = 1.80 min; MS (ESI) m / z : 507.1 [M+H]+. Exact mass: 506.2152. NMR (400 MHz, DMSO-d6) 5 8.91 (s, 1H) , 8.25 (d, J = 8.6 Hz, 1H) , 8.03 (dd, J = 9.2, 5.4 Hz,

[0473] 1H) , 7.76 (d, J = 9.0 Hz, 1H) , 7.76 (d, J = 9.0 Hz, 1H) .O

[0474] Hz, 1H) , 7.73 (dd, J = 9.4, 2.9 Hz, 1H) , 7.65 (td, J = 8.9,

[0475] 2.9 Hz, 1H) , 7.38 (d, J = 2.6 Hz, 1H) , 7.36 (d, J = 8.2, 5.4 Hz, 1H) .36 (d, J = 8.6 Hz, 1H) , 6.97 (dd, J = 9.1, 2.6 Hz, 1H) , 4.91 (s, 2H) , 4.04 - 3.80 (m, 2H) , 3.57 (d, J = 7.1 Hz, 2H) , 2H (d, J = 7.1 Hz, 2H) .l Hz, 2H) , 2.72 - 2.56 (m, 2H) , 2.08 - 1.86 (m, 1H) , 1.73 (d, J = 12.7 Hz, 2H) , 1.38 (s, 9H) 1.27 - 0.94 (m, 2H) . tert-butyl3- (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl)methyl) amino) pyrrolidin-l-carboxylate (compound 5.51, Scheme 5)

[0476] The titrated compound was synthesised according to general Process N, starting with the intermediate 5.26 (143 mg, 0.45 mmol) , 6-fluoro-2- ( iodomethyl ) quinoline 5.6 (141 mg, 0.49 mmol) and potassium carbonate (3 eq, 1.34 mmol, 186 mg) in dry acetonitrile (0.1 M, 4 mL) . Purification by reversed- phase flash chromatography (H2O / MeCN 40:60) yielded the pure titrated compound as brown oil (38.7 mg, yield 18%) . Characterization: Rt = 1.51 min; MS (ESI) m / z : 479.2 [M+H]+. Exact mass: 478.1839. NMR (400 MHz, DMSO-d6) 5 8.99 (s, 1H) , 8.30 (d, J = 8.6 Hz, 1H) , 8.03 (dd, J = 9.3, 5.4 Hz,

[0477] 1H) , 7.80 (d, J = 9.0 Hz, 1H) , 7.76 (dd, J = 9.4, 2.9 Hz,

[0478] 1H) , 7.66 (td, J = 8.9, 2.9 Hz, 1H) , 7.57 (d, J = 2.9 Hz,

[0479] 1H) .57 (d, J = 2.5 Hz, 1H) , 7.46 (d, J = 8.6 Hz, 1H) , 7.04 (dd, J = 9.1, 2.6 Hz, 1H) , 4,94 - 4.63 (m, 2H) , 3.78 - 3.59 (m, 1H) , 3.49 - 3.31 (m, 2H) , 3.29 - 3.07 (m, 2H) , 1.35 (d, J = 17.2 Hz, 9H) . tert-butyl 4- (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl)methyl) amino) azepan-1 -carboxylate (compound 5.52, Scheme 5)

[0480] The titrated compound was synthesised according to general Process N, starting with the intermediate 5.27 (171 mg, 0.49 mmol) , 6-fluoro-2- ( iodomethyl ) quinoline 5.6 (155 mg, 0.54 mmol) and potassium carbonate (3 eq, 1.48 mmol, 204 mg) in dry acetonitrile (0.1 M, 5 mL) . Purification by reversed- phase flash chromatography (H2O / MeCN 25:75) yielded the pure titrated compound as brown foam (38.9 mg, 16% yield) . Characterization: Rt = 1.80 min; MS (ESI) m / z : 507.2 [M+H]+. Exact mass: 506.2152. iH NMR (400 MHz, DMSO-d6) 5 8.12 (d, J = 2.3 Hz, 1H) , 7.43 (d, J = 8.6 Hz, 1H) , 7.21 (dd, J = 9.2,

[0481] 5.4 Hz, 1H) , 6.95 (dd, J = 9.2, 5.4 Hz, 1H) .95 (dd, J = 9.1,

[0482] 5.6 Hz, 1H) , 6.90 (dd, J = 9.4, 2.9 Hz, 1H) , 6.82 (td, J =

[0483] 8.9, 2.9 Hz, 1H) , 6.64 (d, J = 8.6 Hz, 1H) , 6.6 (d, J = 8.6

[0484] Hz, 1H) .6 Hz, 1H) , 6.57 (d, J = 7.5 Hz, 1H) , 6.12 (t, J =

[0485] 9.4 Hz, 1H) , 3.87 (s, 2H) , 3.26 - 3.09 (m, 1H) , 2.76 - 2.56

[0486] (m, 2H) , 3.26 - 2H (m, 2H) .56 (m, 2H) , 2.48 - 2.40 (m, 2H) , 1.30 - 1.04 (m, 2H) , 1.02 - 0.81 (m, 4H) , 0.55 (d, J = 19.7 Hz, 9H) . tert-butyl 4- (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl)methyl) amino) piperidin-l-carboxylate (compound 5.53, Scheme 5)

[0487] The title compound was synthesised according to Process N, starting with tert-butyl 4- (benzo [d] thiazol-6- ylamino) piperidin-l-carboxylate 5.28 (1 eq, 700 mg, 1.786 mmol) in dry acetonitrile (0.1 M, 18 mL) , 6-fluoro-2- ( iodomethyl ) quinoline 5.6 (1.15 eq, 2.05 mmol, 590 mg) , potassium carbonate (3 eq, 5.36 mmol, 740 mg) , stirring the reaction mixture at reflux overnight. The crude product was purified on silica gel using 100:0 to 50:50 cyclohexane / ethyl acetate as an eluent to obtain a mixture of the product with the starting material. The mixture was further purified on silica gel in reverse phase using 90:10 to 50:50 water / acetonitrile as an eluent to obtain the compound as a white solid in a yield of 26% (230 mg) . Characterization: Rt 1.72 min, apolar method, MS = 493.0 [M+H]+. Exact mass: 492.1995. !H NMR (400 MHz, DMSO) 5 8.97 (s, 1H) , 8.27 (d, J = 8.6 Hz, 1H) , 8.05 (dd, J = 9.2, 5.4 Hz, 1H) , 7.80 (d, J = 9.2, 5.4 Hz, 1H) .8O (d, J = 9.1 Hz, 1H) , 7.75 (dd, J = 9.4, 2.9 Hz, 1H) , 7.67 (td, J = 8.9, 2.9 Hz, 1H) , 7.52 (d, J =

[0488] 2.5 Hz, 1H) , 7.48 (d, J = 8.6 Hz, 1H) , 7.04 (dd, J = 9.2,

[0489] 2.6 Hz, 1H) , 4.75 (s, 2H) , 4.18 (t, J = 11.7 Hz, 1H) , 4.07

[0490] (d, J = 26.5 Hz, 1H) .07 (d, J = 26.0 Hz, 2H) , 2.93 (s, 3H) ,

[0491] 1.85 (d, J = 12.1 Hz, 2H) , 1.66 - 1.51 (m, 2H) , 1.38 (s,

[0492] 9H) .

[0493] N- (4- (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl ) methyl ) amino) cyclohexyl ) acetamide (compound 5.54, Scheme 5)

[0494] The titrated compound was synthesised according to Process M, starting with N- (4- (benzo [d] thiazol-6- ylamino ) cyclohexyl ) acetamide 5.31 (1 eq, 245 mg, 0.84 mmol) , 6-f luoroquinolin-2-carbaldehyde 1.9 (297 mg, 1.7 mmol, 2 eq) , trifluoroacetic acid (3 eq, 2.5 mmol, 191 qL) , phenylsilane (3 eq, 2.5 mmol, 308 qL) , in dry tetrahydrofuran THF (0.07 M, 12 mL) at room temperature. The crude product was first purified by column chromatography on silica gel (hexane / i -PrOH from 99:1 to 80:20) and then by column chromatography on C18 reversed-phase silica gel (water / acetonitrile 90:10 to 50:50) to obtain the pure titrated product as a light yellow solid in a 10% yield (37 mg) . Characterization: MS (ESI) m / z = 449.2 [M+H]+. Exact mass: 448.1733.1H NMR (400 MHz, dmso) 5 8.94 (s, 1H) , 8.26

[0495] (d, J = 8.5 Hz, 1H) , 8.05 (dd, J = 9.2, 5.4 Hz, 1H) , 7.80 - 7.70 (m, 3H) , 7.66 (td, J = 8.9, 2.9 Hz, 1H) , 7.48 - 7.42

[0496] (m, 2H) , 6. (dd, J = 9.9, 2H) .97 (dd, J = 9.2, 2.5 Hz, 1H) ,

[0497] 4.76 (s, 2H) , 3.95 (d, J = 12.1 Hz, 1H) , 3.50 (d, J = 11.6

[0498] Hz, 2H) , 1.84 (d, J = 10.8 Hz, 5H) , 1.77 (s, 3H) , 1.64 (q,

[0499] J = 12.3 Hz, 2H) , 1.40 (q, J = 12.1 Hz, 2H) .

[0500] N- ( (6-fluoroquinolin-2-yl) methyl) -N- (tetrahydro-2H-pyran-4- yl) benzo [d] thiazol-6-amine (compound 5.55, Scheme 5) The title compound was synthesised according to Process N, starting with N- ( tetrahydro-2H-pyrano-4-yl ) benzo [d] thiazol- 6-amine 5.29 (130 mg, 0.55 mmol, 1 eq) in dry acetonitrile (0.1 M, 5.5 mL) , potassium carbonate (3 eq, 1.66 mmol, 232 mg) and 6-fluoro-2- (iodomethyl) quinoline 5.6 (1.15 eq, 0.61 mmol, 175 mg) , stirring the reaction mixture at 60°C overnight. The crude product was purified on silica gel using 100:0 to 60:40 cyclohexane / ethyl acetate as an eluent. The compound was further purified by means of a mixture of eluents. The compound was further purified by reversed-phase silica gel column chromatography, using 90:10 to 60:40 water / acetonitrile as an eluent to obtain the compound as a white solid in 50% yield (110 mg) . Characterization: Rt 1.00 min, apolar method, MS (ESI) m / z = 393.9 [M+H]+, exact mass: 393.1311. !H NMR (400 MHz, DMSO) 5 8.97 (s, 1H) , 8.27 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.2, 5.4 Hz, 1H) , 7.80 (d, J = 9.2, 5.4 Hz, 1H) .8O (d, J = 9.1 Hz, 1H) , 7.75 (dd, J = 9.4, 2.9 Hz, 1H) , 7.67 (td, J = 8.9, 3.0 Hz, 1H) , 7.54 (d, J = 2.6 Hz, 1H) , 7.54 (d, J = 2.6 Hz, 1H) , 7.5 (d, J = 2.6 Hz, 1H) .6 Hz, 1H) , 7.49 (d, J = 8.6 Hz, 1H) , 7.04 (dd, J = 9.1, 2.6 Hz, 1H) , 4.78 (s, 2H) , 4.24 (tt, J = 10.1, 5.1 Hz, 1H) .1, 5.1 Hz, 1H) , 3.92 (dd, J = 10.7, 3.6 Hz, 2H) , 3.53 (td, J = 11.1, 3.4 Hz, 2H) , 1.83 - 1.69 (m, 4H) .

[0501] N- ( (6-ethoxyquinolin-2-yl) methyl) -N- (thiazol -5 -methyl) cyclopentanamine (compound 5.56, Scheme 5)

[0502] The titrated compound was synthesised according to Process E, starting with the intermediate 5.30 (0.265 mmol, 1 eq) in dry dichloromethane (900 pL) , the aldehyde 5.10 (153 mg, 0.265 mmol) , acetic acid (catalytic) and sodium triacetoxyborohydride (4 eq, 225 mg, 1.06 mmol) , stirring the reaction mixture overnight at room temperature. Purification by flash chromatography on silica gel ( cyclohexane / EtOAc 70:30) yielded the pure titrated compound (25 mg, yield 25 %) . Characterization: Rt = 1.61 min; MS (ESI) m / z : 368.5 [M+H]+, exact mass: 353.1562.1H NMR (400 MHz, DMSO) 5 8.97 (d, J = 0.8 Hz, 1H) , 8.18 (d, J = 8.5 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.77 (s, 1H) , 7.58 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.0, 2.8 Hz, 1H) , 7.30 (d, J = 2.8 Hz, 1H) , 4.5 (d, J = 2.8 Hz, 1H) .8 Hz, 1H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.92 (s, 2H) , 3.83 (s, 2H) , 3.07 (t, J = Hz, 1H) , 1.84 - 1.69 (m, 2H) , 1.64 - 1.53 (m, 2H) , 1.51 - 1.42 (m, 4H) , 1.39 (t, J = 7.0 Hz, 3H) .

[0503] 2- ( (benzo [d] thiazol-6-yl (piperidin-l-io-4- ylmethyl) ammonium) methyl) -6-fluoroquinolin-l-ium chloride (compound 5.57, Scheme 5)

[0504] The compound was synthesised according to general process 01 using the intermediate 5.50 (104 mg, 0.21 mmol) in dioxane (0.1 M, 2 mL) and HC1 4M in dioxane (8 eq, 1.64 mmol, 410 pL) , stirring the reaction mixture at room temperature for 6 h. The solvent was evaporated to obtain the desired compound as a yellow powder in quantitative yield (105 mg) . Characterization: Rt = 1.74 min; MS (ESI) m / z : 407.2 [M+H]+. Exact mass: 406.1627. NMR (400 MHz, DMSO-d6) 5 8.95 (d, J = 1.2 Hz, 1H) , 8.34 (d, J = 8.7 Hz, 1H) , 8.08 (dd, J = 9.3, 5.3 Hz, 1H) , 7.79 (d, J = 9.0 Hz, 2H) , 7.70 (td, J = 9.0, 3.2 Hz, 1H) , 7.51 - 7.31 (m, 2H) , 7.01 (dd, J = 9.0, 2H) .O1 (dd, J = 9.2, 2.6 Hz, 1H) , 4.96 (s, 2H) , 3.59 (d, J = 7.1 Hz, 2H) , 3.32 - 3.21 (m, 2H) , 2.84 (q, J = 12.0 Hz, 2H) , 2.21 - 2.08 (m, 1H) , 1.92 (d, J = 13.1 Hz, 2H) , 1.52 - 1.32 (m, 2H) .

[0505] 2- ( (benzo [d] thiazol-6-yl (pyrrolidin-l-io-3- yl) ammonium) methyl) -6-fluoroquinolin-l-ium chloride

[0506] (compound 5.58, Scheme 5) The compound was synthesised according to general process 01 using the intermediate 5.51 (38 mg, 0.079 mmol) in dioxane (0.1 M, 800 pL) and HC1 4M in dioxane (8 eq, 0.635 mmol, 160 pL) , stirring the reaction mixture at room temperature for 6 h. The solvent was evaporated to obtain the desired compound as a yellow powder in quantitative yield (38 mg) . Characterization: Rt = 1.66 min; MS (ESI) m / z : 379.1 [M+H]+. Exact mass: 378.1314. NMR (400 MHz, DMSO-d6) 5 9.17 (b, 1H) , 9.08 (b, 1H) , 9.04 (s, 1H) , 8.37 (d, J = 8.6 Hz, 1H) , 8.08 (dd, J = 9.6 Hz, 1H) 08 (dd, J = 9.3, 5.4 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.80 (dd, J = 9.4, 2.9 Hz, 1H) , 7.70 (td, J = 8.9, 2.9 Hz, 1H) , 7.62 - 7.43 (m, 2H) , 7.06 (dd, J

[0507] = 9.1, 2.5 Hz, 1H) , 5.04 - 4.62 (m, 3H) , 3.70 - 3.57 (m, 1H) , 3.5 (td, J = 9.4, 2.9 Hz, 1H) .57 (m, 1H) , 3.46 - 3.36 (m, 1H) , 3.21 - 3.05 (m, 2H) , 2.36 - 2.25 (m, 1H) , 1.99 (dt, J = 19.9, 9.2 Hz, 1H) .

[0508] 2- ( (azepan-l-io-4-yl (benzo [d] thiazol-6-yl) ammonium) methyl) - 6-fluoroquinolin-l-ium chloride (compound 5.59, Scheme 5)

[0509] The compound was synthesised according to general process 01 using the intermediate 5.52 (38 mg, 0.075 mmol) in dioxane (0.1 M, 750 pL) and HC1 4M in dioxane (8 eq, 0.600 mmol, 150 pL) , stirring the reaction mixture at room temperature for

[0510] 4 h. The solvent was evaporated to obtain the desired compound as a yellow powder in quantitative yield (37 mg) . Characterization: Rt = 1.75 min; MS (ESI) m / z : 407.2 [M+H]+. Exact mass: 406.1627. NMR (400 MHz, DMSO-d6) 5 9.39 (b, 1H) , 9.26 (b, 1H) , 9.03 (s, 1H) , 8.65 (d, J = 8.7 Hz, 1H) , 8.36 (dd, J = 9.7 Hz, 1H) .36 (dd, J = 9.3, 5.1 Hz, 1H) , 7.98 (dd, J = 9.1, 2.9 Hz, 1H) , 7.89 (td, J = 8.9, 2.8 Hz, 1H) , 7.71 (d, J = 8.7 Hz, 1H) , 7.7 (s, 1H) .7.59 (d, J = 2.5 Hz, 1H) , 7.09 (dd, J = 9.1, 2.6 Hz, 1H) , 5.00 (d, J = 6.2 Hz, 2H) , 4.36 (s, 1H) , 3.30 - 3.15 (m, 3H) , 3.13 - 3.00 (m, 1H) , 2.26 - 2.09 (m, 2H) , 2.06 - 1.66 (m, 4H) .

[0511] 2- ( (benzo [d] thiazol-6-yl (piperidin-l-io-4-yl) ammonium) methyl) -6-fluoroquinolin-l-ium chloride (compound 5.60, Scheme 5)

[0512] The titrated compound was synthesised according to Process 01, starting with tert-butyl 4- (benzo [d] thiazol-6-yl ( ( 6- f luoroquinolin-2-yl ) methyl) amino) piperidin-l-carboxylate 5.53 (230 mg, 0.47 mmol, 1 eq) in dioxane (0.1 M) , 4M HC1 in dioxane (8 eq, 3.74 mmol, 0.9 mL) , stirring the reaction mixture at room temperature overnight. The solvent was evaporated to obtain the desired compound as a brown powder in quantitative yield (235 mg) . Characterization: 1.72 min, generic method, MS (ESI) m / z = 392.9 [M+H]+. Exact mass: 392.1471. !H NMR (400 MHz, DMSO) 5 9.03 (s, 1H) , 8.96 (s,

[0513] 1H) , 8.73 (s, 1H) , 8.46 (d, J = 8.6 Hz, 1H) , 8.18 (dd, J =

[0514] 9.3, 5.2 Hz, 1H) , 7.89 - 7.82 (m, 2H) , 7.77 (td, J = 8.9, 2.9 Hz, 1H) , 7.64 - 7.56 (m, 2H) , 7.10 (dd, J = 9.2, 2.6 Hz, 1H) , 4.85 (s, 2H) , 4.35 (d, J = 9.6 Hz, 1H) , 3.35 (d, J =

[0515] 12.4 Hz, 2H) , 3.10 (s, 2H) , 2.00 (d, J = 8.5 Hz, 4H) .

[0516] N- (1 , 4 -di oxaspiro [4,5] decan-8-yl) benzo [d] thiazol-6-amine (compound 6.3, Scheme 6)

[0517] The titrated compound was synthesised according to Process E, starting with benzo [d] thiazol- 6-amine 6.1 (1 eq, 1.28 mmol, 192 mg) in dry dichloromethane (0.3 M, 2.47 mL) , 1,4- cyclohexanedione acetal monoethylene 6.2 (1 eq, 1.28 mmol, 200 mg) , acetic acid (10 eq, 12.8 mmol, 732 pL) and sodium triacetoxyborohydride (4 eq, 12.8 mmol, 732 pL) .2 (1 eq, 1.28 mmol, 200 mg) , acetic acid (10 eq, 12.8 mmol, 732 pL) and sodium triacetoxyborohydride (4 eq, 1.085 g, 5.12 mmol) , and the mixture was stirred at RT overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10 to 50:50) yielded the pure titrated product as a white foamy solid in a yield of 77% (408 mg) . Characterization: Rt 1.86 min, generic method, MS (ESI) m / z = 290.9 [M+H]+. Exact mass: 290.1089. iH NMR (400 MHz, DMSO) 5 8.87 (s, 1H) , 7.72

[0518] (d, J = 8.8 Hz, 1H) , 7.15 (d, J = 2.3 Hz, 1H) , 6.85 (dd, J

[0519] = 8.9, 2.3 Hz, 1H) , 5.85 (d, J = 8.0 Hz, 1H) , 3.87 (d, J = 2.0 Hz, 1H) .87 (d, J = 2.0 Hz, 4H) , 3.84 - 3.82 (m, 1H) ,

[0520] 1.91 (dd, J = 12.6, 4.1 Hz, 2H) , 1.73 (d, J = 12.9 Hz, 1H) ,

[0521] 1.69 - 1.55 (m, 2H) , 1.52 - 1.40 (m, 3H) .

[0522] N- ( (6-fluoroquinolin-2-yl) methyl) -N- (1 , 4 -dioxaspiro [4.5] decan-8-yl) benzo [d] thiazol-6-amine (compound 6.4, Scheme 6)

[0523] The titrated compound was synthesised according to Process N, starting with N- ( 1 , 4-dioxaspiro [ 4.5 ] decan-8- yl) benzo [d] thiazol- 6-amine 6.3 (1.1 eq, 111 mg, 0.38 mmol) in dry acetonitrile (0.1 M, 3.5 mL) , 6-fluoro-2- ( iodomethyl ) quinoline 5.6 (1 eq, 0.35 mmol, 100 mg) , and potassium carbonate (3 eq, 1.05 mmol, 145 mg) , and the mixture was stirred at reflux overnight. Purification on a silica gel column (dichloromethane / methanol from 100:0 to 95:05) yielded the desired product as a white foamy solid in a yield of 47% (75 mg) . Characterization: Rt 2.44 min, generic method, MS (ESI) m / z = 450.0 [M+H]+. Exact mass: 449.1573. !H NMR (400 MHz, DMSO) 5 8.96 (s, 1H) , 8.27 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.3, 5.4 Hz, 1H) , 7.80 (d, J = 9.1 Hz, 1H) , 7.75 (dd, J = 9.4, 2.9 Hz, 1H) , 7.67 (td, J = 8.9, 2.9 Hz, 1H) .9, 2.9 Hz, 1H) , 7.51 (d, J = 2.6 Hz, 1H) , 7.46 (d, J = 8.6 Hz, 1H) , 7.02 (dd, J = 9.1, 2.6 Hz, 1H) , 4.72 (s, 2H) , 4.10 (s, 1H) , 3.85 (s, 4H) , 1.76 (td, J = 23.7, 12.9 Hz, 8H) .

[0524] 4- (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl) methyl) amino) cyclohexan-l-one (compound 6.5, Scheme 6)

[0525] The titrated compound was synthesised according to Process

[0526] P, starting with ( ( 6-f luoroquinolin-2-yl ) methyl ) -N- ( 1 , 4- dioxaspiro [4.5] decan-8-yl) benzo [d] thiazol- 6-amine 6.4 (1 eq, 230 mg, 0.51 mmol) in TFA / DCM 1:4 (0.1 M, 5.11 mL) , and water (100 pL) , stirring the mixture at room temperature overnight. The crude product was used as such for the next step. The compound was obtained in 94% yield as a white foamy solid. Characterization: Rt 0.87 min, apolar method, MS = 406.1 [M+H]+. Exact mass: 405.1311. iH NMR (400 MHz, DMSO) 5 8.98 (s, 1H) , 8.28 (d, J = 8.4 Hz, 1H) , 8.05 (dd, J = 9.2, 5.4 Hz, 1H) , 7.82 (d, J = 9.1 Hz, 1H) , 7.75 (dd, J = 9.4, 2.9 Hz, 1H) , 7.67 (td, J = 8.9, 3.0 Hz, 1H) , 7.57 (d, J = 2.9, 3.0 Hz, 1H) .57 (d, J = 2.6 Hz, 1H) , 7.50 (d, J = 8.6 Hz, 1H) , 7.07 (dd, J = 9.1, 2.6 Hz, 1H) , 4.79 (s, 2H) , 4.58

[0527] (t, J = 11.6 Hz, 1H) , 2.80 - 2.67 (m, 2H) , 2.26 (d, J = 14.5

[0528] Hz, 2H) , 2.12 (s, 2H) , 1.99 (s, 2H) .

[0529] 4- (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl) methyl) amino) cyclohexan-l-ol (compound 6.6, Scheme 6)

[0530] The titrated product was synthesised according to Process Q, starting with 4- (benzo [d] thiazol-6-yl ( ( 6-f luoroquinolin-2- yl) methyl) amino) cyclohexan-l-one 6.5 (195 mg, 0.94 mmol, 1 eq) in methanol (0.2 M, 4.7 mL) , and sodium borohydride (1.2 eq, 1.13 mmol, 43 mg) , stirring the reaction mixture for 1 hr. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 90:10) yielded the pure product titrated as a white foamy solid in a yield of 91% (180 mg) . Characterization: Rt 2.03 min, generic method, MS (ESI) m / z = 408.2 [M+H]+. Exact mass: 407.1468. iH NMR (400 MHz, DMSO) 5 8.95 (s, 1H) , 8.26 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.2, 5.4 Hz, 1H) , 7.78 (d, J = 9.1 Hz, 1H) , 7.69 - 7.63 (m, 1H) , 7.48 - 7.42 (m, 2H) , 6.97 (dd, J = 9.1, 2.6 Hz, 1H) .1, 2.6 Hz, 1H) , 4.74 (s, 2H) , 4.58 (d, J = 4.3 Hz, 1H) , 3.96 (t, J = 11.5 Hz, 1H) , 3.47 - 3.38 (m, 1H) , 1.85 (t, J = 15.4 Hz, 5H) , 1.60 (q, J = 12.1 Hz, 2H) , 1.42 (q, J = 11.5 Hz, 2H) .

[0531] N- ( (6-fluoroquinolin-2-yl) methyl) -N- (l-methylpiperidin-4- yl) benzo [d] thiazol-6-amine (compound 7.1, Scheme 7)

[0532] To the solution of 2- ( (benzo [d] thiazol-6-yl (piperidin-l-io-

[0533] 4-yl) ammonium) methyl) -6-f luoroquinolin-l-ium chloride 5.60 (1 eq, 50 mg, 0.1 mmol) in dry dichloromethane (0.1 M, 1 mL) , triethylamine (6.6 eq, 0.66 mmol, 91 pL) was added. A gas evolution was observed. The mixture was shaken for 5 min to obtain the free amine, which was reacted with paraformaldehyde in water (36%) (1.2 eq, 0.12 mmol, 8 pL) , acetic acid (10 eq, 1.0 mmol, 57 pL) and sodium triacetoxyborohydride (4 eq, 0.75 mmol, 84 mg) , according to Process E described above. The crude product was purified on silica gel using 100:0 to 80:19:1 dichloromethane / methanol / ammonia as an eluent to obtain the compound as a white foamy solid in 37% yield (15 mg) . Characterization: Rt 1.71 min, generic method, MS = 407.2 [M+H]+. Exact mass: 406.1627. iH NMR (400 MHz, DMSO) 5 8.96

[0534] (s, 1H) , 8.27 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.2, 5.4

[0535] Hz, 1H) , 7.79 (d, J = 9.1 Hz, 1H) , 7.75 (dd, J = 9.4, 2.9

[0536] Hz, 1H) , 7.67 (td, J = 8.9, 3.0 Hz, 1H) , 7.51 - 7.44 (m, J = 8.9, 3.0 Hz, 1H) .51 - 7.44 (m, 2H) , 7.00 (dd, J = 9.2, 2.6 Hz, 1H) , 4.76 (s, 2H) , 3.93 (dt, J = 11.2, 6.4 Hz, 1H) , 2.81 (t, J = 9.9 Hz, 2H) , 2.17 (s, 3H) , 2.14 - 2.04 (m, 2H) , 1.86 - 1.67 (m, 4H) .

[0537] N- (l-butylpiperidin-4-yl) -N- ( (6-fluoroquinolin-2-yl) methyl) benzo [d] thiazol-6-amine (compound 7.2, Scheme 7)

[0538] To the solution of 2- ( (benzo [d] thiazol-6-yl (piperidin-l-io- 4-yl) ammonium) methyl) -6-f luoroquinolin-l-ium chloride 5.60 (1 eq, 50 mg, 0.1 mmol) in dry dichloromethane (0.1 M, 1 mL) , triethylamine (6.6 eq, 0.66 mmol, 91 pL) was added. Gas development was observed. The mixture was stirred for 5 min to obtain the free amine, which was reacted with butyraldehyde (3 eq, 0.3 mmol, 27 pL) , acetic acid (10 eq, 1.0 mmol, 57 pL) and sodium triacetoxyborohydride (4 eq, 0.75 mmol, 84 mg) , according to Process E described above. The crude product was purified on silica gel using 100:0 to 80:19:1 dichloromethane / methanol / ammonia as an eluent to obtain the compound as a white foamy solid in 66% yield (30 mg) . Characterization: 2.02 min, generic method, MS (ESI) m / z = 449.0[M+H] + . Exact mass: 448.2097. iH NMR (400 MHz, DMSO) 5 8.96 (s, 1H) , 8.27 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.3, 5.4 Hz, 1H) , 7.79 (d, J = 9.1 Hz, 1H) , 7.75 (dd, J = 9.1 Hz, 1H) .75 (dd, J = 9.4, 2.9 Hz, 1H) , 7.67 (td, J = 8.9, 2.9 Hz, 1H) , 7.52 - 7.44 (m, 2H) , 7.01 (dd, J = 9.1, 2.6 Hz, 1H) , 4.76 (s, 2H) , 4.00 - 3.85 (m, 2H) , 3.85 (m, 2H) .OO -

[0539] 3.85 (m, 1H) , 2.92 (d, J = 11.1 Hz, 2H) , 2.27 (dd, J = 8.2,

[0540] 6.4 Hz, 2H) , 2.07 (dd, J = 12.6, 10.3 Hz, 2H) , 1.81 (d, J = 11.8 Hz, 2H) , 1.81 (s, 2H) .8 Hz, 2H) , 1.77 - 1.64 (m, 2H) ,

[0541] 1.38 (p, J = 7.1 Hz, 2H) , 1.27 (dq, J = 14.7, 7.1 Hz, 2H) ,

[0542] 0.87 (t, J = 7.3 Hz, 3H) .

[0543] N- ( (6-fluoroquinolin-2-yl) methyl) -N- (1-isopropylpiperidin - 4-yl) benzo [d] thiazol-6-amine (compound 7.3, Scheme 7)

[0544] To the solution of 2- ( (benzo [d] thiazol-6-yl (piperidin-l-io- 4-yl) ammonium) methyl) -6-f luoroquinolin-l-ium chloride 5.60 (1 eq, 50 mg, 0.1 mmol) in dry dichloromethane (0.1 M, 1 mL) , triethylamine (6.6 eq, 0.66 mmol, 91 pL) was added. A gas evolution was observed. The mixture was stirred for 5 min to obtain the free amine, which was reacted with acetone (2 eq, 0.2 mmol, 15 pL) , acetic acid (10 eq, 1.0 mmol, 57 pL) and sodium triacetoxyborohydride (4 eq, 0.75 mmol, 84 mg) , according to Process E described above. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 50:50) yielded the pure titrated product as a white foamy solid in a yield of 64% (29 mg) .

[0545] Characterization: Rt 1.82 min, generic method, MS (ESI) m / z = 435.3 [M+H] + . iH NMR (400 MHz, DMSO) 5 8.96 (s, 1H) , 8.27 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.2, 5.4 Hz, 1H) , 7.79 (d, J = 9.2, 5.4 Hz, 1H) .79 (d, J = 9.1 Hz, 1H) , 7.75 (dd,

[0546] J = 9.4, 2.9 Hz, 1H) , 7.67 (td, J = 8.9, 2.9 Hz, 1H) , 7.50

[0547] (d, J = 2.6 Hz, 1H) , 7.50 (d, J = 2.6 Hz, 1H) .6 Hz, 1H) , 7.47 (d, J = 8.6 Hz, 1H) , 4.76 (s, 2H) , 3.93 (s, 1H) , 2.85

[0548] (d, J = 10.9 Hz, 2H) , 2.36 (d, J = 15.0 Hz, 2H) , 1.84 (d, J

[0549] = 11.8 Hz, 2H) , 1.68 (q, J = 11.7 Hz, 2H) , 0.97 (d, J = 6.5 Hz, 6H) .

[0550] N- ( (6-fluoroquinolin-2-yl) methyl) -N- (l-isobutylpiperidin-4- yl) benzo [d] thiazol-6-amine (compound 7.4, Scheme 7)

[0551] To the solution of 2- ( (benzo [d] thiazol-6-yl (piperidin-l-io- 4-yl) ammonium) methyl) -6-f luoroquinolin-l-ium chloride 5.60 (1 eq, 50 mg, 0.1 mmol) in dry dichloromethane (0.1 M, 1 mL) , triethylamine (6.6 eq, 0.66 mmol, 91 pL) was added. A gas evolution was observed. The mixture was shaken for 5 min to obtain the free amine, which was reacted with isobutyraldehyde (2 eq, 0.2 mmol, 18 pL) , acetic acid (10 eq, 1.0 mmol, 57 pL) and sodium triacetoxyborohydride (4 eq, 0.75 mmol, 84 mg) , according to Process E described above. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 50:50) yielded the pure titrated product as a white foamy solid in a yield of 66% (30 mg) . Characterization: Rt 1.96 min, MS (ESI) m / z = 449.3 [M+H]+. Exact mass: 448.2097. iH NMR (400 MHz, DMSO) 5 8.96 (s, 1H) , 8.27 (d, J = 8.6 Hz, 1H) , 8.06 (dd, J = 9.3, 5.4 Hz, 1H) , 7.80 (d, J = 9.1 Hz, 1H) , 7.74 (dd, J = 9.4, 2.9 Hz, 1H) , 7.67 (td, J = 8.9, 2.9 Hz, 1H) , 7.51 - 7.44 (m, J = 8.9, 2.9 Hz, 1H) .51 - 7.44 (m, 2H) , 7.01 (dd, J = 9.1, 2.6 Hz, 1H) , 4.77 (s, 2H) , 3.98 - 3.86 (m, 1H) , 2.88 (d, J = 11.0 Hz, 2H) , 2.11 - 2.00 (m, 4H) , 1.88 - 1.64 (m, 5H) , 0.84 (d, J = 6.6 Hz, 6H) . tert-butyl 3- (benzo [d] thiazol-6-ylamino) -8- azabicyclo [3.2.1 ] octane-8-carboxylate (compound 8.2, Scheme

[0552] 8)

[0553] The titrated compound was synthesised according to Process E, starting with benzo [d] thiazol- 6-amine 6.1 (150 mg, 1.0 mmol, 1.0 eq) in dry dichloromethane (0.3 M, 3.3 mL) , tertbutyl 3-oxo-8-azabicyclo [ 3.2.1 ] octane-8-carboxylate 8.1 (1 eq, 1.0 mmol, 225 mg) , acetic acid (1 eq, 1.0 mmol, 59 pL) and sodium triacetoxyborohydride (2 eq, 2.0 mmol, 424 mg) . The crude product was used as such for the next step. Purification by silica gel column chromatography (cyclohexane / i-PrOH from 99:1 to 80:20) yielded the product as a light brown solid. MS (ESI) m / z = 360.1 [M+H]+. Exact mass : 359.1667. tert-butyl 3- (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl) methyl) amino) -8 -azabi cyclo [3.2.1] octane- 8 -carboxylate

[0554] (compound 8.3, Scheme 8)

[0555] The titrated compound was synthesised according to Process M, starting with 6-f luoroquinolin-2-carbaldehyde 1.9 (2 eq) , tert-butyl 3- (benzo [d] thiazol-6-ylamino) -8- azabicyclo [ 3.2.1 ] octane-8-carboxylate 8.2 (1 eq) in dry tetrahydrofuran (0.2 M) , trifluoroacetic acid (3 eq) , phenylsilane (3 eq) . The crude product was purified on silica gel by column chromatography using 100:0 to 90:10 dichloromethane / acetone as an eluent to obtain the compound as a beige solid. Characterisation: LCMS only, MS (ESI) m / z = 519.1 [M+H]+. Exact mass: 518.2152.

[0556] 2- ( (benzo [d] thiazol-6-yl ( (1R, 5S) -8-azabicyclo [3.2.1] octane- 8-io-3-yl) ammonium) methyl) -6-fluoroquinolin-l-ium chloride

[0557] (compound 8.4, Scheme 8)

[0558] The titrated compound was synthesised according to Process 02, starting with tert-butyl 3- (benzo[d]thiazol-6-yl ( (6- f luoroquinolin-2-yl ) methyl ) amino) -8-azabicyclo

[0559] [ 3.2.1 ] octane-8-carboxylate 8.3 (1 eq) in methanol (0.2 M) , chlorotrimethylsilane (0.1 ml) and phenylsilane (3 eq) . The reaction mixture was evaporated and treated with ether to form a precipitate. The precipitate was filtered to obtain the compound as an orange solid in a 5% yield over three steps (30 mg) . Characterization: MS (ESI) m / z = 419.2 [M+H]+. Exact mass: 418.1627. iH NMR (400 MHz, DMSO) 5 9.16 (d, J = 10.9 Hz, 1H) , 9.06 (s, 1H) , 8.98 (s, 1H) , 8.40 (d, J = 8.7 Hz, 1H) , 8.15 (dd, J = 9.3, 5.3 Hz, 1H) , 7.88 - 7.70 (m, 3H) , 7.66 (d, J = 2.5 Hz, 1H) , 7.47 (d, J = 8.6 Hz, 1H) , 7.47 (d, J = 8.5 Hz, 1H) .6 Hz, 1H) , 7.13 (dd, J = 9.1, 2.5 Hz, 1H) , 4.85 (s, 2H) , 4.63 (t, J = 8.2 Hz, 1H) , 2.44 - 2.51 (m, 6H, superimposed on solvent signal) , 2.02 (t, J = 4.8 Hz, 4H) , 1.79 (dd, J = 14.1, 9.3 Hz, 2H) . tert-butyl 7- (benzo [d] thiazol-6-ylamino) -2-azaspiro [3.5] nonano-2 -carboxylate (compound 9.2, Scheme 9)

[0560] The titrated product was synthesised according to Process E, starting with benzo [d] thiazol- 6-amine 6.1 (150 mg, 1.0 mmol, 1.0 eq) in dry DCM (0.3 M, 3.3 mL) , tert-butyl 7-oxo-2- azaspiro [ 3.5 ] nonano-2-carboxylate 9.1 (1 eq, 1.0 mmol, 239 mg) , acetic acid (1 eq, 1.0 mmol, 59 pL) and sodium triacetoxyborohydride (2 eq, 2.0 mmol, 424 mg) . The crude product was purified on silica gel using cyclohexane i-PrOH as an eluent from 99:1 to 80:20 to obtain the product as a light brown solid. Characterisation: LSMS only, MS (ESI) m / z = 374.0 [M+H]+. 373.1824. tert-butyl 7- (benzo [d] thiazol-6-yl ( (6-fluoroquinolin-2- yl) methyl) amino) -2 -azaspiro [3.5] nonano-2 -carboxylate

[0561] (compound 9.3, Scheme 9)

[0562] The titrated compound was synthesised according to Process

[0563] M, starting with 6-f luoroquinolin-2-carbaldehyde 1.9 (2 eq) , tert-butyl 7- (benzo [d] thiazol-6-ylamino) -2- azaspiro [ 3.5 ] nonano-2-carboxylate 9.2 (1 eq) in dry tetrahydrofuran (0.2 M) , trifluoroacetic acid (3 eq) , phenylsilane (3 eq) . The crude product was purified on silica gel by column chromatography using 100:0 to 90:10 dichloromethane / acetone as an eluent to obtain the compound as a beige solid. Characterisation: LCMS only, MS (ESI) m / z = 533.1 [M+H]+. Exact mass: 532.2308.

[0564] 2- ( (benzo [d] thiazol-6-yl (2 -azaspiro [3.5] nonan-2-io-7- yl) ammonium) methyl) -6-fluoroquinolin-l-ium chloride

[0565] (compound 9.4, Scheme 9)

[0566] The titrated compound was synthesised according to Process 02, starting with tert-butyl 7- (benzo [d] thiazol-6-yl ( ( 6- f luoro quinol in-2 -yl ) methyl ) amino ) -2-aza spiro [3.5] nonano-2- carboxylate 9.3 (1 eq) in methanol (0.2 M) , chlorotrimethylsilane (0.1 ml) and phenylsilane (3 eq) . The reaction mixture was evaporated and treated with ether to form a precipitate. The precipitate was filtered to obtain the compound as an orange solid in a yield of 33% in three steps (168 mg) . MS (ESI) m / z = 433.2 [M+H]+. Exact mass: 432.1784. !H NMR (400 MHz, DMSO) 5 9.13 (s, 2H) , 9.00 (s, 1H) , 8.58 (d, J = 8.7 Hz, 1H) , 8.30 (dd, J = 9.4, 5.1 Hz, 1H) , 7.98 - 7.91 (m, 2H) 98 - 7.91 (m, 1H) , 7.84 (dd, J =

[0567] 24.1, 9.1 Hz, 2H) , 7.66 (d, J = 8.7 Hz, 1H) , 7.53 (d, J =

[0568] 2.5 Hz, 1H) , 7.04 (dd, J = 9.1, 2.6 Hz, 1H) .1, 2.6 Hz, 1H) ,

[0569] 4.93 (s, 2H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.60 (t, J = 6.3 Hz,

[0570] 2H) , 2.50 (1H superimposed on solvent signal) , 2.10 (d, J =

[0571] 12.7 Hz, 2H) , 1.79 (d, J = 12.0 Hz, 2H) , 1.65 (dd, J = 14.7,

[0572] 11.5 Hz, 2H) , 1.52 (q, J = 12.1 Hz, 2H) .

[0573] 3- (benzo [d] thiazol-6-ylamino) CYdohex-2-en-l-one (compound

[0574] 10.2, Scheme 10)

[0575] 1 , 3-cyclohexanedione 10.1 (200 mg, 1.78 mmol, 1 eq) , benzo [d] thiazol- 6-amine 6.1 (1 eq, 1.78 mmol, 268 mg) and para-toluene sulfonic acid monohydrate (0.1 eq, 0.178 mmol, 34 mg) were dissolved in toluene (0.2 M, 8.9 mL) in a microwave reactor, in the presence of a 4A molecular sieve (0.2 g) , and the mixture was heated under microwave irradiation for 4h at 100°C. Subsequently, the reaction mixture was allowed to cool and cautiously quenched with a saturated aqueous solution of NaHCOs (check pH around 8) . The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Purification on a silica gel column (dichloromethane / methanol from 100:0 to 90:10) yielded the pure product as a light yellow oil in a yield of 49% (215 mg) . Characterization: Rt 1.28 min, generic method, MS (ESI) m / z = 244.9 [M+H]+. Exact mass: 244.0670. !H NMR (400 MHz, DMSO) 5 9.32 (s, 1H) , 9.03 (s, 1H) , 8.06 (d, J = 8.7 Hz, 1H) , 7.99 (d, J = 2.1 Hz, 1H) , 7.35 (dd, J = 8.7, 2.2 Hz, 1H) .7, 2.2 Hz, 1H) , 5.38 (s, 1H) , 2.55 (t, J = 6.1 Hz, 2H) , 2.19 (dd, J = 7.1, 5.8 Hz, 2H) , 1.92 (p, J = 6.3 Hz, 2H) . rac- (1R, 3R) -3- (benzo [d] thiazol-6-ylamino) cyclohexan-l-ol (compound 10.3, Scheme 10) and rac- (1R, 3S) -3- (benzo [d] thiazol-6-ylamino) cyclohexan-l-ol (compound 10.4,

[0576] Scheme 10)

[0577] Compound 10.3 Compound 10.4

[0578] The titrated compounds were obtained according to Process Q, starting with 3- (benzo [d] thiazol- 6-ylamino ) cyclohex-2-en-l- one 10.2 (160 mg, 0.65 mmol, 1 eq) in dry ethanol (0.2 M, 3.3 mL) , sodium borohydride (6 eq, 3.9 mmol, 148 mg) , stirring at room temperature for 24 h. The crude product was purified by basic aluminium oxide column chromatography using 100:0 to 90:10 dichloromethane / methanol as an eluent to obtain the two separate diastereoisomers, fraction 1 and fraction 2, as white foamy solids, with a yield of 12% (20 mg) and 21% (35 mg) , respectively. Fraction 1 was identified as rac- (1R, 3R) -3- (benzo [d] thiazol- 6-ylamino ) cyclohexan-l-ol and fraction 2 as rac- ( 1R, 3S ) -3- (benzo [d] thiazol- 6- ylamino) cyclohexan-l-ol . rac- (1R, 3R) -3- (benzo [d] thiazol-6-ylamino) cyclohexan-l-ol

[0579] (compound 10.3) : Characterization: Rt 1.56 min, generic method, MS (ESI) m / z = 248.9 [M+H]+. Exact mass: 248.0983. iH NMR (400 MHz, DMSO) 5 8.86 (s, 1H) , 7.72 (d, J = 8.9 Hz,

[0580] 1H) , 7.10 (d, J = 2.3 Hz, 1H) , 6.85 (dd, J = 8.9, 2.3 Hz,

[0581] 1H) , 5.75 (d, J = 8.0 Hz, 1H) , 4.48 (d, J = 3.0 Hz, 1H) , 3.5

[0582] (d, J = 3.0 Hz, 1H) , 3.5 (d, J = 3.0 Hz, 1H) , 3.5 (d, J =

[0583] 3.0 Hz, lH) .4 Hz, 1H) , 3.96 (s, 1H) , 3.64 (dd, J = 10.9, 6.5 Hz, 1H) , 1.83 (s, 2H) , 1.68 (dd, J = 13.1, 8.8 Hz, 1H) , 1.49 (td, J = 16.8, 8.3 Hz, 4H) , 1.26 (q, J = 9.6 Hz, 1H) . rac- (1R, 3S) -3- (benzo [d] thiazol-6-ylamino) cyclohexan-l-ol

[0584] (compound 10.4) : Characterization: Rt 1.56 min, generic method, MS (ESI) m / z = 248.9 [M+H]+. Exact mass: 248.0983. iH NMR (400 MHz, DMSO) 5 8.87 (s, 1H) , 7.72 (d, J = 8.8 Hz, 1H) , 7.12 (d, J = 2.3 Hz, 1H) , 6.82 (dd, J = 8.9, 2.3 Hz,

[0585] 1H) , 5.81 (d, J = 8.3 Hz, 1H) , 4.61 (d, J = 4.6 Hz, 1H) ,

[0586] 3.54 - 3.42 (m, OH) , 3.27 (d, J = 3.7 Hz, 1H) , 2.18 (d, J = 12.0 Hz, 1H) , 1.93 (d, J = 12.6 Hz, 1H) , 1.83 (d, J = 11.8

[0587] Hz, 1H) , 1.70 (dt, J = 13.5, 3.5 Hz, 1H) , 1.37 - 1.22 (m,

[0588] 1H) , 1.12 - 0.92 (m, 2H) . rac- (1S,3S) -3- [1 , 3-benzothiazol-6-yl- [ (6-fluoro-2- quinolyl) methyl ] amino] cyclohexanol (compound 10.5, Scheme 10)

[0589] The titrated compound was synthesised according to Process M, starting with rac- ( 1R, 3R) -3- (benzo [d] thiazol-6- ylamino) cyclohexan-l-ol 10.3 (1 eq, 20 mg, 0.08 mmol) and 6- f luoroquinolin-2-carbaldehyde 1.9 (2 eq, 0.16 mmol 28 mg) , trifluoroacetic acid (3 eq, 0.24 mmol) , phenylsilane (3 eq, 0.24 mmol, 30 pL) . The crude product was purified on silica gel using dichloromethane / methanol as an eluent from 100:0 to 80:20 and then in reverse phase using water / acetonitrile as an eluent from 90:10 to 50:50 to obtain the pure titrated product as a white foamy solid in 24% yield (8 mg) . Characterization: Rt 2.20 min, generic method, MS (ESI) m / z = 407.9 [M+H]+, 466.1 [M+CH3COO] . Exact mass: 407.1468. iH NMR (400 MHz, DMSO) 5 8.87 (s, 1H) , 8.20 (d, J = 8.6 Hz, 1H) , 7.98 (dd, J = 9.2, 5.4 Hz, 1H) , 7.73 (d, J = 9.1 Hz, 1H) , 7.7 (d, J = 9.1 Hz, 1H) .1 Hz, 1H) , 7.67 (dd, J = 9.4, 2.9 Hz, 1H) , 7.59 (td, J = 8.9, 2.9 Hz, 1H) , 7.38 (d, J =

[0590] 8.6 Hz, 1H) , 7.31 (d, J = 2.5 Hz, 1H) , 6.5 (d, J = 2.5 Hz,

[0591] 1H) , 6.5 (d, J = 2.5 Hz, 1H) .5 Hz, 1H) , 6.91 (dd, J = 9.2,

[0592] 2.6 Hz, 1H) , 4.75 - 4.62 (m, 2H) , 4.60 (s, 1H) , 4.30 (t, J

[0593] = 12.0 Hz, 1H) , 4.01 (s, 1H) , 1.87 - 1.70 (m, 4H) , 1.64 -

[0594] 1.50 (m, 2H) , 1.44 (d, J = 10.0 Hz, 1H) , 1.33 - 1.22 (m, 1H) . rac- (1R,3S) -3- [1 , 3-benzothiazol-6-yl- [ (6-fluoro-2 -quinolyl) methyl ] amino] cyclohexanol (compound 10.6, Scheme 10)

[0595] The titrated compound was synthesised according to Process M, starting with rac- ( 1R, 3S ) -3- (benzo [d] thiazol- 6- ylamino) cyclohexan-l-ol 10.4 (1 eq, 35 mg, 0.14 mmol.14 mmol) and 6-f luoroquinolin-2-carbaldehyde 1.9 (2 eq, 0.28 mmol, 50 mg) , trifluoroacetic acid (3 eq, 0.42 mmol, 32 pL) , phenylsilane (3 eq, 0.42 mmol, 52 pL) . Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 80:20) yielded the pure titrated product as a white foamy solid in a yield of 17% (10 mg) . Characterization: Rt 2.11 min, generic method, MS (ESI) m / z = 407.9 [M+H]+, 466.1 [M+CH3COO ] — . Exact mass: 407.1468. di NMR (400 MHz, DMSO) 5 8.88 (d, J = 1.7 Hz, 1H) , 8.20 (d, J = 8.6 Hz, 1H) , 7.99 (dd, J = 9.2, 5.4 Hz, 1H) , 7.72 (d, J = 9.1 Hz, 1H) , 7.72 (d, J = 9.1 Hz, 1H) .1 Hz, 1H) , 7.67 (dd, J = 9.4, 2.9 Hz, 1H) , 7.60 (td, J = 8.9, 3.0 Hz, 1H) , 7.41 - 7.35 (m, 2H) , 6.91 (dd, J = 9.2, 2.6 Hz, 1H) .2, 2.6 Hz, 1H) , 4.69 (s, 2H) , 4.58 (d, J = 5.0 Hz, 1H) , 3.92 (s, 1H) , 3.55 (dd, J = 12.6, 2.9 Hz, 1H) , 1.98 (d, J = 10.9 Hz, 1H) , 1.98 (d, J = 10.0 Hz, 1H) .9 Hz, 1H) , 1.74 (d, J = 13.2 Hz, 2H) , 1.64 (d, J = 10.3 Hz, 1H) , 1.37 - 1.24 (m, 3H) , 1.08 - 0.91 (m, 1H) .

[0596] 2-methyl-6-nitroquinoline (compound 11.2, Scheme 11)

[0597] The compound was synthesised according to Process Al, starting with 4-nitroaniline 11.1 (1 eq, 2 g, 14.48 mmol) in 6M HC1 (72 mL, 30 eq) and a solution of crotonaldehyde (2 eq, 28.96 mmol, 2.4 mL) in toluene (1.5M, 19.3 mL) and the mixture was stirred at 100°C for 5h. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10 to 80:20) yielded the pure titration product as an ochre solid in a yield of 66% (1.83 g) . Characterization: Rt 1.81 min, MS (ESI) m / z = 188.8 [M+H]+. Exact mass: 188.0586.TH NMR (400 MHz, DMSO) 5 9.02 (d, J = 2.6 Hz, 1H) , 8.59 (d, J = 8.5 Hz, 1H) , 8.43 (dd, J = 9.2, 2.7 Hz, 1H) , 8.11 (d, J = 9.2 Hz, 1H) , 7.64 (d, J = 8.5 Hz, 1H) , 2.73 (s, 3H) .

[0598] 6-nitroquinolin-2-carbaldehyde (compound 11.3, Scheme 11)

[0599] The titrated compound was synthesised according to Process C, starting with 2-methyl- 6-nitroquinoline 11.2 (1 eq, 4.67 mmol, 880 mg) in dioxane (0.2 M, 23.3 mL) , and selenium dioxide (1.3 eq, 6.079 mmol, 675 mg) , stirring the reaction mixture for 2 h at 80°C. The compound was obtained pure without purification by column chromatography (88% yield, 840 mg, brown solid) . Characterization: Rt 1.86 min, MS (ESI) m / z = 202.9 [M+H]+. Exact mass: 202.0378.1H NMR (400 MHz, DMSO) 5 10.17 (d, J = 0.9 Hz, 1H) , 9.22 (d, J = 2.6 Hz, 1H) , 8.96 (d, J = 8.5 Hz, 1H) , 8.59 (dd, J = 9.3, 2.6 Hz, 1H) , 8.45 (d, J = 9.3 Hz, 1H) , 8.17 (d, J = 8.5 Hz, 1H) .

[0600] N-cyclohexyl-N- ( (6-nitroquinolin-2- yl) methyl) benzo [d] thiazol-6-amine (compound 11.4, Scheme 11)

[0601] The titrated compound was synthesised according to Process M, starting with N-cyclohexylbenzo [d] thiazol- 6-amine 5.12 (1 eq, 440 mg, 1.896 mmol) , 6-nitroquinolin-2-carbaldehyde 11.3 (2 eq, 3.79 mmol, 767 mg) , trifluoroacetic acid (3 eq, 5.69 mmol, 436 pL) and phenylsilane (3 eq, 5.69 mmol, 702 pL) in dry tetrahydrofuran (0.2 M, 9.5 mL) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 50:50) yielded the pure titration product as a foamy yellow solid in a yield of 65% (525 mg) . Characterization: Rt 1.98 min, apolar method, MS = 419.2 [M+H]+. Exact mass: 418.1463. !H NMR (400 MHz, DMSO) 5 9.02 (d, J = 2.6 Hz, 1H) , 8.95 (s, 1H) , 8.61 (d, J = 8.6 Hz, 1H) , 8.47 (dd, J = 9.3, 2.7 Hz, 1H) , 8.19 (d, J = 9.3 Hz, 1H) , 7.80 (d, J = 9.1 Hz, 1H) , 7.62 (d, J = 8.6 Hz, 1H) , 7.45 (d, J = 2.6 Hz, 1H) , 6.5 (s, 1H) .6 Hz, 1H) , 6.98 (dd, J = 9.2, 2.6 Hz, 1H) , 4.84 (s,

[0602] 2H) , 3.98 (s, 1H) , 1.88 (d, J = 9.4 Hz, 2H) , 1.77 (d, J =

[0603] 10.7 Hz, 2H) , 1.63 (d, J = 13.0 Hz, 1H) , 1.49 (q, J = 11.6

[0604] Hz, 4H) , 1.16 (t, J = 8.9 Hz, 1H) .

[0605] N- ( (6-aminoquinolin-2-yl) methyl) -N-cyclohexylbenzo [d] thiazol-6-amine (compound 11.5, Scheme 11)

[0606] To the solution of -cyclohexyl - - ( ( 6-nitroquinolin-2- yl) methyl) benzo [d] thiazol- 6-amine 11.4 (1 eq, 0.41 mmol, 170 mg) in tetrahydrofuran (0.1 M, 4.1 mL) at room temperature, sodium borohydride (2 eq, 0.81 mmol, 31 mg) and Pd / C 10%wt (35 mg, 20% wt of starting material) were added, followed by the cautious addition of methanol (0.5 mL) . Gas development was observed. The mixture was stirred for 1 h until the reaction was complete. The mixture was filtered on a celite buffer and eluted with ethyl acetate. The filtrate was washed with brine. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 90:10) yielded the pure titrated compound as a yellowish solid in a yield of 48% (80 mg) . Characterization: Rt 1.24 min, apolar method, MS (ESI) m / z = 389.1 [M+H]+. Exact mass: 388.1722. iH NMR (400 MHz, DMSO) 5 8.93 (s, 1H) , 7.80 (dd, J = 20.2, 8.9 Hz, 2H) , 7.67 (d, J = 9.0 Hz, 1H) , 7.40 (d, J = 2.0 Hz, 1H) .40 (d, J = 2.5 Hz, 1H) , 7.20 - 7.11 (m, 2H) , 6.97 (dd, J = 9.2, 2.6 Hz, 1H) , 6.75 (d, J = 2.5 Hz, 1H) , 5. (s, 2H) , 5. (s, 2H) .51 (s, 2H) , 4.64 (s, 2H) , 3.93 (s, 1H) , 3.18 (d, J = 5.2 Hz, 1H) , 1.86 (d, J = 9.9 Hz, 2H) , 1.77 (d, J = 10.7 Hz, 2H) , 1.63 (d, J = 12.9 Hz, 1H) , 1.49 (p, J = 11.9 Hz, 4H) , 1.15 (d, J = 12.3 Hz) .

[0607] N-cyclohexyl -N- ( (6- (dimethyl ami no) quinolineyl) methyl) benzo [d] thiazol-6-amine (compound 11.6, Scheme 11)

[0608] The titrated compound was synthesised according to Process E, starting with N- ( ( 6-aminoquinolin-2-yl ) methyl ) -N- cyclohexylbenzo [d] thiazol- 6-amine 11.5 (1 eq, 0.154 mmol, 60 mg) , paraformaldehyde 36 wt% in water (2 eq, 0.302 mmol, 15 pL) , acetic acid (10 eq, 1.54 mmol, 88 pL) and sodium triacetoxyborohydride (4 eq, 0.616 mmol, 88 pL) in dry dichloromethane (0.1 M, 1.6 mL) , stirring the reaction mixture at room temperature overnight. Purification by silica gel column chromatography (dichloromethane / methanol from 100:0 to 90:10) yielded the pure titrated product as a brown solid in a 50% yield (32 mg) . Characterization: Rt 2.05 min, generic method, MS = 417.2 [M+H]+. Exact mass: 416.2035. !H NMR (400 MHz, DMSO) 5 8.93 (s, 1H) , 7.98 (d, J = 8.5 Hz, 1H) , 7.81 (d, J = 9.3 Hz, 1H) , 7.78 (d, J = 9.1 Hz, 1H) , 7.78 (d, J = 9.1 Hz, 1H) .1 Hz, 1H) , 7.44 (dd, J =

[0609] 9.3, 2.9 Hz, 1H) , 7.41 (d, J = 2.6 Hz, 1H) , 7.25 (d, J = 8.6

[0610] Hz, 1H) , 6.98 (dd, J = 9.2, 2.6 Hz, 1H) , 6.89 (d, J = 2.8 Hz, 1H) , 4.68 (s, 2H) , 3.94 (s, 1H) , 3.01 (s, 6H) , 1.87 (d, J = 10.2 Hz, 2H) , 1.87 (d, J = 8.6 Hz, 2H) , 1.25 (d, J = 8.6

[0611] Hz, 1H) .2 Hz, 2H) , 1.77 (d, J = 10.6 Hz, 2H) , 1.63 (d, J =

[0612] 12.8 Hz, 1H) , 1.48 (q, J = 12.1 Hz, 4H) , 1.22-1.06 (m, 1H) . 6-fluoro-4 -me thoxy-2 -methylquinoline (compound 12.1, Scheme 12)

[0613] The titrated compound was synthesised according to Process I, starting with 2-methylquinolin-4-ol 3.1 (80 mg, 0.45 mmol, 1 eq) in dry DMF (0.3 M, 1.5 mL) , potassium carbonate (3 eq, 1.35 mmol, 189 mg) and methyl iodide (2 eq, 0.90 mmol, 57 pL) , stirring the reaction mixture for 20 h at room temperature. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 80:20 to 50:50) yielded the pure titrated compound, white solid, with a yield of 46% (40 mg) . Characterization: Rt 1.78 min, MS (ESI) m / z = 191.7 [M+H]+. Exact mass: 191.0746. NMR (400 MHz, DMSO) 5 7.90 (dd, J = 9.2, 5.4 Hz, 1H) , 7.69 (dd, J = 9.7, 2.9 Hz, 1H) , 7.58 (td, J = 8.9, 3.0 Hz, 1H) , 6.97 (s, 1H) , 4.01 (s, 3H) , 2.59 (s, 3H) .

[0614] 4-ethoxy-6-fluoro-2-methylquinoline (compound 12.2, Scheme

[0615] 12)

[0616] The titrated compound was synthesised according to Process I, starting with 6-f luoro-2-methylquinolin-4-ol 3.1 (80 mg, 0.45 mmol, 1 eq) in dry DMF (0.3 M, 1.5 mL) , potassium carbonate (3 eq, 1.35 mmol, 189 mg) , ethyl iodide (2 eq, 0.90 mmol, 73 pL) , stirring the reaction mixture at room temperature for 20 h. The compound was obtained pure without column chromatographic purification. Yield: 88% (82 mg, white solid) . Characterization: Rt 2.06 min, generic method, MS (ESI) m / z = 206.2 [M+H]+. Exact mass: 205.0903. iH NMR (400 MHz, DMSO) 5 7.89 (dd, J = 9.2, 5.4 Hz, 1H) , 7.69 (dd, J = 9.7, 3.0 Hz, 1H) , 7.58 (td, J = 8. 8, 3.0 Hz, 1H) .8, 3.0 Hz, 1H) , 6.95 (s, 1H) , 4.28 (q, J = 7.0 Hz, 2H) , 2.58 (s, 3H) , 1.46 (t, J = 7.0 Hz, 3H) .

[0617] 4-chloro-6-fluoro-2-methylquinoline (compound 12.3, Scheme 12)

[0618] 6-f luoro-2-methylquinolin-4-ol 3.1 (200 mg, 1.13 mmol, 1 eq) was dissolved in phosphoryl chloride (2 mL) and the mixture was refluxed at 100°C for 3h. The mixture was allowed to cool and the residue was cautiously quenched with saturated Na2COs and ice. The aqueous layer was extracted with ethyl acetate (3x) . The combined organic layers were dried over anhydrous Na2SO4 to obtain the product pure enough to be used directly for the next step. The compound was obtained in quantitative yield (221 mg, white solid) . Characterization: Rt 2.32 min, generic method, MS (ESI) m / z = 195.8, 197.8 [M+H]+. Exact mass: 195.0251. NMR (400 MHz, CDC13) 5 8.02 (dd, J = 9.2, 5.3 Hz, 1H) , 7.79 (dd, J = 9.4, 2.9 Hz, 1H) , 7.49 (ddd, J = 9.2, 8.1, 2.9 Hz, 1H) , 7.41 (d, J = 0.8 Hz, 1H) , 2.71 (s, 3H) .

[0619] 6-fluoro-4-methoxyquinolin-2-carbaldehyde (compound 12.4,

[0620] Scheme 12)

[0621] The titrated compound was synthesised according to Process C, starting with 6-f luoro-4-methoxy-2-methylquinoline 12.1 (40 mg, 0.21 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 1 mL) , selenium dioxide (1.3 eq, 0.27 mmol, 30 mg) , stirring the reaction mixture at 80°C for 2h. The compound was obtained pure without column chromatographic purification. Yield: 92%

[0622] (40 mg, light brown solid) . Characterization: Rt 2.07 min, generic method, MS (ESI) m / z = 205.8 [M+H]+. (400 MHz, CDC13) 5 10.13 (s, 1H) , 8.19 (dd, J = 9.2, 5.3 Hz, 1H) , 7.85 (dd, J = 9.3, 2.9 Hz, 1H) , 7.56 (ddd, J = 9.1, 8.0, 2.8 Hz, 1H) , 7.40 (s, 1H) , 4.13 (s, 3H) .

[0623] 4-ethoxy-6-fluoroquinolin-2-carbaldehyde (compound 12.5,

[0624] Scheme 12)

[0625] The titrated compound was synthesised according to Process C, starting with 4-ethoxy-6-f luoro-2-methylquinoline 12.2 (80 mg, 0.39 mmol, 1 eq) in dry 1,4-dioxane (0.2 M, 1.9 mL) , selenium dioxide (1.3 eq, 0.51 mmol, 56 mg) , stirring the reaction mixture at 80°C for 2 h. The compound was obtained pure without column chromatographic purification. Yield: 74% (64 mg, light brown solid) . Characterization: Rt 2.32 min, MS (ESI) m / z = 220.0 [M+H]+ . Exact mass: 219.0696. iH NMR (400 MHz, DMSO) 5 10.02 (s, 1H) , 8.23 (dd, J = 9.2, 5.4 Hz, 1H) , 7.86 - 7.82 (m, 1H) , 7.79 (td, J = 8.8, 3.0 Hz, 1H) , 7.38 (s, 1H) , 4.47 - 4.28 (m, 2H) , 1.49 (t, J = 6.9 Hz, 3H) . 4-chloro-6-fluoroquinolin-2-carbaldehyde (compound 12.6,

[0626] Scheme 12)

[0627] The titrated compound was synthesised according to Process C, starting with 4-chloro-6-f luoro-2-methylquinoline 12.3 (240 mg, 1.23 mmol, 1 eq) in dry 1,4-dioxane (0.3 M, 4.1 mL) , selenium dioxide (1.3 eq, 1.59 mmol, 177 mg) , stirring the reaction mixture at 80°C for 2 h. The compound was obtained pure without column chromatographic purification. Yield: 45% (117 mg, light brown solid) . Characterization: Rt 2.32 min, generic method, MS (ESI) m / z = 209.9, 211.9 [M+H]+. Exact mass: 209.0044. NMR (400 MHz, DMSO) 5 10.08 (s, 1H) , 8.41 (dd, J = 9.3, 5.4 Hz, 1H) , 8.03 (dd, J = 9.5, 2.8 Hz, 1H) , 7.97 (ddd, J = 9.2, 8.3, 2.8 Hz, 1H) .

[0628] N-cyclohexyl-N- ( (6-fluoro-4-methoxyquinolin-2- yl) methyl) benzo [d] thiazol-6-amine (compound 12.7, Scheme 12)

[0629] The titrated compound was synthesised according to Process M, starting with N-cyclohexylbenzo [d] thiazol- 6-amine 5.12 (26 mg, 0.11 mmol, 1 eq) and 6-f luoro-4-methoxyquinolin-2- carbaldehyde 12.4 (1.5 eq, 0.17 mmol, 35 mg) in dry tetrahydrofuran, trifluoroacetic acid (3 eq, 0.34 mmol, 25 pL) , phenylsilane (3 eq, 0.34 mmol, 42 pL) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 90:10 to 80:20) yielded the pure titrated product as a white solid in a yield of 65% (31 mg) . Characterization: Rt 2.10 min, apolar method, MS (ESI) m / z = 421.9 [M+H]+. Exact mass: 421.1624. !H NMR (400 MHz, DMSO) 5 8.95 (s, 1H) , 7.99 (dd, J = 9.2, 5.4 Hz, 1H) , 7.80 (d, J = 9.1 Hz, 1H) , 7.72 (dd, J = 9.7, 2.9 Hz, 1H) , 7.64 (td, J = 8.8, 3.0 Hz, 1H) , 7.46 (d, J = 2.6 Hz, 1H) , 6.99 (dd, J = 9.6 Hz, 1H) .99 (dd, J = 9.2,

[0630] 2.6 Hz, 1H) , 6.94 (s, 1H) , 4.69 bs, 1H) , 3.95 (s, 2H) , 3.89

[0631] (s, 3H) , 1.91 (s, 2H) , 1.79 (d, J = 10.5 Hz, 2H) , 1.64 (d,

[0632] J = 13.0 Hz, 1H) , 1.49 (q, J = 11.2 Hz, 4H)

[0633] N-cyclohexyl-N- ( (4-ethoxy-6-fluoroquinolin-2- yl) methyl) benzo [d] thiazol-6-amine (compound 12.8, Scheme 12)

[0634] The titrated compound was synthesised according to Process

[0635] M, starting with N-cyclohexylbenzo [d] thiazol- 6-amine 5.12 (20 mg, 0.09 mmol, 1 eq) , 4-ethoxy-6-f luoroquinolin-2- carbaldehyde 12.5 (1.5 eq, 0.13 mmol, 28 mg) in dry tetrahydrofuran, trifluoroacetic acid (3 eq, 0.26 mmol, 20 pL) , phenylsilane (3 eq, 0.26 mmol, 32 pL) . Purification by silica gel column chromatography (cyclohexane / ethyl acetate 90:10 to 80:20) yielded the pure titrated product as a golden foamy solid in a yield of 55% (21 mg) . Characterization: Rt 2.38 min, MS (ESI) m / z = 436.0 [M+H]+. Exact mass: 435.1781. !H NMR (400 MHz, DMSO) 5 8.95 (s, 1H) , 7.98 (dd, J = 9.2, 5.4 Hz, 1H) , 7.79 (d, J = 9.1 Hz, 1H) , 7.71 (dd, J = 9.6,

[0636] 2.9 Hz, 1H) , 7.64 (td, J = 8.8, 3.0 Hz, 1H) , 7.45 (d, J = 2.6 Hz, 1H) , 6.98 (dd, J = 9.1, 2.6 Hz, 1H) , 6.90 (s, 1H) , 4. (s, 2H) , 4. (s, 2H) , 4. (s, 2H) .68 (s, 2H) , 4.13 (q, J =

[0637] 6.9 Hz, 2H) , 3.96 (d, J = 10.8 Hz, 1H) , 1.91 (d, J = 9.3 Hz, 2H) , 1.78 (d, J = 10.6 Hz, 2H) , 1.63 (d, J = 12.1 Hz, 2H) , 2H (s, 2H) .63 (d, J = 12.8 Hz, 1H) , 1.49 (q, J = 10.9 Hz, 4H) , 1.35 (t, J = 6.9 Hz, 3H) , 1.19 (dd, J = 18.8, 11.7 Hz, 1H) .

[0638] N- ( (4-chloro-6-fluoroquinolin-2-yl)methyl) -N- cyclohexylbenzo [d] thiazol-6-amine (compound 12.9, Scheme 12)

[0639] The titrated compound was synthesised according to Process M, starting with N-cyclohexylbenzo [d] thiazol- 6-amine 5.12 (50 mg, 0.22 mmol, 1 eq) , 4-chloro-6-f luoroquinolin-2- carbaldehyde 12.6 (90 mg, 0.43 mmol, 2 eq) , trifluoroacetic acid (3 eq, 0.65 mmol, 50 pL) , phenylsilane (3 eq, 0.65 mmol, 80 pL) . Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 90:10) yielded the pure titrated product as a pale yellow solid in a yield of 31% (30 mg) . Characterization: Rt 2.63 min, apolar method, MS (ESI) m / z = 425.9, 427.9 [M+H]+. Exact mass: 425.1129. iH NMR (400 MHz, DMSO) 5 9.01 (s, 1H) , 8.20 (dd, J = 9.2, 5.4 Hz, 1H) , 7.90 (dd, J = 9.6, 2.8 Hz, 1H) , 7.88 - 7.82 (m, 2H) , 7.64 (s, 1H) , 7.52 (d, J = 2.6 Hz, 1H) , 7.04 (dd, J = 9.6 Hz, 1H) .1, 2.6 Hz, 1H) , 4.82 (s, 2H) , 4.00 (s, 1H) , 1.90 (d, 2H) , 1.81 (d, J = 9.9 Hz, 2H, J = 9.7 Hz) , 1.67 (d, J = 13.0 Hz, 1H) , 1.52 (q, J = 10.4 Hz, 4H) , 1.23 - 1.15 (m, 1H) .

[0640] N- ( (6-fluoroquinolin-2-yl) methyl) cyclopentanamine (compound 13.1, Scheme 13)

[0641] The titrated compound was synthesised according to general Process E, starting with 6-f luoroquinolin-2-carbaldehyde 1.9 (1 eq, 50 mg, 0.29 mmol) , cyclopentanamine (1 eq, 28 pL, 0.29 mmol) , sodium triacetoxiborhydride (4 eq, 1.14 mmol, 242 mg) in dry dichloromethane (0.3 M, 1 mL) , without adding acetic acid. The crude product was subjected directly to the subsequent reaction without further purification. Characterization: Rt = 1.47 min; MS (ESI) m / z: 244.8 [M+H]+. Exact mass: 244.1376. iH NMR (400 MHz, DMSO-d6) 5 8.29 (d, J = 8.6 Hz, 1H) , 8.01 (dd, J = 9.2, 5.5 Hz, 1H) , 7.74 (dd, J = 9.4, 2.9 Hz, 1H) , 7.66 (d, J = 8.4, 2.9 Hz, 1H) .66 (d, J 8,3 Hz, 1H) , 7, 65 - 7,58 (m, 1H) , 3,94 (s, 2H) , 3,07

[0642] 2,98 (m, 1H) , 1,77 - 1,55 (m, 4H) , 1,55 - 1,27 (m, 4H) .

[0643] N- ( (6-ethoxyquinolin-2-yl) methyl) -4-methoxybutan-l-amine (compound 13.2, Scheme 13)

[0644] The titrated compound was synthesised according to general Process E, starting with 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 80 mg, 0.40 mmol) , 4-methoxybutan-l-amine (1 eq, 41 mg, 0.40 mmol) , sodium triacetoxyborohydride (4 eq, 1.59 mmol, 337 mg) in dry dichloromethane (0.3 M, 1.3 mL) , without adding acetic acid. The crude product was subjected directly to the subsequent reaction without further purification. Characterization: Rt = 1.62 min; MS (ESI) m / z : 289.7 [M+H]+. Exact mass: 288.1838. iH NMR (400 MHz, DMSO-d6) 5 8.18 (d, J = 8.6 Hz, OH) , 7.84 (d, J = 9.0 Hz, 1H) , 7.54 (d, J = 8.5 Hz, OH) , 7.38 - 7.28 (m, 1H) , 6.54 (s, 1H) , 4.15 (q, J = 6.5 Hz, 1H) .15 (q, J = 6.9 Hz, 2H) , 3.89 (d, J = 34.8 Hz, 1H) , 3.25 - 3.21 (m, 2H) , 2.60 - 2.52 (m, 2H) , 1.58 - 1.46 (m, 4H) , 1.40 (t, J = 7.0 Hz, 3H) .

[0645] N- ( ( 6 -ethoxyquinolin-2-yl) methyl) -3 , 3 , 3 -tri fluoropropan- 1- amine (compound 13.3, Scheme 13)

[0646] The titrated compound was synthesised according to general Process E, starting with 6-ethoxyquinolin-2-carbaldehyde

[0647] 5.10 (1 eq, 80 mg, 0.40 mmol) , 3, 3, 3-trif luoropropan-l-amine hydrochloride (1 eq, 60 mg, 0.40 mmol) , sodium triacetoxyborohydride (4 eq, 1.59 mmol, 337 mg) in dry dichloromethane (0.3 M, 1.3 mL) , without addition of acetic acid. The crude product was subjected directly to the subsequent reaction without further purification. Characterization: Rt = 1.91 min; MS (ESI) m / z : 299.9 [M+H]+. Exact mass: 298.1293. NMR (400 MHz, DMSO-d6) 5 8.19 (d, J

[0648] = 8.4 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.53 (d, J = 8.5

[0649] Hz, 1H) , 7.35 (dd, J = 9.0, 2.8 Hz, 1H) , 7.32 (d, J = 2.8

[0650] Hz, 1H) .32 (d, J = 2.8 Hz, 1H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.93 (s, 2H) , 2.77 (t, J = 7.3 Hz, 2H) , 2.49 - 2.36 (m, 2H) , 1.40 (t, J = 7.0 Hz, 3H) .

[0651] 4-( ( (6-ethoxyquinolin-2-yl) methyl) amino) butan-l-ol (compound 13.4, Scheme 13)

[0652] The titrated compound was synthesised according to general Process E, starting with 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 80 mg, 0.40 mmol) , 4-aminobutan-l-ol (1 eq, 37 pL, 0.40 mmol) , sodium triacetoxiborhydride (4 eq, 1.59 mmol, 337 mg) in dry dichloromethane (0.3 M, 1.3 mL) , without adding acetic acid. The crude product was subjected directly to the subsequent reaction without further purification.

[0653] Characterization: Rt = 1.40 min; MS (ESI) m / z : 275.6 [M+H]+. Exact mass: 274.1681. NMR (400 MHz, DMSO-d6) 5 8.18 (d, J

[0654] = 8.4 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.54 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 8.9, 2.9 Hz, 1H) , 7.31 (d, J = 2. .7 Hz, 1H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.91 (d, J = 1.6 Hz, 2H) , 3.45 - 3.36 (m, 2H) , 2.57 - 2.51 (m, 2H) , 1.55 - 1.44 (m, 4H) , 1.40 (t, J = 7.0 Hz, 3H) .

[0655] N- ( (6-ethoxyquinolin-2-yl)methyl)butan-l-amine (compound 13.5, Scheme 13)

[0656] The titrated compound was synthesised according to general Process E, starting with 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 80 mg, 0.40 mmol, 1 eq) , butan-l-amine (1 eq, 39 pL, 0.40 mmol, 1 eq) , sodium triacetoxyborohydride (4 eq, 1.59 mmol, 337 mg) in dry dichloromethane (0.3 M, 1.3 mL) , without adding acetic acid. The crude product was subjected directly to the subsequent reaction without further purification. Characterization: Rt = 1.71 min; MS (ESI) m / z : 259.7 [M+H]+. Exact mass: 258.1732. iH NMR (400 MHz, DMSO- d6) 5 8.18 (d, J = 8.5 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.55 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.0, 2.8 Hz, 1H) , 7.31 (d, J = 2.7 Hz, 1H) , 4.15 (q, J = 7.0, 2.8 Hz, 1H) .15 (q, J = 7.0 Hz, 2H) , 3.91 (s, 2H) , 2.56 - 2.51 (m, 2H) , 1.44 - 1.38 (m, 2H) , 1.40 (t, J = 7.0 Hz, 2H) , 1.37 - 1.27 (m, 2H) , 0.86 (t, J = 7.3 Hz, 3H) . (tert-butyl ((lr,4r)-4-(( (6 -fluoroquinol in-2 -yl) methyl) amino) cyclohexyl) carbamate (Compound 13.6, Scheme 13)

[0657] The titrated compound was synthesised according to general Process E, starting with 6-f luoroquinolin-2-carbaldehyde 1.9 (100 mg, 0.57 mmol, 1 eq) , 1-N-Boc-trans-l , 4- cyclohexyldiamine (122 mg, 0.57 mmol, 1 eq) , sodium triacetoxyborohydride (4 eq, 2.28 mmol, 484 mg) in dry dichloromethane (0.3 M, 2 mL) , without adding acetic acid. The crude product was subjected directly to the subsequent reaction without further purification. Characterization: Rt = 1.78 min; MS (ESI) m / z : 374.6 [M+H]+. Exact mass: 373.2166.

[0658] !H NMR (400 MHz, DMSO-d6) 5 8.29 (d, J = 8.5 Hz, 1H) , 8.01 (dd, J = 9.2, 5.4 Hz, 1H) , 7.74 (dd, J = 9.5, 2.9 Hz, 1H) , 7.66 (d, J = 8.5 Hz, 1H) , 7.64 - 7. 59 (m, 1H) , 7.59 (m, 1H) .59 (m, 1H) , 6.64 (d, J = 8.0 Hz, 1H) , 3.98 (s, 2H) , 3.65 - 3.58 (m, 1H) , 2.36 - 2.18 (m, 2H) , 1.78 - 1.66 (m, 3H) , 1.36 (s, 9H) , 1.14 - 1.04 (m, 5H) .

[0659] N- ( (6-ethoxyquinolin-2-yl) methyl) cyclohexanamine (compound 13.7, Scheme 13)

[0660] The titrated compound was synthesised according to Process E, starting with 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq,

[0661] 70 mg, 0.348 mmol) , cyclohexylamine (1 eq, 0.348 mmol, 40 qL) , sodium triacetoxyborohydride (4 eq, 1.39 mmol, 295 mg) in dry dichloromethane (0.3 M, 1 mL) , without adding acetic acid. The reaction mixture was stirred for 3 h. The compound was obtained pure without purification by column chromatography (yield 95%, 94 mg, brown oil) . Characterization: Rt 1.89 min, generic method, MS (ESI) m / z = 285.2 [M+H]+. Exact mass: 284.1889. NMR (400 MHz, DMSO) 5 8.17 (d, J = 8.5 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.56 (d, J = 8.5 Hz, 1H) , 7.37 - 7.30 (m, 2H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.95 (s, 2H) , 3.5 (s, 2H) .95 (s, 2H) , 2.46 - 2.35 (m, 1H) , 1.86 (d, J = 12.2 Hz, 2H) , 1.65 (d, J = 4.5 Hz, 2H) , 1.54 (s, 1H) , 1.40 (t, J = 6.9 Hz, 3H) , 1.26 - 1.00 (m, 5H) .

[0662] 2-( ( (6-ethoxyquinolin-2-yl) methyl) amino) ethane-l-ol (compound 13.8, Scheme 13)

[0663] The titrated compound was synthesised according to Process E, starting with 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 70 mg, 0.348 mmol) , 2-aminoethan-l-ol (1 eq, 0.348 mmol, 21 qL) , sodium triacetoxyborohydride (4 eq, 1.39 mmol, 295 mg) in dry dichloromethane (0.17 M, 2 mL) , without adding acetic acid. The reaction mixture was stirred for 3 h. The compound was obtained pure without purification by column chromatography (quantitative yield, 85 mg, yellow oil) . Characterization: Rt 2.29 min, polar method, MS (ESI) m / z = 247.6 [M+H]+ . Exact mass: 246.1368. NMR (400 MHz, DMSO) 5 8.19 (d, J = 8.3 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) , 7.54 (d, J = 8.5 Hz, 1H) , 7.38 - 7.29 (m, 2H) , 4.20 - 4.10 (m, 2H) .20 - 4.10 (m, 2H) , 3.94 (d, J = 2.1 Hz, 2H) , 3.49 (t, J = 5.7 Hz, 2H) , 2.62 (t, J = 5.8 Hz, 2H) , 1.40 (td, J = 7.0, 2.3 Hz, 3H) .

[0664] N- ( (6-ethoxyquinolin-2-yl) methyl) -2-methoxyethan-l-amine

[0665] (compound 13.9, Scheme 13)

[0666] The titrated compound was synthesised according to Process E, starting with 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 70 mg, 0.348 mmol) , 2-methoxyethan-l-amine (1 eq, 0.348 mmol, 30 pL) , sodium triacetoxyborohydride (4 eq, 1.39 mmol, 295 mg) in dry dichloromethane (0.17 M, 2 mL) , without adding acetic acid. The reaction mixture was stirred for 3 h. The compound was obtained pure without purification by column chromatography (quantitative yield, 90 mg, yellow oil) . Characterization: Rt 1.50 min, generic method, MS (ESI) m / z = 261.5 [M+H]+. Exact mass: 260.1525. iH NMR (400 MHz, DMSO) 5 8.18 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) , 7.53 (d, J = 8.5 Hz, 1H) , 7.35 (dd, J = 9.0, 2.8 Hz, 1H) , 7.32 (d, J = 2.8 Hz, 1H) , 4.5 (d, J = 2.8 Hz, 1H) .8 Hz, 1H) , 4.15 (q, J = 6.9 Hz, 2H) , 3.94 (s, 2H) , 3.42 (t, J = 5.6 Hz, 2H) , 3.24 (s, 3H) , 2.71 (t, J = 5.6 Hz, 2H) , 1.40 (t, J = 7.0 Hz, 3H) . tert-butyl (4- ( ( (6-ethoxyquinolin-2- yl ) methyl ) amino) cyclohexyl ) carbamate (compound 13.10, Scheme 13)

[0667] The titrated compound was synthesised according to Process E, starting with 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 70 mg, 0.348 mmol) , tert-butyl ( 4-aminocyclohexyl ) carbamate (1 eq, 0.348 mmol, 75 mg) , sodium triacetoxyborohydride (4 eq, 1.39 mmol, 295 mg) in dry dichloromethane (0.3 M, 1 mL) , without adding acetic acid. The reaction mixture was stirred for 3 h. The compound was obtained pure without purification by column chromatography (quantitative yield, 140 mg, orange solid) . Characterization: Rt 1.99 min, generic method, MS (ESI) m / z = 400.3 [M+H]+. Exact mass: 399.2522. iH NMR (400 MHz, DMSO) 5 8.17 (d, J = 8.5 Hz, 1H) , 7.84 (d, J = 9.1 Hz, 1H) , 7.55 (d, J = 8.5 Hz, 1H) , 7.37 - 7.30 (m, 2H) , 6.65 (bs, 1H) , 4.15 (q, J = 7.5 Hz, 1H) .15 (q, J = 7.0 Hz, 2H) , 3.94 (s, 2H) , 3.18 (bs, 1H) , 2.35 - 2.26 (m, 1H) , 1.91 (bs, 2H) , 1.75 (bs, 2H) , 1.44-1.32 (m, 11 H) , 1.09 (q, J = 9.1

[0668] Hz, 2H) . N- ( ( 6 -ethoxyquinol in-2-yl) methyl) benzo [d] thiazol-6-amine

[0669] (compound 13.11, Scheme 13)

[0670] To the solution of 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 2.38 mmol, 500 mg) and benzo [d] thiazol- 6-amine 6.1 (1 eq, 2.38 mmol, 373 mg) in absolute ethanol (0.2 M, 12.4 mL) at room temperature, acetic acid (2 eq, 4.96 mmol, 284 pL) was added and the mixture was stirred overnight at room temperature. Next, sodium borhydride (6 eq, 14.88 mmol, 562 mg) was slowly added at 0°C and the mixture was stirred at room temperature for 4 h. The mixture was quenched with saturated aqueous Na2COs and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on neutral aluminium oxide (cyclohexane / i-propanol from 100:0 to 90:10) to obtain the pure titrated compound as a yellowish foamy solid in 90% yield (748 mg) . Characterization: Rt 2.21 min, generic method, MS (ESI) m / z = 335.9 [M+H]+. Exact mass: 335.1092. iH NMR (400 MHz, DMSO) 5 8.89 (s, 1H) , 8.19 (d, J = 8.5 Hz, 1H) , 7.92 (d, J = 9.1 Hz, 1H) , 7.76 (d, J = 8.9 Hz, 1H) , 7.50 (d, J = 8.5 Hz, 1H) , 7.38 (dd, J = 9.1, 2.8 Hz, 1H) , 7.32 (d, J = 2.8 Hz, 1H) .32 (d, J = 2.8 Hz, 1H) , 7.15 (d, J = 2.2 Hz, 1H) , 6.96 (dd, J = 8.9, 2.3 Hz, 1H) , 6.82 (t, J = 6.0 Hz, 1H) , 4.56 (d, J = 6.0 Hz, 2H) , 4.15 (q, J = 7.0 Hz, 2H) , 1.40 (t, J = 7.0 Hz, 3H) .

[0671] N- ( (6-fluoroquinolin-2-yl) methyl) -N- (thiazol -5 -methyl) cyclopentanamine (compound 13.13, Scheme 13)

[0672] The titrated compound was synthesised according to general Process E using the intermediate 13.1 (0.29 mmol, 1 eq) , thiazol-5-carbaldehyde 13.12 (1 eq, 28 pL, 0.29 mmol) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.14 mmol, 242 mg) , in dry dichloromethane (0.3 M, 1 mL) . The mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel ( cyclohexane / EtOAc 75:25) yielded the pure titrated compound as orange oil (55.8 mg, yield 57%) . Characterization: Rt = 1.49 min; MS (ESI) m / z : 342.6 [M+H]+. Exact mass: 341.1362. !H NMR (400 MHz, DMSO-d6) 5 8.97 (d, J = 0.8 Hz, 1H) , 8.31 (d, J = 8.5 Hz, 1H) , 8.02 (dd, J = 9.2, 5.5 Hz, 1H) , 7.77

[0673] (d, J = 0.9 Hz, 1H) , 7.74 (dd, J = 9.4, 2.9 Hz, 1H) , 7.68

[0674] (dd, J = 8.4, 2.9 Hz, 1H) .68 (dd, J = 8.5, 0.9 Hz, 1H) , 7.62

[0675] (td, J = 8.9, 2.9 Hz, 1H) , 3.94 (s, 2H) , 3.87 (s, 2H) , 3.07

[0676] (p, J = 7.9 Hz, 1H) , 1.76 (s, 2H) , 1.58 (d, J = 12.0 Hz,

[0677] 2H) , 1.54 1.28 (m, 4H) . N- ( (6-ethoxyquinolin-2-yl) methyl) -4-methoxy-N- (thiazol-5- methyl) bu tan- 1 -amine (compound 13.14, Scheme 13)

[0678] The titrated compound was synthesised according to the general Process E using the intermediate 13.2 (1 eq, 0.40 mmol) , thiazol-5-carbaldehyde 13.12 (39 pL, 0.40 mmol) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.59 mmol, 337 mg) , in dry dichloromethane (0.3 M, 1.2 mL) . The mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel ( cyclohexane / acetone 65:35) yielded the pure titrated compound as brown oil (39.8 mg, yield 26%) . Characterization: Rt = 1.08 min; MS (ESI) m / z : 386.7 [M+H]+. Exact mass: 385.1824. iH NMR (400 MHz, DMSO-d6) 5 9.01 (d, J = 0.9 Hz, 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) ,

[0679] 7.79 (d, J = 0.9 Hz, 1H) , 7.55 (d, J = 8.5 Hz, 1H) , 7.34

[0680] (dd, J = 9.0, 2.8 Hz, 1H) , 7.32 (d, J = 2.8 Hz, 1H) .32 (d,

[0681] J = 2.8 Hz, 1H) , 4.15 (q, J = 6.9 Hz, 2H) , 3.89 (s, 2H) ,

[0682] 3.78 (s, 2H) , 3.19 (t, J = 6.2 Hz, 2H) , 3.13 (d, J = 0.5 Hz, 2H) , 3.5 (d, J = 0.5 Hz, 2H) .13 (d, J = 0.9 Hz, 3H) , 2,44 (t, J = 6.7 Hz, 2H) , 1.57 - 1.41 (m, 4H) , 1.39 (t, J = 7.0

[0683] Hz, 3H)

[0684] N- ( (6-ethoxyquinolin-2-yl) methyl) -3 , 3 , 3-trifluoro-N- ( thiazol -5 -methyl) propan- 1 -amine (compound 13.15, Scheme 13)

[0685] The titrated compound was synthesised according to general Process E using the intermediate 13.3 (1 eq, 0.084 mmol) , thiazol-5-carbaldehyde 13.12 (1 eq, 8 pL, 0.084 mmol) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 0.336 mmol, 7 8mg) , in dry dichloromethane (0.2 M, 650 pL) . The mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel ( cyclohexane / acetone 60:40) yielded the pure titrated compound as yellow oil (18.8 mg, yield 57%) . Characterization: Rt = 2.42 min; MS (ESI) m / z : 396.2 [M+H]+. Exact mass: 395.1279. NMR (400 MHz, DMSO-d6) 5 9.03 (s, 1H) , 8.22 (d, J = 8.5 Hz, 1H) , 7.86 (d, J = 9.0 Hz, 1H) , 7.83 (s, 1H) , 7.55 (d, J = 8.5 Hz, 1H) , 7.35 (dd, J = 9.0, 2.8 Hz, 1H) , 7.33 (d, J = 2.8 Hz, 1H) .33 (d, J = 2.7 Hz, 1H) , 4.15 (q, J = 6.9 Hz, 2H) , 3.95 (s, 2H) , 3.85 (s, 2H) , 2.70 (dd, J = 8.3, 6.3 Hz, 2H) , 2.63 - 2.52 (m, 1H) , 1.40 (t, J = 7.0 Hz, 3H) .

[0686] 4- ( ( (6-ethoxyquinolin-2-yl) methyl) (thiazol -5 -methyl) amino) butan-l-ol (compound 13.16, Scheme 13) The titrated compound was synthesised according to general

[0687] Process E using the intermediate 13.4 (1 eq, 0.40 mmol) , thiazol-5-carbaldehyde 13.12 (1 eq, 39 pL, 0.40 mmol) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.59 mmol, 337 mg) , in dry dichloromethane (0.3 M, 1.2 mL) . The mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel ( cyclohexane / acetone 70:30) yielded the pure compound as orange oil (59.6 mg, yield 44%) . Characterization: Rt = 0.57 min; MS (ESI) m / z: 372.5 [M+H]+. Exact mass: 371.1667. NMR (400 MHz, DMSO-d6) 5 9.01 (d, J = 0.8 Hz, 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.1 Hz, 1H) , 7.79 (d, J = 0.1 Hz, 1H) .79 (d, J = 0.9 Hz, 1H) , 7.56 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.0, 2.8 Hz, 1H) , 7.31 (d, J = 2.8 Hz, 1H) , 4.36 (d, J = 5.7 Hz, 1H) , 4.14 (q, J = 6.9 Hz, 2H) , 3.88 (s, 2H) , 3.78 (s, 2H) , 3.31 (q, J = 6.2 Hz, 2H) , 2.42 (t, J = 7.1 Hz, 2H) , 1.51 (p, J = 7.0 Hz, 2H) , 1.39 (t, J = 7.0 Hz, 3H) .

[0688] N- ( (6-ethoxyquinolin-2-yl) methyl) -N- (thiazol-5- methyl) bu tan- 1 -amine (compound 13.17, Scheme 13)

[0689] The titrated compound was synthesised according to general Process E using the intermediate 13.5 (1 eq, 0.40 mmol) , thiazol-5-carbaldehyde 13.12 (1 eq, 39 pL, 0.40 mmol) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.59 mmol, 337 mg) , in dry dichloromethane (0.3 M, 1.2 mL) . The mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel ( cyclohexane / acetone 65:35) yielded the pure titrated compound as brown oil (62.0 mg, yield 44%) . Characterization: Rt = 1.58 min; MS (ESI) m / z : 356.7 [M+H]+. Exact mass: 355.1718. iH NMR (400 MHz, DMSO-d6) 5 9.01 (d, J = 0.8 Hz, 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) ,

[0690] 7.79 (d, J = 0.0 Hz, 1H) .79 (d, J = 0.9 Hz, 1H) , 7.56 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.0, 2.8 Hz, 1H) , 7.31 (d, J = 2.8 Hz, 1H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.91 - 3.86 (m, 2H) ,

[0691] 3.79 (s, 2H) , 2.43 (t, J = 7.1 Hz, 2H) , 1.50 - 1.42 (m, 2H) , 1.39 (t, J = 7.0 Hz, 3H) , 1.23 (h, J = 7.3 Hz, 2H) , 0.77 (t, J = 7.4 Hz, 3H) . tert-butyl ( (lr,4r) -4-( ( (6-fluoroquinolin-2-yl) methyl) (thiazol -5 -methyl) amino) cyclohexyl) carbamate (Compound 13.18, Scheme 13)

[0692] The titrated compound was synthesised according to general Process E using the intermediate 13.6 (1 eq, 0.57 mmol) , thiazol-5-carbaldehyde 13.12 (1 eq, 56 pL, 0.57 mmol) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.59 mmol, 337 mg) , in dry dichloromethane (0.3 M, 1.2 mL) . The mixture was stirred at room temperature overnight.

[0693] Purification by flash chromatography on silica gel ( cyclohexane / acetone 50:50) yielded the pure titrated compound as yellow oil (83.7 mg, yield 31%) . Characterization: Rt = 1.40 min; MS (ESI) m / z : 471.7 [M+H]+. Exact mass: 470.2152. iH NMR (400 MHz, DMSO-d6) 5 9.01 (d, J = 0.8 Hz, 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) , 7.79 (d, J = 0.9 Hz, 1H) , 7.56 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.0, 2.8 Hz, 1H) , 7.31 (d, J = 2.8 Hz, 1H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.91 - 3.86 (m, 2H) , 3.79 (s, 2H) , 2.43 (t, J = 7.1 Hz, 2H) , 1.50 - 1.42 (m, 2H) , 1.39 (t, J = 7.0 Hz, 3H) , 1.23 (h, J = 7.3 Hz, 2H) , 0.77 (t, J = 1.4 Hz, 3H) .

[0694] N- ( (6-ethoxyquinolin-2-yl) methyl) -N- (thiazol -5 -methyl) cyclohexanamine (compound 13.19, Scheme 13)

[0695] The titrated compound was synthesised according to Process E, starting with N- ( ( 6-ethoxyquinolin-2- yl ) methyl ) cyclohexanamine 13.7 (1 eq, 94 mg, 0.33 mmol) , thiazol-5-carbaldehyde 13.12 (1 eq, 0.33 mmol, 29 pL) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.32 mmol, 280 mg) , in dry dichloromethane (0.15 M, 2.2 mL) . The mixture was stirred at room temperature overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate from 100:0 to 80:20) yielded the pure titrated compound as a white powder in a yield of 56% (70 mg) . Characterization: Rt 1.85 min, apolar method, MS (ESI) m / z = 382.2 [M+H]+. Exact mass: 381.1875. NMR (400 MHz, DMSO) 5 8.94 (s, 1H) , 8.19 (d, J = 8.5 Hz, 1H) , 7.83 (d, J = 9.0 Hz, 1H) , 7.74 (s, 1H) , 7.61 (d, J = 8.5 Hz, 1H) , 7.37 - 7.28 (m, 2H) , 4.15 (q, J = 6.9 Hz, 2H) , 3.92 (s, 2H) , 3.9 (s, 2H) , 3.9 (s, 2H) , 3.9 (s, 2H) .92 (s, 2H) , 3.87 (s, 2H) , 2.50-2.43 (m, 1H, superimposed on solvent signal) , 1.84 (d, J = 12.4 Hz, 2H) , 1.72 (s, 2H) , 1.54 (s, 1H) , 1.43-1.27 (m, 5H) , 1.10 (q, J = 10.9 Hz, 3H) .

[0696] 2- ( ( (6-ethoxyquinolin-2-yl) methyl) (thiazol -5 -methyl) amino) ethan-l-ol (compound 13.19, Scheme 13)

[0697] The titrated compound was synthesised according to Process

[0698] E, starting with 2- ( ( ( 6-ethoxyquinolin-2- yl) methyl) amino) ethane-l-ol 13.8 (1 eq, 78 mg, 0.318 mmol) , thiazol-5-carbaldehyde 13.12 (1 eq, 0.318 mmol, 27 pL) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.272 mmol, 270 mg) , in dry dichloromethane (0.16 M, 2.0 mL) . The mixture was stirred at room temperature overnight. The crude product was purified by silica gel chromatography (dichloromethane 100:0 to 90:10) . The product was further purified by a second silica gel column chromatography using 100:0 to 90:10 cyclohexane / propanol as an eluent to obtain the pure titrated compound as pale yellow oil in a yield of 27% (30 mg) . Characterization: Rt 1.78 min, generic method, MS (ESI) m / z = 344.0 [M+H]+. Exact mass: 343.1354. NMR (400 MHz, DMSO) 5 9.02 (d, J = 0.7 Hz, 1H) , 8.22 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) , 7.81 (d, J = 0.8 Hz, 1H) , 7.61 (d, J = 8.5 Hz, 1H) , 7.35 (dd, J = 9.0, 2.8 Hz, 1H) , 7.33 (d, J = 2.8 Hz, 1H) .33 (d, J = 2.7 Hz, 1H) , 4.56 (t, J = 5.4 Hz, 1H) , 4.15 (q, J = 6.9 Hz, 2H) , 3.98 (s, 2H) , 3.86 (s, 2H) , 3.51 (q, J = 6.1 Hz, 2H) , 2.58 (t, J = 6.4 Hz, 2H) , 1.40 (t, J = 7.0 Hz, 3H) .

[0699] N- ( (6-ethoxyquinolin-2-yl) methyl) -2-methoxy-N- (thiazol-5- methyl) e than- 1 -amine (compound 13.21, Scheme 13)

[0700] The titrated compound was synthesised according to Process E, starting with N- ( ( 6-ethoxyquinolin-2-yl ) methyl ) -2- methoxyethan-l-amine 13.9 (1 eq, 70 mg, 0.269 mmol) , thiazol- 5-carbaldehyde 13.12 (1 eq, 0.269 mmol, 23 pL) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.076 mmol, 228 mg) , in dry dichloromethane (0.14 M, 2.0 mL) . The mixture was stirred at room temperature overnight. Purification by chromatography on silica gel ( cyclohexane / acetone 80:20 to 60:40) yielded the pure titrated product as a pale yellow oil in a yield of 59% (57 mg) . Characterization: Rt 2.11 min, generic method, MS (ESI) m / z = 357.7 [M+H]+. Exact mass: 357.1511.1H NMR (400 MHz, DMSO) 5 9.02 (d, J = 0.8 Hz, 1H) , 8.22 (d, J = 8.5 Hz, 1H) , 7.86 (d, J = 9.0 Hz, 1H) , 7.81 (d, J = 0.9 Hz, 1H) , 7.59 (d, J = 8.5 Hz, 1H) , 7.35 (dd, J = 9.0, 2.8 Hz, 1H) , 7.32 (d, J = 2.8 Hz, 1H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.98 (s, 2H) , 3.86

[0701] (s, 2H) , 3.53 - 3.41 (m, 3H) , 3.20 (s, 3H) , 2.66 (t, J = 5.9 Hz, 2H) , 1.40 (t, J = 6.9 Hz, 3H) . tert-butyl (4- ( ( (6-ethoxyquinolin-2-yl) methyl) (thiazol-5- methyl ) amino) cyclohexyl ) carbamate (compound 13.22, Scheme 13)

[0702] The titrated compound was synthesised according to Process E, starting with tert-butyl ( 4- ( ( ( 6-ethoxyquinolin-2- yl ) methyl ) amino ) cyclohexyl ) carbamate 13.10 (1 eq, 140 mg, 0.348 mmol) , thiazol-5-carbaldehyde 13.12 (1 eq, 0.348 mmol, 30 pL) , catalytic acetic acid and sodium triacetoxyborohydride (4 eq, 1.32 mmol, 295 mg) , in dry dichloromethane (0.15 M, 2.3 mL) . The mixture was stirred at room temperature overnight. Purification by silica gel column chromatography yielded the pure titrated compound as a white powder in a yield of 36% (63 mg) . Characterization: Rt 1.85 min, apolar method, MS (ESI) m / z = 497.3 [M+H]+. Exact mass: 496.2508. iH NMR (400 MHz, DMSO) 5 8.94 (d, J = 0.7 Hz, 1H) , 8.19 (d, J = 8.6 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.75 (s, 1H) , 7.59 (d, J = 8.5 Hz, 1H) , 7.38 - 7.29 (m, 2H) , 6.61 (d, J = 8.1 Hz, 1H) , 4.15 (q, J = 6.9 Hz, 2H) , 3.15 (d, J = 9.9 Hz, 2H) .9 Hz, 2H) , 3.90 (s, 2H) , 3.86 (s, 2H) , 3.17 (s, 1H) , 2.52 (bs, 1H, superimposed on the solvent signal) , 1.79 (bs, 4H) , 1.47 (bs, 2H) , 1.40 (t, J = 7.0 Hz, 3H) , 1.36 (s, 9H) , 1.04 (q, J = 12.4 Hz, 2H) .

[0703] 2- ( ( (4-ammonium-cyclohexyl) (thiazol-5- methyl) ammonium) methyl) -6-fluoroquinolin-l-ium chloride (compound 13.24, Scheme 13)

[0704] The compound was synthesised according to general Process 01 using the intermediate 13.18 (1 eq, 22 mg, 0.048 mmol) in dioxane (0.1 M, 500 pL) and HC1 4M in dioxane (8 eq, 0.389 mmol, 100 pL) , stirring the reaction mixture at room temperature for 3 h. The solvent was evaporated to obtain the desired compound as a yellow powder in quantitative yield (37 mg) . Characterization: Rt = 1.60 min; MS (ESI) m / z : 371.2 [M+H]+. Exact mass: 370.1627. NMR (400 MHz, DMSO-d6) 5 9.01 (d, J = 0.8 Hz, 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) , 7.79 (d, J = 0.0 Hz, 1H) .79 (d, J = 0.9 Hz, 1H) , 7.56 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.0, 2.8 Hz, 1H) , 7.31 (d, J = 2.8 Hz, 1H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.91 - 3.86 (m, 2H) , 3.79 (s, 2H) , 2.43 (t, J = 7.1 Hz, 2H) , 1.50 - 1.42 (m, 2H) , 1.39 (t, J = 7.0 Hz, 3H) , 1.23 (h, J = 7.3 Hz, 2H) , 0.77 (t, J = 1.4 Hz, 3H) .

[0705] N1-( (6-ethoxyquinolin-2-yl) methyl) -N1-(thiazol-5- ylmethyl) -cyclohexan-1 , 4 -diamine (compound 13.25, Scheme 13)

[0706] The titrated compound was synthesised according to Process 01, starting with tert-butyl ( 4- ( ( ( 6-ethoxyquinolin-2- yl)methyl) ( thiazol-5-ylmethyl ) amino ) cyclohexyl ) carbamate 13.22 (1 eq, 63 mg, 0.126 mmol) dissolved in dioxane (0.1, 1.3 mL) and HC1 4M in dioxane (8 eq, 0.253 mL) , stirring the reaction mixture at room temperature for 5h. The hydrochloric salt resulting from the deprotection was unstable. After evaporation of the solvent, the crude product was dissolved in ethyl acetate and washed with 2M NaOH aqueous solution to obtain the free amine. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2 SO4, filtered and evaporated. Purification by silica gel column chromatography (dichloromethane / methanol / ammonia from 100:0:0 to 80:19:1) yielded the pure titrated compound as yellow oil in a yield of 42% (21 mg) . Characterization: Rt 1.71 min, generic method, MS (ESI) m / z = 397.2 [M+H]+. Exact mass: 396.1984. !H NMR (400 MHz, DMSO) 5 8.95 (d, J = 0.8 Hz, 1H) , 8.19 (d, J = 8.6 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.75 (s, 1H) , 7.60 (d, J = 8.5 Hz, 1H) , 7.36 - 7.29 (m, 2H) , 4.15 (q, J = 6.5 Hz, 1H) , 4.5 (q, J = 6.5 Hz, 1H) , 4.5 (q, J = 6.5 Hz, 1H) .15 (q, J = 6.9 Hz, 2H) , 3.91 (s, 2H) , 3.86 (s, 2H) , 3.33 (1H superimposed on signal D2 0) , 2.50-2.45 (m, 1H) , 1.79 (d, J = 11.5 Hz, 4H) , 1.51-1.37 (m, 5H) , 0.93 (q, J = 11.8 Hz, 2H) .

[0707] 1- (6-ethoxyquinolin-2-yl) -N- (thiazol -5 -methyl) me thanamine (compound 14.2, Scheme 14)

[0708] To the solution of thiazol-5-ylmethanaminium chloride 14.1 (1 eq, 500 mg, 3.33 mmol) in dry dichloromethane (0.1 M, 33 mL) at room temperature, triethylamine (2 eq, 6.66 mmol, 0.92 mL) was added. A gas evolution was observed. The mixture was stirred for 1 h to obtain the free amine, which was reacted with ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 0.33 mmol, 670 mg) and sodium triacetoxyborohydride (4 eq, 13.35 mmol, 2.82 g) , without adding acetic acid, according to Process E described above. The reaction mixture was stirred overnight. Purification by silica gel column chromatography ( cyclohexane / acetone 70:30) yielded the pure titrated compound as light brown oil in a yield of 56% (564 mg) . Characterization: Rt 1.64 min, generic method, MS (ESI) m / z = 300.2 [M+H]+. Exact mass: 299.1092. iH NMR (400 MHz, DMSO) 5 9.02 - 8.95 (m, 1H) , 8.20 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) , 7.76 (d, J = 1.1 Hz, 1H) , 7.56 (d, J = 8.0 Hz, 1H) .56 (d, J = 8.5 Hz, 1H) , 7.39 - 7.30 (m, 2H) , 4.15 (q, J = 7.0 Hz, 2H) , 3.99 (d, J = 1.0 Hz, 2H) , 3.93 (s, 2H) , 1.41 (t, J = 7.0 Hz, 3H) .

[0709] 3- ( ( ( (6-ethoxyquinolin-2-yl) methyl) (thiazol -5 -methyl) amino) propanoic acid (compound 14.4, Scheme 14)

[0710] To the solution of 1- ( 6-ethoxyquinolin-2-yl ) -N- ( thiazol-5- ylmethyl ) methanamine 14.2 (1 eq, 0.167 mmol, 50 mg) in dry acetonitrile (0.1 M, 1.7 mL) , 3-bromopropionic acid 14.3 (2 eq, 0.334 mmol, 51 mg) and triethylamine (5 eq, 0.835 mmol, 116 pL) were added, and the reaction mixture was stirred at reflux for 24 h. Then 2 eq of 3-bromopropionic acid (51 mg) was added and the mixture was stirred under reflux for a further 24 h. The mixture was allowed to cool to room temperature and dried under vacuum to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane / methanol 100:0 to 90:10) . The residue obtained was dissolved in i-propanol to obtain a white precipitate (triethylammonium bromide) which was filtered. The filtrate was dried to obtain the pure product titrated in a 25% yield (12 mg) . Characterization: Rt 1.51 min, generic method, MS (ESI) m / z = 370.4 [M-H]~, 372.2 [M+H]+. Exact mass: 371.1304. NMR (400 MHz, DMSO) 5 9.03 (s,

[0711] 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.86 (d, J = 8.9 Hz, 1H) ,

[0712] 7.81 (s, 1H) , 7.56 (d, J = 8.5 Hz, 1H) , 7.38 - 7. 30 (m,

[0713] 2H) , 7.30 (m, 2H) .3O (m, 2H) , 4.16 (q, J = 6.9 Hz, 2H) , 3.93 (s, 2H) , 3.83 (s, 2H) , 2.73 (t, J = 7.2 Hz, 2H) , 2.45 (t, J = 7.3 Hz, 2H) , 1.40 (t, J = 6.9 Hz, 3H) .

[0714] N- ( (6-ethoxyquinolin-2-yl) methyl) -N- (thiazol -5 -methyl) cyclobutanamine (compound 14.5, Scheme 14)

[0715] The titrated compound was synthesised according to Process E, starting with 1- ( 6-ethoxyquinolin-2-yl) -N- (thiazol-5- ylmethyl ) methanamine 14.2 (1 eq, 50 mg, 0.168 mmol) , cyclobutanone (1 eq, 0.168 mmol, 12.5 pL) , catalytic acetic acid, sodium triacetoxyborohydride (4 eq, 0.668 mmol, 141 mg) in dry dichloromethane (0.1 M, 1.7 mL) , stirring the reaction mixture overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 100 to 70:30) yielded the pure titrated compound as transparent oil in a yield of 51% (30 mg) . Characterization: Rt 2.49 min, generic method, MS (ESI) m / z = 354.6 [M+H]+. Exact mass: 353.1562. !H NMR (400 MHz, DMSO) 5 9.00 (d, J = 0.8 Hz, 1H) , 8.19 (d, J = 8.5 Hz, 1H) , 7.87 (d, J = 9.0 Hz, 1H) , 7.76 (d, J = 0.0 Hz, 1H) .76 (d, J = 0.9 Hz, 1H) , 7.55 (d, J = 8.5 Hz, 1H) , 7.35 (dd, J = 9.0, 2.8 Hz, 1H) , 7.32 (d, J = 2.7 Hz,

[0716] 1H) , 4.16 (q, J = 7.0 Hz, 2H) , 3.83 (s, 2H) , 3.70 (s, 2H) , 3.23 - 3.10 (m, 1H) , 1.92 (q, J = 7.9 Hz, 2H) , 1.92 (q, J = 2.5 Hz, 1H) .9 Hz, 2H) , 1.81 (tt, J = 11.1, 8.7 Hz, 2H) , 1.55 (ddt, J = 18.4, 10.4, 7.6 Hz, 2H) , 1.40 (t, J = 7.0 Hz, 3H) .

[0717] N- ( (6-ethoxyquinolin-2-yl) methyl) -N- (thiazol -5 -methyl) tetrahydrofuran-3-amine (compound 14.6, Scheme 14)

[0718] The titrated compound was synthesised according to Process

[0719] E, starting with 1- ( 6-ethoxyquinolin-2-yl) -N- (thiazol-5- ylmethyl ) methanamine 14.2 (1 eq, 60 mg, 0.20 mmol) , dihydrofuran-3 ( 2H) -one (1 eq, 0.20 mmol, 15 pL) , catalytic acetic acid, sodium triacetoxyborohydride (4 eq, 0.80 mmol, 170 mg) in dry dichloromethane (0.1 M, 2.0 mL) , stirring the reaction mixture overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 70:30 to 50:50) yielded the pure titrated compound as a yellowish oil in a yield of 53% (39 mg) . Characterization: Rt 2.05 min, generic method, MS (ESI) m / z = 370.2 [M+H]+. Exact mass: 369.1511. iH NMR (400 MHz, DMSO) 5 9.00 (s, 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.86 (d, J = 9.0 Hz, 1H) , 7.80 (s, 1H) , 7.56 (d, J = 8.5 Hz, 1H) , 7.35 (dd, J = 9.0, 2.8 Hz, 1H) , 7.33 (d, J = 2.8 Hz, 1H) , 4. (q, J = 6.8 Hz, 1H) .15 (q, J = 6.9 Hz, 2H) , 3.92 (s, 2H) , 3.90 - 3.77 (m, 3H) , 3.72 - 3.61 (m, 2H) , 3.56 (q, J = 8,0 Hz, 1H) , 2.01 (qd, J = 7.8, 3.9 Hz, 1H) , 1.93 - 1.80 (m, 1H) , 1.40 (t, J = 7.0 Hz, 3H) . tert-butyl 4- ( ( (6-ethoxyquinolin-2-yl) methyl) (thiazol-5- methyl) amino) piperidin-1 -carboxylate (compound 14.7, Scheme 14)

[0720] The titrated compound was synthesised according to Process E, starting with 1- ( 6-ethoxyquinolin-2-yl) -N- (thiazol-5- ylmethyl ) methanamine 14.2 (1 eq, 60 mg, 0.20 mmol) , tertbutyl 4-oxopiperidin-l-carboxylate (1 eq, 0.20 mmol, 40 mg) , catalytic acetic acid, sodium triacetoxyborohydride (4 eq, 0.80 mmol, 170 mg) in dry dichloromethane (0.1 M, 2.0 mL) , stirring the reaction mixture overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 80:20 to 50:50) yielded the pure titrated compound as yellowish oil in a yield of 36% (35 mg) . Characterization: Rt 2.60 min, generic method, MS (ESI) m / z = 483.4 [M+H]+. Exact mass: 482.2352. iH NMR (400 MHz, DMSO) 5 8.94 (d, J = 0.7 Hz, 1H) , 8.19 (d, J = 8.5 Hz, 1H) , 7.83 (d, J = 9.0 Hz, 1H) , 7.75 (d, J = 0.9 Hz, 1H) , 7.59 (d, J = 8.5 Hz, 1H) ,

[0721] 7.34 (dd, J = 9.1, 2.8 Hz, 1H) , 7.31 (d, J = 2.8 Hz, 1H) ,

[0722] 4.15 (q, J = 7.0 Hz, 2H) , 3.96 (d, J = 18.8 Hz, 4H) , 3.88

[0723] (s, 2H) , 2.70 - 2.56 (m, 3H) , 1.77 (d, J = 12.3 Hz, 2H) ,

[0724] 1.48-1.32 (m, 14H) .

[0725] N- ( (6-ethoxyquinolin-2-yl) methyl) -N- (thiazol-5- methyl) piperidin-4 -amine (compound 14.8, Scheme 14)

[0726] The titrated compound was synthesised according to Process 01, starting with tert-butyl 4- ( ( ( 6-ethoxyquinolin-2- yl)methyl) ( thiazol-5-ylmethyl ) amino ) piperidin-1- carboxylate 14.7 (1 eq, 30 mg, 0.062 mmol) dissolved in dioxane (1 mL) and HC1 4M in dioxane (8 eq, 0.12 mL) , stirring the reaction mixture at room temperature for 3h. The hydrochloric salt resulting from the deprotection was unstable. After evaporation of the solvent, the crude product was dissolved in ethyl acetate and washed with 2M NaOH aqueous solution to obtain the free amine. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2 SO4, filtered and evaporated. Purification by silica gel column chromatography (dichloromethane / methanol / ammonia from 100:0:0 to 80:19:1) yielded the pure titrated compound as white powder in a yield of 42% (10 mg) . Characterization: Rt 1.71 min, generic method, MS (ESI) m / z = 383.2 [M+H]+.1H NMR (400 MHz, DMSO) 5 8.95 (d, J = 0.8 Hz, 1H) , 8.20 (d, J = 8.5 Hz, 1H) , 7.84 (d, J = 9.0 Hz, 1H) , 7.76 (s, 1H) , 7.60 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.1, 2.8 Hz, 1H) , 7.31 (d, J =

[0727] 2.8 Hz, 1H) , 4.15 (q, J = 6.0 Hz, 1H) , 7.15 (q, J = 6.0 Hz,

[0728] 1H) , 7.15 (q, J = 6.0 Hz, 1H) .15 (q, J = 6.9 Hz, 2H) , 3.94

[0729] (s, 2H) , 3.88 (s, 2H) , 3.02 (d, J = 12.1 Hz, 2H) , 2.64 -

[0730] 2.54 (m, 1H) , 2.40 (t, J = 12.1 Hz, 2H) .4O (t, J = 12.0 Hz, 2H) , 1.76 (d, J = 12.4 Hz, 2H) , 1.56 - 1.44 (m, 2H) , 1.40 (t, J = 7.0 Hz, 3H) . tert-butyl 7- ( ( (6-ethoxyquinolin-2-yl) methyl) (thiazol-5- methyl) amino) -2-azaspiro [3.5 ] nonano-2 -carboxylate (compound 14.9, Scheme 14)

[0731] The titrated compound was synthesised according to Process E, starting with 1- ( 6-ethoxyquinolin-2-yl) -N- (thiazol-5- ylmethyl ) methanamine 14.2 (1 eq, 60 mg, 0.20 mmol) , spiro [ 3.5 ] nonan-7-one (1 eq, 0.20 mmol, 48 mg) , catalytic acetic acid, sodium triacetoxyborohydride (4 eq, 0.80 mmol, 170 mg) in dry dichloromethane (0.1 M, 2.0 mL) , stirring the reaction mixture overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 80:20 to 50:50) yielded the pure titrated compound as yellowish oil in a yield of 34% (35 mg) . Characterization: Rt 1.84 min, apolar method, MS (ESI) m / z = 523.3 [M+H]+. Exact mass: 522.2665. (400 MHz, DMSO) 5 8.95 (d, J = 0.8 Hz, 1H) ,

[0732] 8.19 (d, J = 8.6 Hz, 1H) , 7.83 (d, J = 9.0 Hz, 1H) , 7.75 (s,

[0733] 1H) , 7.34 (dd, J = 9.0, 2.8 Hz, 1H) , 7.31 (d, J = 2.8 Hz, 1H) , 4. (t, J = 6.0 Hz, 1H) .14 (t, J = 6.9 Hz, 2H) , 3.91 (s, 2H) , 3.85 (s, 2H) , 3.53 (s, 2H) , 3.17 (d, J = 5.2 Hz, 3H) ,

[0734] 2.42 (s, 1H) , 1.84 (d, J = 12.0 Hz, 2H) , 1.73 (d, J = 11.7

[0735] Hz, 2H) , 1.45-1.21 (m, 16 H) .

[0736] N- ( (6-ethoxyquinolin-2-yl) methyl) -N- (thiazol -5 -methyl) -2- azaspiro [3.5 ] nonan-7-amine (compound 14.10, Scheme 14)

[0737] The titrated product was synthesised from tert-butyl 7- ( ( (6- ethoxyquinolin-2-yl ) methyl ) ( thiazol-5-methyl ) amino) -2- azaspiro [ 3.5 ] nonano-2-carboxylate 14.9 (1 eq, 0.067 mmol, 35 mg) dissolved in a dry dichloromethane / trif luoroacetic acid 10:1 (2 mL) mixture, and stirring the reaction mixture for 2 h. Purification by silica gel column chromatography (dichloromethane / methanol / ammonia from 100:0:0 to 80:19:1) yielded the pure titrated compound as a white foamy solid in a 70% yield (20 mg) . Characterization: Rt 1.86 min, generic method, MS (ESI) m / z = 423.2 [M+H]+. Exact mass: 422.2140. !H NMR (400 MHz, DMSO) 5 8.94 (d, J = 0.8 Hz, 1H) , 8.19 (d, J = 8.6 Hz, 1H) , 7.83 (d, J = 9.0 Hz, 1H) , 7.75 (s, 1H) , 7.59 (d, J = 8.5 Hz, 1H) , 7.37 - 7.28 (m, 2H) , 4.14 (q, J = 7.0 Hz, 2H) , 3.90 (s, 2H) , 3.84 (s, 2H) , 3.9 (s, 2H) , 3.9 (s, 2H) .84 (s, 2H) , NH superimposed on signal D2 0, 3.24 (s,

[0738] 2H) , 3.10 (s, 2H) , 2.41 (t, J = 10.2 Hz, 1H) , 1.97 (d, J =

[0739] 12.5 Hz, 2H) , 1.14 (q, J = 7.0 Hz, 2H) , 1.5 (s, 2H) .5 Hz,

[0740] 2H) , 1.71 (d, J = 12.0 Hz, 2H) , 1.40 (t, J = 6.9 Hz, 3H) ,

[0741] 1.32 (t, J = 12.2 Hz, 2H) , 1.19 (t, J = 12.8 Hz, 2H) .

[0742] N- ( ( 6 -ethoxyquinol in-2-yl) methyl) -N- (thiazol -5 -methyl) -1,4- dioxaspiro [4.5 ] decan-8-amine (Compound 15.1, Scheme 15)

[0743] The titrated compound was synthesised according to Process E, starting with 1- ( 6-ethoxyquinolin-2-yl) -N- (thiazol-5- ylmethyl ) methanamine 14.2 (1 eq, 60 mg, 0.2 mmol) dissolved in dry dichloromethane (0. M, 2 mL) , 1,4- dioxaspiro [4, 5] decan-8-one 6.2 (1 eq, 0.2 mmol, 31 mg) , catalytic acetic acid, sodium triacetoxyborohydride (4 eq, 0.8 mmol, 170 mg) , stirring the reaction mixture overnight. Purification by silica gel column chromatography ( cyclohexane / ethyl acetate 80:20 to 50:50) yielded the pure titrated compound as yellow oil in a 49% yield (43 mg) . Characterization: Rt 1.09 min, apolar method, MS (ESI) m / z = 440.3 [M+H]+. Exact mass: 439.1930. NMR (400 MHz, DMSO) 5 8.94 (d, J = 0.8 Hz, 1H) , 8.19 (d, J = 8.5 Hz, 1H) , 7.84 (d, J = 9.1 Hz, 1H) , 7.75 (d, J = 0.1 Hz, 1H) .75 (d, J = 0.9

[0744] Hz, 1H) , 7.59 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.0, 2.8 Hz, 1H) , 7.30 (d, J = 2.7 Hz, 1H) , 4.15 (q, J = 6.5 Hz, 1H) .15 (q, J = 6.9 Hz, 2H) , 3.92 (s, 2H) , 3.86 (s, 2H) , 3.82 (dt, J = 9.7, 4.8 Hz, 4H) , 2.59 (t, J = 11.4 Hz, 1H) , 1.79 (d, J = 12.3 Hz, 2H) , 1.69 (d, J = 12.6 Hz, 2H) , 1.59 (q, J = 13.1 Hz, 2H) , 1.39 (q, J = 6.1 Hz, 5H) .

[0745] 4- ( ( (6-ethoxyquinolin-2-yl) methyl) (thiazol -5 -methyl) amino) cyclohexan-l-one (compound 15.2, Scheme 15)

[0746] The titrated compound was synthesised according to Process P, starting with N- ( ( 6-ethoxyquinolin-2-yl ) methyl ) -N- ( thiazol -5- ylme thy 1 ) -1, 4 -dioxaspiro [4.5] de can- 8 -amine 15.1 (1 eq, 43 mg, 0.098 mmol) in DCM / TFA (4:1, 2 mL) and water (50 pL) , stirring the mixture at room temperature overnight. The compound was obtained pure without purification by column chromatography (quantitative yield, 38 mg, pale yellow oil) . Characterization: Rt 2.07 min, generic method, MS (ESI) m / z = 396.2 [M+H]+. Exact mass: 395.1667. iH NMR (400 MHz, DMSO) 5 8.96 (d, J = 0.8 Hz, 1H) , 8.21 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 9.0 Hz, 1H) , 7.79 (d, J = 0.0 Hz, 1H) .79 (d, J = 0.9 Hz, 1H) , 7.62 (d, J = 8.5 Hz, 1H) , 7.34 (dd, J = 9.0, 2.8

[0747] Hz, 1H) , 7.32 (d, J = 2.7 Hz, 1H) , 4.15 (q, J = 6.9 Hz, 2H) ,

[0748] 3.97 (s, 2H) , 3.92 (s, 2H) , 3.03 (t, J = 11.2 Hz, 1H) , 2.36

[0749] (td, J = 14.0, 5.7 Hz, 2H) .O, 5.7 Hz, 2H) , 2.21 (d, J = 14.4

[0750] Hz, 2H) , 2.06 (bs, 2H) , 1.92 - 1.79 (m, 2H) , 1.40 (t, J =

[0751] 6.9 Hz, 3H) .

[0752] 4- ( ( (6-ethoxyquinolin-2-yl) methyl) (thiazol -5 -methyl) amino) cyclohexan-l-ol (compound 15.3, Scheme 15)

[0753] The compound was synthesised according to Process Q, starting with 4- ( ( ( 6-ethoxyquinolin-2-yl ) methyl ) (thiazol-5- ylmethyl) amino) cyclohexan-l-one 15.2 (1 eq, 0.096 mmol, 38 mg) , sodium borohydride (2 eq, 0.192 mmol, 7 mg) in dry methanol (2 mL) , stirring the mixture for 1 h. Purification by silica gel column chromatography (dichloromethane / methanol 100:0 to 80:20) yielded the pure product in a 63% yield (24 mg) . Characterization: Rt 1.92 min, generic method, MS (ESI) m / z = 398.2 [M+H]+. Exact mass: 397.1824. iH NMR (400 MHz, DMSO) 5 9.00 (d, J = 0.8 Hz, 1H) , 8.24 (d, J = 8.5 Hz, 1H) , 7.89 (d, J = 9.1 Hz, 1H) , 7.80 (d, J = 0.1 Hz, 1H) .80 (d, J = 0.9 Hz, 1H) , 7.64 (d, J = 8.5 Hz, 1H) , 7.39 (dd, J = 9.1, 2.8 Hz, 1H) , 7.35 (d, J = 2.8 Hz, 1H) , 4. (d, J = 4.5 Hz, 1H) .54 (d, J = 4.5 Hz, 1H) , 4.20 (q, J = 7.0 Hz, 2H) , 3.94 (s, 3H) , 3.90 (s, 2H) , 3.42 - 3,36 (signal superimposed on D2O, 1H) , 2.54 - 2.43 (m, 1H) , 1.94 - 1.77 (m, 4H) , 1.51 - 1.28 (m, 5H) , 1.16 - 1.01 (m, 2H) .

[0754] N-cyclohexyl-N- ( (6-fluoroquinolin-2-yl) methyl) -1,2,3- thiadiazole-4 -carboxamide (compound 16.1, Scheme 16)

[0755] The titrated compound was synthesised according to Process

[0756] W, starting with N- ( ( 6-f luoroquinolin-2- yl ) methyl ) cyclohexanamine 1.15 (0.33 mmol, 1.0 eq, 78 mg) ,

[0757] I , 2 , 3-thiadiazole-4-carboxylic acid (1.1 eq, 0.36 mmol, 47 mg) in dry acetonitrile (0.1 M, 3.3 mL) , HATU (1.1 eq, 0.36 mmol, 137 mg) .1 eq, 0.36 mmol, 47 mg) in dry acetonitrile (0.1 M, 3.3 mL) , HATU (1.1 eq, 0.36 mmol, 137 mg) , N, N- diisopropylethylamine (2.0 eq, 0.66 mmol, 115 pL) . Purification by silica gel column chromatography (hexane / i- PrOH 100:0 to 80:20) yielded the product titrated pure as light brown oil in a yield of 66% (80 mg) . Characterization: MS (ESI) m / z = 371,2 [M+H]+. Exact mass: 370.1264. iH NMR

[0758] (400 MHz, DMSO) 5 9.67 (s, 1H) , 8.34 (d, J = 8.6 Hz, 1H) ,

[0759] 8.04 (dd, J = 9.2, 5.4 Hz, 1H) , 7.82 - 7.76 (m, 1H) , 7.67

[0760] (td, J = 9.5, 3.8 Hz, 1H) , 7.60 (d, J = 8.5 Hz, 1H) , 4.99

[0761] (d, J = 9.5 Hz, 1H) .99 (d, J = 9.9 Hz, 2H) , 3.76 (t, J =

[0762] II.8 Hz, 1H) , 1.81 (d, J = 12.1 Hz, 2H) , 1.71 (d, J = 10.6 Hz, 2H) , 1.57 1.43 (m, 2H) , 1.30 (d, J = 12.7 Hz, 1H) ,

[0763] 1.05 (d, J = 12.7 Hz, 3H) .

[0764] N-cyclohexyl-N- ( (6-fluoroquinolin-2-yl) methyl) thiazol-5- carboxamide (compound 16.2, Scheme 16)

[0765] The titrated compound was synthesised according to Process W, starting with N- ( ( 6-f luoroquinolin-2- yl ) methyl ) cyclohexanamine 1.15 (0.33 mmol, 1.0 eq, 78 mg) , thiazolic-5-carboxylic acid (1.1 eq, 0.36 mmol, 46 mg) in dry acetonitrile (0.1 M, 3.3 mL) , HATU (1.1 eq, 0.36 mmol, 137 mg) , N, N-diisopropylethylamine (2.0 eq, 0.66 mmol, 115 pL) . Purification by silica gel column chromatography (hexane / i -PrOH from 100:0 to 80:20) yielded the pure titrated compound as light brown oil in a yield of 45% (55 mg) . Characterization: MS (ESI) m / z = 370.2 [M+H]+. Exact mass: 369.1311. !H NMR (400 MHz, DMSO) 5 9.18 (bs, 1H) , 8.32 (d, J = 8.6 Hz, 1H) , 8.20 (s, 1H) , 8.02 (dd, J = 9.2, 5.4 Hz, 1H) ,

[0766] 7.77 (dd, J = 9.4, 2.9 Hz, 1H) , 7.65 (td, J = 8.9, 2.9 Hz,

[0767] 1H) , 7.52 (d, J = 8.9, 2.9 Hz, 1H) .52 (d, J = 8.6 Hz, 1H) ,

[0768] 4.92 (s, 2H) , 3.30 (signal superimposed on D2 0, 1H) , 1.83 - 1.62 (m, 4H) , 1.52 (d, J = 13.0 Hz, 2H) , 1.22 (d, J = 11.8

[0769] Hz, 2H) , 1.11 - 0.96 (m, 1H) .

[0770] N- ( (6-fluoroquinolin-2-yl) methyl) -N- (thiazol -5 -methyl) cyclohexanamine (compound 16.3, Scheme 16)

[0771] The titrated compound was synthesised according to Process N, starting with N- ( ( 6-f luoroquinolin-2- yl ) methyl ) cyclohexanamine 1.15 (0.33 mmol, 1.0 eq, 85 mg) in dry acetonitrile (0.1 M, 3.3 mL) , 5- ( chloromethyl ) thiazole (1.05 eq, 0.346 mmol) , potassium carbonate (2.5 eq, 0.825 mmol, 114 mg) . Purification by silica gel column chromatography (hexane / f -propanol 100:0 to 90:10) yielded the pure titrated compound as a white crystalline powder in a yield of 60% (70 mg) . Characterization: MS (ESI) m / z = 356.2 [M+H]+. Exact mass: 355.1518. iH NMR (400 MHz, DMSO) 5 8.93 (d, J = 0.8 Hz, 1H) , 8.31 (d, J = 8.7 Hz, 1H) , 8.00 (dd, J = 9.3, 5.4 Hz, 1H) , 7.77 - 7.67 (m, 3H) , 7.62 (td, J = 8.9, 2.9 Hz, 1H) , 3.91 (d, J = 7.9, 2.9 Hz, 1H) .91 (d, J = 7.7 Hz, 4H) , 2.43-2.50 (m, 1H, superimposed on solvent signal) , 1.84 (d, J = 12.2 Hz, 2H) , 1.71 (s, 2H) , 1.54 (s, 1H) , 1.38 - 1.27 (m, 2H) , 1.13 - 1.04 (m, 3H) .

[0772] N- ( (2-chloro-thiazol-5-yl)methyl) -N-( (6-fluoroquinolin-2- yl) methyl) cyclohexanamine (compound 16.4, Scheme 16)

[0773] The titrated compound was synthesised according to Process N, starting with N-( (6-fluoroquinolin-2- yl ) methyl ) cyclohexanamine 1.15b (1.94 mmol, 1.0 eq, 500 mg) in dry acetonitrile (0.1 M, 19.4 mL) , 2-chloro-5- ( chloromethyl ) thiazole (1.05 eq, 2.04 mmol, 348 mg) , potassium carbonate (2.5 eq, 4.85 mmol, 670 mg) . Purification by silica gel column chromatography (hexane / i -PrOH 100:0 to 80:20) yielded the pure compound as a white crystalline powder (600 mg, 80%) . Characterization: MS (ESI) m / z = 390.2, 392.0 [M+H]+. Exact mass: 389.1129. NMR (400 MHz, DMSO) 5 8.33 (d, J = 8.6 Hz, 1H) , 8.00 (dd, J = 9.3, 5.4 Hz, 1H) , 7.74 (dd, J = 9.4, 2.9 Hz, 1H) , 7.67 (d, J = 8.8 Hz, 1H) , 7.65 - 7.59 (m, 1H) , 7.50 (s, 1H) , 3.92 (s, 2H) , 3.50 (s, 1H) .92 (s, 2H) , 3.87 (s, 2H) , 2.53 (1H, signal superimposed on solvent signal) , 1.83 (d, J = 12.1 Hz, 2H) , 1.76 - 1.69 (m, 2H) , 1.54 (s, 1H) , 1.33 (q, J = 11.7 Hz, 2H) , 1.11 (d, J = 17.6 Hz, 3H) .

[0774] N- ( (2- ( (diphenylmethylene) amino) thiazol -5 -yl) methyl) -N-( (6- fluoroquinolin-2-yl) methyl) cyclohexanamine (compound 17.2, Scheme 17)

[0775] To the mixture of N- ( ( 2-chlorothiazol-5-yl ) methyl ) -N- ( ( 6- f luoroquinolin-2-yl ) methyl ) cyclohexanamine 16.4 (250 mg, 0.64 mmol, 1.0 eq) , diphenylmethanamine 17.1 (1.05 eq, 0.672 mmol, 122 mg) and CS2CO3 (1.5 eq, 0.96 mmol, 313 mg) in 1.4- dioxane dry (0.1 M, 6.4 mL) at room temperature in an inert atmosphere, Pd2dba3 (0.12 eq, 0.076 mmol, 70 mg) and XantPhos (0.2 eq, 0.12 mmol, 70 mg) and the reaction mixture was stirred at 95°C overnight. The reaction mixture was evaporated and quenched with a saturated aqueous solution of Na2CO3. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified on silica gel using 100:0 to 60:40 hexane / acetone as an eluent to obtain the compound as an off-white solid in a yield of 37% (125 mg) . Characterisation: LMCS only, MS (ESI) m / z = 535.1 [M+H]+. Exact mass: 534.2253.

[0776] 2- ( ( ( (2-ammonothiazol-5-yl)methyl) (cyclohexyl) ammonium) methyl) -6-fluoroquinolin-l-ium chloride (compound 17.4, Scheme 17)

[0777] To the solution of N- ( (2- ( (diphenylmethylene) amino) thiazol- 5-yl) methyl) -N- ( ( 6-f luoroquinolin-2- yl ) methyl ) cyclohexanamine (145 mg, 0.27 mmol, 1.0 eq) in 1,4-dioxane (0.06 M, 5 mL) concentrated HC1 aq (1 mL) was added and the mixture was stirred at room temperature for 1 h. The solvents were evaporated and the resulting residue was triturated with ether to form a precipitate, which was filtered and washed thoroughly with acetonitrile and ether to obtain the pure titrated compound as a white solid in a 70% yield (90 mg) . Characterization: MS (ESI) m / z = 371,2 [M+H] + . Exact mass: 370.1627. NMR (400 MHz, CD3OD) 5 8.39 (d, J = 8.5 Hz, 1H) , 8.25 (dd, J = 10.2, 5.2 Hz, 1H) , 7.69 (dd, J = 10.6, 5.0 Hz, 2H) , 7.50 (t, J = 4.3 Hz, 2H) , 4.86

[0778] (s, 2H) , 4.73 (s, 2H) , 3.67 (t, J = 12.1 Hz, 1H) , 3.67 (t,

[0779] J = 12.1 Hz, 1H) , 3.5 (s, 2H) .1 Hz, 1H) , 3.49 (q, J = 7.0

[0780] Hz, 1H) , 2.28 (d, J = 11.5 Hz, 2H) , 1.98 (d, J = 13.2 Hz,

[0781] 2H) , 1.75 - 1.64 (m, 3H) , 1.49 (q, J = 13.2 Hz, 2H) , 1.31 (t, J = 13.3 Hz, 1H) , 1.18 (t, J = 7.1 Hz, 1H) .

[0782] N- ( (6-fluoroquinolin-2-yl) methyl) -N- ( (2-methoxythiazol-5- yl ) methyl ) cyclohexanamine (Compound 17.3, Scheme 17)

[0783] To the solution of N- ( ( 2-chloro-thiazol-5-yl ) methyl ) -N- ( ( 6- f luoroquinolin-2-yl ) methyl ) cyclohexanamine 16.4 (165 mg, 0.42 mmol, 1.0 eq) , in dry dimethyl sulfoxide (0.1 M, 4.2 mL) at room temperature, sodium methoxide (3 eq, 0.126 mmol, 170 mg) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was cautiously quenched with water. The mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified on silica gel using hexane / acetone from 90:10 to 60:40 to obtain the compound as a white solid in a yield of 37% (60 mg) . Characterization: MS (ESI) m / z = 386.2 [M+H]+. Exact mass: 385.1624. NMR

[0784] (400 MHz, dmso) 5 8.31 (d, J = 8.6 Hz, 1H) , 8.00 (dd, J = 9.2, 5.4 Hz, 1H) , 7.73 (dd, J = 9.4, 2.9 Hz, 1H) .4, 2.9 Hz,

[0785] 1H) , 7.67 (d, J = 8.5 Hz, 1H) , 7.62 (td, J = 8.9, 2.9 Hz,

[0786] 1H) , 7.00 (s, 1H) , 3.92 (d, J = 0.8 Hz, 3H) , 3.00 (s, 3H) .8

[0787] Hz, 3H) , 3.88 (s, 2H) , 3.72 (s, 2H) , 2.48 (1H, superimposed on solvent signal) , 1.80 (d, J = 12.2 Hz, 2H) , 1.72 (d, J = 10.4 Hz, 2H) , 1.53 (s, 1H) , 1.28 (dd, J = 26.4, 15.1 Hz, 2H) , 1.08 (t, J = 11.2 Hz, 3H) .

[0788] 2- ( (cyclohexyl ( (2-hydroxythiazol-5- yl) methyl) ammonium) methyl) -6-fluoroquinolin-l-ium chloride (compound 17.5, Scheme 17)

[0789] To the solution of N- ( ( 6-fluoroquinolin-2-yl) methyl) -N- ( (2- methoxythiazol-5-yl ) methyl ) cyclohexanamine 17.3 (30 mg, 0.078 mmol, 1.0 eq) in 1,4-dioxane (5 ml) , concentrated aqueous HC1 (0.05 ml) was added and the mixture was stirred at room temperature overnight. The solvents were evaporated and the resulting residue was triturated with ether to obtain a precipitate, which was filtered and washed thoroughly with acetonitrile and ether to obtain the compound as a yellow solid in 64% yield (22 mg) . Characterization: MS (ESI) m / z = 372.1 [M+H]+. Exact mass: 371.1468. iH NMR (400 MHz, DMSO) 5 11.24 (s, 1H) , 8.42 (d, J = 8.5 Hz, 1H) , 8.13 (dd, J = 9.3, 5.4 Hz, 1H) , 7.85 (dd, J = 9.3, 2.9 Hz, 1H) , 7.76 (td, J = 8.8, 2.9 Hz, 1H) , 7.54 (d, J = 8.5 Hz, 1H) , 7.14 - 7.10 (m, 1H) , 4.69 (s, 2H) , 4.41 (s, 2H) , 2.50 (1H superimposed on solvent signal) 2.16 - 2.05 (m, 2H) , 1.83 (d, J = 12.9 Hz, 2H) , 1.57 (d, J = 16.9 Hz, 2H) , 1.37-1.21 (m, 2H) , 1.19

[0790] (t, J = 12.2 Hz, 1H) .

[0791] Biological data

[0792] Fluorescent Cl“ influence assay in HEK cells.

[0793] Culture and transfection of HEK cells. HEK293T cells were cultured and transfected as described in Savardi et al., Chem 2020. Briefly, the cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 1% L-glutamine, 100 U / ml penicillin and 100 pg / ml streptomycin, at 37 °C in a humidified atmosphere of 5% CO2 • To perform the Cl~ influx assay, 3 million HEK293T cells were plated in a 10 cm cell culture dish and transfected with a transfection mixture comprising 5 ml DMEM, 4 ml Opti- MEM, 8 pg mbYFPQS plasmid (Addgene #80742) , 8 pg PRK-NKCC1 plasmid or empty PRK plasmid as mock control and 32 ul of Lipofectamin 2000. After 4 hours, the cells were harvested and plated in 96-well plates with black walls and a transparent bottom at a density of 2.5xl04. After 48 hours, the cells were used for the assay. All the reagents were purchased from Life Technologies, unless stated otherwise.

[0794] Assay for the measurement of Cl“ in HEK cells. The assay was performed as described in protocols in the literature (Savardi et al., Chem 2020; Borgogno et al., J. Med. Chem 2021) . Briefly, the transfected cells were treated with DMSO (as a negative control) or with different concentrations (10 or 50 pM) of the target compound in 200 pl / well of a hypotonic Cl~ free solution (67. 5 mM Na+Gluconate, 2.5mM K+Gluconate, 15mM HEPES pH 7.4 , 5 mM Glucose, ImM Na2HPO4, 1 m NaH2PO4, 1 mM MgSO4, 1 mM CaSO4) and incubated for 30 minutes. Then, the plates were loaded into a Tecan Spark multiplate reader equipped with an automatic liquid injector system and the fluorescence of Cl~sensitive mbYFPQS was measured (excitation 485 nm and emission 535 nm) . For each well, fluorescence was recorded for 20 s baseline and then for 60 s after application of NaCl solution (final concentration of 74 mM in the test well) . The fluorescence of mbYFPQS is inversely correlated with intracellular Cl~ concentration, so the influx of chloride into the cells causes a decrease in mbYFPQS fluorescence. For data analysis, the fluorescence value was normalised for each time point to the average fluorescence value of the first 20 s of the baseline (AF / F0) and the decrease in fluorescence upon application of NaCl was expressed as the average o f the last 10 s of the normalised fluorescence values . In addition, for each plate , to isolate the sole contribution of NKCC1 in Cl~ variations , the last 10 s value of the normalised AF / FO values obtained from mock cells (both control and treated) was subtracted from the respective AF / FO values obtained from NKCC1 - trans fected cells . The percentage of the normalised fluorescence decrease compared to the DMSO control was then calculated, and consequently the percentage of inhibition ( 100 - % of the fluorescence decrease ) .

[0795] The results are shown in Table 1 .

[0796] Table 1

[0797]

Claims

CLAIMS1.- Compound of Formula (I) :(I) or its pharmaceutically acceptable salts, zwitterions, enantiomers, diastereoisomers, geometric isomers, solvates and tautomers in which:Ri is selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -O-Ci-Cealkyl , -O-C4-C10 cycloalkyl optionally substituted with a Ci-Ce alkyl, -O-Ci-Ce haloalkyl, -NH2, -NH-Ci-Ce alkyl, -NH-C4-C10 heterocycloalkyl, -N-di-Ci- C6alkyl, -NHSO2-C1-C6 alkyl, -NHC (=0) Ci-C6alkyl, -NHC (=0) C3- Ce cycloalkyl;R2 is selected from the group consisting of H, OH, halogen, -O-Ci-Ce alkyl optionally substituted with a substituent Rs,R3 is selected from the group consisting of H, C1-C4 alkyl substituted with a substituent R7, phenyl optionally substituted with a substituent RB, monocyclic or bicyclic aromatic Ce-Cio heterocycle having 1 or 2 heteroatoms, C (=0) monocyclic aromatic C5-C10 heterocycle having 1 or 2 heteroatoms ;R4 is selected from the group consisting of H,- linear or branched Ci-Ce alkyl substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl , OH, -O-Ci-Ce alkyl , halogen, COOH;- C3-C6 cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, NH2, -NHC (=0) Ci-Ce alkyl ;- monocyclic or bicyclic C3-C10 heterocycloal kyl comprising 1 or 2 heteroatoms optionally substituted with a substituent selected from the group consisting of linear or branched Ci-Ce alkyl ;- spiro-bonded Ce-Cio heterobicycloalkyl comprising one or two heteroatoms ; o R3 and R4 taken together with the nitrogen to which they are bound form a cycle having the formulawherein Ra, Rb , Rc , Ra, Re and Rf are independently selected from the group consisting of H, halogen, C1-C3 haloalkyl , OH, -C (=0) NH-Rg where Rg is independently selected from the group consisting of- phenyl optionally substituted with a substituent selected from the group consisting of halogen, -0-C1-C6 alkyl, -SO2NH2, -SO2NH-CI-C6alkyl, -SO2N (CI-C6alkyl) 2, CN, C(=O)NH2;- monocyclic or bicyclic aromatic C1-C10 heterocycle; provided that at least one of Ra, Rb, Rc, Rd, Re and Rf is not H;Rs is selected from the group consisting of phenyl fluorophenyl, pyrazine;R7 is selected from the group consisting of C3-C6 cycloalkyl, C4-C6 heterocycloalkyl comprising a heteroatom selected from N and 0, monocyclic or bicyclic aromatic C5- C10 heterocycle having 1 to 4 heteroatoms optionally substituted with at least one substituent R9;Rs is selected from the group consisting of CONH2, CN, halogen, OH, methoxy, CF3, C1-C4 alkyl, NH2;R9 is selected from the group consisting of linear or branched Ci-Ce alkyl, halogen, NH2, OH, -O-C1-C4 alkyl, phenyl ; provided that the compound of formula I is not one of the compounds :2.- Compound according to claim 1, characterised inthat :Ri is selected from the group consisting of C1-C4 al kyl , C1-C4 fluoroalkyl , halogen, -O-C1-C3 alkyl , -O-C1-C3 haloalkyl , -NH2, -NH-C1-C3 alkyl , -N-di-Ci-C3alkyl , -NHSO2- C1-C4 alkyl , -NHC (=0) C1-C3 alkyl , -NHC (=0) C3-C6cycloalkyl ;R2 is selected from the group consisting of H, halogen, -O-C1-C4 alkyl optionally substituted with a substituent Re;R3 is selected from the group consisting of H, C1-C4 alkyl substituted with a substituent R7, phenyl optionally substituted with a substituent RB , monocyclic or bicyclic aromatic Ce-Cio heterocycle having 1 or 2 heteroatoms , C (=0) monocyclic aromatic C5-C6 heterocycle having 1 or 2 heteroatoms ,R4 is selected from the group consisting of H,- linear or branched C1-C4 alkyl substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl , OH, -O-C1-C3 alkyl , halogen, COOH;- C4-C6 cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, NH2, -NHC (=0) C1-C3 alkyl ;- monocyclic or bicyclic C4-C10 heterocycloal kyl comprising a heteroatom and optionally substituted with a linear or branched C1-C4 alkyl ;- spiro-bonded Ce-Cio heterobicycloalkyl comprising one or two heteroatoms ;Rs is selected from the group consisting of phenyl , fluorophenyl , pyrazine ;R7 is selected from the group consisting of monocyclic or bicyclic aromatic C5-C10 heterocycle having 1 to 3 heteroatoms optionally substituted with at least one R9 substituent ;Rs is selected from the group consisting of CONH2 , CN;R9 is selected from the group consisting of halogen, NH2 , OH, -O-C1-C4 alkyl , phenyl .

3. - Compound according to claim 1 , characterised in that :Ri is selected from the group consisting of C1-C4 al kyl , C1-C3 haloalkyl , halogen, -NHSO2-C1-C4 alkyl , -NHC (=0) C1-C3 alkyl , -NHC (=0) C3-C6 cycloalkyl ;R2 is selected from the group consisting of H, -O-C1-C4 alkyl optionally substituted with a substituent Rs;R3 and R4 taken together with the nitrogen to which they are bound form a cycle having the formulawhere Ra, Rb , Rc , Rd, Re and Rf are independently selected from the group consisting of H, halogen, OH, -C (=0) NH-Rgwherein Rg is selected from the group consisting of:- phenyl optionally substituted with a substituent selected from the group consisting of halogen, -0- Ci-C6alkyl, -SO2NH2, -SO2NH-CI-C6alkyl, -SO2N (CI-C6alkyl) 2 , CN, -C(=0)NH2;- monocyclic or bicyclic aromatic -C3-C10 heterocycle; provided that at least one of Ra, Rb, Rc, Rd, Re and Rf is not H;Rs is selected from the group consisting of phenyl, fluorophenyl, pyrazine.4.- Compound according to any one of claims 1 or 2, characterised in that:R7 is selected from the group consisting of oxazole optionally substituted with at least one substituent R9; oxadiazole optionally substituted with at least one substituent R9; quinoline optionally substituted with at least one substituent R9; thiazole optionally substituted with at least one substituent R9; isoxazole optionally substituted with at least one substituent R9.5.- Compound according to any one of claims 1 or 2, characterised in that:R4 is selected from the group consisting of:- linear C1-C4 alkyl substituted with at least one substituent selected from the group consisting of C3- Ce cycloalkyl, OH, -O-C1-C3 alkyl, halogen, COOH;- C4-C6 cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, NH2, -NHC (=0) C1-C3 alkyl;- monocyclic or bicyclic C4-C10 heterocycloalkyl comprising a heteroatom selected between N and 0 optionally substituted with a linear or branched Ci- C4 alkyl;- spiro-bonded C10 heterobicycloalkyl comprising a nitrogen atom.6.- Compound according to any of the preceding claims, characterised in that:Ri is selected from the group consisting of butyl, trifluoromethyl, fluorine, methoxyl, ethoxyl, -0-CF3, NHC(=O)CH3, -NHC (=0) ethyl, -NHC (=0) cyclohexyl , -NHSO2-butyl , N(CH3)2;R2is selected from the group consisting of H, chlorine, ethoxyl, methoxyl optionally substituted with a substituent selected from the group consisting of phenyl, fluorophenyl, pyrazine ;R3 is selected from the group consisting of H, methyl substituted with a substituent R7, phenyl optionally substituted with a substituent RB, benzothiazole, benzoimidazole, benzoxazole, pyridine, pyrimidine, thiazole, thiophene, quinoxaline, quinazoline, 2-benzoxazolinone, 3,4- dihydro-1, 4-benzoxazin-2-one,R4 is selected from the group consisting of methyl substituted with cyclopropyl; ethyl substituted with a substituent selected from the group consisting of OH, COOH, OCH3 and CF3; butyl substituted with a substituent selected from the group consisting of OH, and OCH3; cyclohexyl optionally substituted with a substituent selected from the group consisting of OH, NH2 and -NHC(=O)CH3; cyclopentyl; cyclobutyl; piperidine optionally substituted with a substituent selected from the group consisting of methyl, isopropyl, isobutyl, butyl; tetrahydropyran; tetrahydrofuran; oxetane; pyrrolidine; azepane; 8- azabicyclo [ 3.2.1 ] octane ; 2-azaspiro [ 3.5 ] nonane ; aziridine; azetidine; pyrrolidine; imidazoline; pyrazoline; piperidine; azocane ; or R3 and R4 taken together with the nitrogen to which they are bound form a cycle having formulawhere Ra, Rb, Rc, Rd, Re and Rf are independently selected from the group consisting of H, fluorine, OH, C(=O)NH-Rgwhere Rg is selected in the group consisting of:- phenyl optionally substituted with a substituent selected from the group consisting of fluorine, OCH3, SO2N(CH3)2, CN, -C(=O)NH2;- pyridine;- benzothiazole;- benzoimidazole;- benzoxazole;- pyrimidine;- thiazole;- oxazole;- thiophene;- quinoxaline;- quinazoline; provided that at least one of Ra, Rb, Rc, Rd, Re and Rf is not H;Rs is selected from the group consisting of phenyl, fluorophenyl, pyrazine;R7 is selected from the group consisting of oxazole optionally substituted with at least one substituent R9; 1 , 3 , 4-oxadiazole optionally substituted with at least one substituent R9; 1 , 2 , 4-oxadiazole optionally substituted with at least one substituent R9; quinoline optionally substituted with at least one substituent R9; thiazole optionally substituted with at least one substituent R9;Rs is selected from the group consisting of C(=0)NH2 andCN;R9 is selected from the group consisting of phenyl, fluorine, chlorine, NH2, OH, OCH3. 7.- Compound according to any of the preceding claims selected from the group consisting of:8.- Compound according to any one of claims 1 to 6 for the use as a medicament.9.- Compound according to any one of claims 1 to 6 for the use in the prevention or treatment of a disorder associated with depolarising GABAergic transmission.10.- Compound for the use according to claim 8, characterised in that said disorder associated with depolarising GABAergic transmission is selected from the group consisting of idiopathic autism, Rett syndrome, fragile X syndrome, Asperger syndrome, Di George syndrome, Angelman syndrome, 15qll.2 duplication, tuberous sclerosis complex, Down syndrome, obsessive compulsive disorder, Prader-Willi syndrome, schizophrenia, depressive-like behaviour, attention deficit and hyperactivity disorder, sleep deprivation, polymicrogyria, focal cortical dysplasia, succinic semialdehyde dehydrogenase deficiency, Dravet syndrome, neonatal seizures, temporal lobe epilepsy, traumatic brain injury, spinal cord injury, peripheral nerve injury, neuropathic pain, nicotine withdrawal-induced hyperalgesia, cerebral stroke, diabetic ketoacidosis induced cerebral edema, hydrocephalus, glioma, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, post-traumatic stress disorder and fetal alcohol spectrum disorder (FASD) .11.- Pharmaceutical composition comprising a compoundof formula (I) according to any one of claims 1 to 7 and at least one pharmaceutically acceptable excipient.12.- Method for the prevention or treatment of a disorder associated with depolarising GABAergic transmission comprising the administration of a pharmaceutically acceptable amount of a compound according to any one of claims 1 to 7.13.- Method according to claim 12, characterised in that said disorder associated with depolarising GABAergic transmission is selected from the group consisting of idiopathic autism, Rett syndrome, fragile X syndrome, Asperger syndrome, Di George syndrome, Angelman syndrome, 15qll.2 duplication, tuberous sclerosis complex, Down syndrome, obsessive compulsive disorder, Prader-Willi syndrome, schizophrenia, depressive-like behaviour, attention deficit and hyperactivity disorder, sleep deprivation, polymicrogyria, focal cortical dysplasia, succinic semialdehyde dehydrogenase deficiency, Dravet syndrome, neonatal seizures, temporal lobe epilepsy, traumatic brain injury, spinal cord injury, peripheral nerve injury, neuropathic pain, nicotine withdrawal-induced hyperalgesia, cerebral stroke, diabetic ketoacidosis induced cerebral edema, hydrocephalus, glioma, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, post-traumatic stress disorder and fetal alcohol spectrum disorder (FASD) .

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