IT202400000099A1 - INTRACELLULAR CHLORIDE CONCENTRATION MODULATORS - Google Patents

Description

[0001] "INTRACELLULAR CHLORIDE CONCENTRATION MODULATORS"

[0004] DESCRIPTION

[0005] TECHNICAL FIELD

[0006] The present invention relates to new quinoline derivatives capable of inhibiting the sodium, potassium and chloride cotransporter (NKCC1).

[0007] CONTEXT OF THE INVENTION

[0008] In recent years, a large literature has indicated that inhibitory GABAergic transmission via Cl<? >permeable GABA<A> receptors in many other neurodevelopmental diseases, including Down syndrome, is defective (Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives. Frontiers in Cellular Neurosci 2014, 8, 119.3; Contestabile, A. et al. The GABAergic Hypothesis for Cognitive Disabilities in Down syndrome. Frontiers in Cellular Neurosciences 2017, 11.54). However, the use of inhibitors of common GABA<A> receptors to restore defective GABAergic transmission does not represent a valid therapeutic option. This is due to the high risk of epileptic seizures in patients.

[0009] Brain disorders characterized by altered GABAergic transmission include idiopathic autism, Rett syndrome, Fragile X syndrome, Asperger syndrome, DiGeorge syndrome, Angelman syndrome, 15q11.2 duplication, tuberous sclerosis complex, Down syndrome, obsessive-compulsive disorder, Prader-Willi syndrome, schizophrenia, depressive-like behaviors, 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, and Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, posttraumatic stress disorder, and fetal alcohol spectrum disorder (FASD). The Na<+>, K<+>, Cl<- >cotransporters (NKCC) 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) along with two negatively charged ions (chloride), a neutral balance of transferred charges is achieved within the cell.

[0010] NKCC1 is widely expressed in exocrine glands and the brain; NKCC2 is found in the kidney, where it serves to extract sodium, potassium, and chloride from the urine so that they can be reabsorbed into the blood.

[0011] In neurons, the Cl<- >importer NKCCl and the Cl<- >exporter KCC2 primarily control the intracellular Cl<- >concentration.

[0012] Alterations in the NKCC1/KCC2 expression ratio (due to increased NKCC1 expression and/or decreased KCC2 expression) have been observed in a variety of brain disorders, both in animal models and in humans. These co-transporter alterations lead to pathological depolarizing (versus physiological hyperpolarizing and inhibitory) action of the neurotransmitter β-aminobutyric acid (GABA) through Cl-permeable GABA<A> receptors in mature neurons; targeting NKCC1 with inhibitors therefore results in therapeutic effects for a variety of diseases.

[0013] Inhibition of NKCC1 by the FDA-approved diuretic bumetanide has recently been shown to be a potential therapeutic strategy in several preclinical/clinical studies in neurological diseases. However, bumetanide has poor cerebral penetration and causes unwanted diuresis due to inhibition of NKCC2 in the kidney.

[0014] To overcome these problems, a growing number of studies have reported prodrugs, analogues and novel molecular entities that are more brain-penetrating and/or selective than bumetanide.

[0015] However, these compounds still have several drawbacks and limitations; bumetanide derivatives are a promising first strategy for the design of more brain-penetrant NKCC1 inhibitors. However, available data do not support the hypothesis that all these bumetanide analogues share the same mechanism of action, calling into question their primary target. Furthermore, some of them may also share the same diuretic effect as bumetanide.

[0016] In recent years, several pharmacological approaches have attempted to restore [Cl-]i in brain disorders by indirectly acting on NKCC1 or KCC2 through upstream components of their signaling pathways. For example, the Ste2Op-related proline-alanine-rich kinase (SPAK) inhibitor ZT-1a, inhibitors of fms-like tyrosine kinase 3 (FLT3 inhibitor KW-2499) or glycogen synthase kinase 3 (GSK3 inhibitor BIO, 6-bromoindirubin-3'-oxime), and activators of sirtuin 1 (SIRT1 agonist resveratrol) and the transient receptor potential cation channel subfamily V member 1 (TRPV1 agonist piperine) have further strengthened the concept that pharmacological restoration of the physiological ratio between the NKCC1/KCC2 transporters can be effective. alleviate the symptoms of various brain disorders. However, the tested compounds also acted on pathways involved in the regulation of several other cellular processes, raising numerous tolerability and toxicity concerns.

[0017] Finally, a novel, selective and more blood-brain barrier penetrating NKCC1 inhibitor, ARN23746, has recently been introduced.

[0018] This novel molecular entity belongs to a novel chemical class of 4-amino-3-(alkylsulfamoyl)-benzoic acids. ARN23746 rescued cognitive deficits in a DS mouse model and social/repetitive behaviors in the VPA mouse model of autism, without diuretic effects and without evident toxicity with chronic treatment in adult animals. ARN23746 represents a good example of how novel non-bumetanide-derived molecules can be developed 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 central nervous system drugs.

[0019] Therefore, there is a need for alternative therapeutic approaches for Down syndrome and other brain disorders that restore defective GABAergic transmission through NKCC1 inhibition.

[0020] The aim of the present invention is therefore to provide new compounds capable of inhibiting the sodium, potassium and chloride cotransporter (NKCC1).

[0021] SUMMARY

[0022] This object is achieved by a compound of formula (I) according to claim 1, its uses according to claims 8, 9 and 10 and a pharmaceutical composition thereof according to claim 11.

[0023] BRIEF DESCRIPTION OF THE FIGURES

[0024] The present invention will now be described in detail with reference to the accompanying drawings, in which:

[0025] Figure 1 illustrates the synthesis scheme of compounds 1.11-1.15;

[0026] Figure 2 illustrates the synthesis scheme of compounds 2.10 - 2.13;

[0027] Figure 3 illustrates the synthesis scheme of compounds 3.8-3.10;

[0028] Figure 4 illustrates the synthesis scheme of compounds 4.4 - 4.13;

[0029] Figure 5 illustrates A) the synthesis scheme of compounds 5.32 - 5.49 and 5.54 - 5.60; B) and C) the structural formulas of compounds 5.11-5.31;

[0030] Figure 6 illustrates the synthesis scheme of compound 6.6;

[0031] Figure 7 illustrates the synthesis scheme of compounds 7.1 - 7.4;

[0032] Figure 8 illustrates the synthesis scheme of compound 8.4;

[0033] Figure 9 illustrates the synthesis scheme of compound 9.4;

[0034] Figure 10 illustrates the synthesis scheme of compounds 10.5 and 10.6;

[0035] Figure 11 illustrates the synthesis scheme of compound 11.6;

[0036] Figure 12 illustrates the synthesis scheme of compounds 12.7 - 12.9;

[0037] Figure 13 illustrates the synthesis scheme of compounds 13.11, 13.13 - 13.17, 13.19 - 13.21, 13.23 - 13.25;

[0038] Figure 14 illustrates the synthesis scheme of compounds 14.2, 14.5, 14.6, 14.8, 14.10;

[0039] Figure 15 illustrates the synthesis scheme of compound 15.3;

[0040] Figure 16 illustrates the synthesis scheme of compounds 16.1-16.4;

[0041] Figure 17 illustrates the synthesis scheme of compounds 17.4 and 17.5.

[0042] DESCRIPTION OF FORMS OF IMPLEMENTATION

[0043] In particular, according to a first aspect of the invention, a compound of formula (I) is provided:

[0046]

[0048] or its pharmaceutically acceptable salts, zwitterions, enantiomers, diastereoisomers, geometric isomers, solvates and tautomers.

[0049] In particular:

[0050] R1 ? chosen from the group consisting of H, C<1>-C<6>alkyl; C<1>-C6 haloalkyl; halogen; -0-C1-C6alkyl; -O-C<4>-C<10 >cycloalkyl optionally substituted with a C<1>-C<6 >alkyl; -O-Ci-Ce haloalkyl; -NH<2>; -NH-Ci-Ce alkyl; -NH-C4-C10 heterocycloalkyl; -N-di-C1-C6 alkyl; -NHSO<2>-C<1>-C6 alkyl; -NHC (=0)Ci-Ce alkyl; -NHC(=O)C<3>-C<6 >cycloalkyl;

[0051] R<2 >? selected from the group consisting of H, OH, halogen, -O-C<1>-C<6 >alkyl optionally substituted with an R6 substituent,

[0052] R3 is selected from the group consisting of H, C<1>-C<4>alkyl optionally substituted with an R<7> substituent, phenyl optionally substituted with an Rs substituent, C6-C10 monocyclic or bicyclic aromatic heterocycle having 1 or 2 heteroatoms, preferably independently selected from O, N, and S; -C(=O) C<5>-C<10 >monocyclic aromatic heterocycle having 1 or 2 heteroatoms, preferably independently selected from O, N, and S;

[0053] R<4 >? chosen from the group consisting of H,

[0054] - C<1>-C<6 >linear or branched alkyl optionally substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl, OH, -O-C<1>-C6 alkyl, halogen, COOH;

[0055] - C<3>-C<6 >cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, NH<2>, -NHC(=O) C<1>-C6 alkyl

[0056] - C<3>-C<10 >monocyclic or bicyclic heterocycloalkyl comprising 1 or 2 heteroatoms, preferably independently selected from N, O and S, and optionally substituted with a substituent selected from the group consisting of C<1>-C6 linear or branched alkyl - C<6>-C<10 >spiro-linked heterobicycloalkyl comprising 1 or 2 heteroatoms, preferably independently selected from N, O and S;

[0057] or R<3 >and FU taken together with the nitrogen to which they are bonded form a ring having the formula

[0058]

[0060] where R<a>, Rb, Re, Rd, Re and R<f >are independently selected from the group consisting of H, halogen, C<1>-C<3 >haloalkyl, OH, -C(=0)NH-Rg where Rg is selected from the group consisting of:

[0061] phenyl optionally substituted with a substituent selected from the group consisting of halogen, -O-C1-C6alkyl,

[0062] C<6>alkyl)<2>, CN, C(=O)NH<2>;

[0063] - C<3>-C<10 >monocyclic or bicyclic aromatic heterocycle comprising 1 or 2 heteroatoms, preferably independently selected from N, O and S;

[0064] R<6 >? selected from the group consisting of phenyl, fluorophenyl, pyrazine;

[0065] R<7 >? selected from the group consisting of C<3>-C<6 >cycloalkyl, C<4>-C<6 >heterocycloalkyl comprising one heteroatom selected from N to O, phenyl optionally substituted with at least one Rg substituent, C<5>-C<10 >monocyclic or bicyclic aromatic heterocycle having from 1 to 4 heteroatoms, preferably and independently selected from O, N and S, optionally substituted with at least one R9 substituent;

[0066] Re? selected from the group consisting of C0NH<2>, CN, halogen, OH, methoxy, CF3, C<1>-C<4 >alkyl, NH<2>;

[0067] R9 ? selected from the group consisting of straight or branched C<1>-C<6 >alkyl, halogen, NH<2>, OH, -O-C1-C<4>alkyl, phenyl.

[0068] In one embodiment Ri ? chosen from the group consisting of C<1>-C<4 >alkyl, C<1>-C<4 >fluoroalkyl, halogen, -O-C<1>-C3 alkyl, -O-C<1>-C3 haloalkyl, -NH<2>, -NH-C<1>-C3 alkyl, -N-di-Ci-C3 alkyl, -NHSO<2>-C<1>-C<4 >alkyl, -NHC (=O)C<1>-C3 alkyl, -NHC(=0)C3-C6 cycloalkyl.

[0069] In a further embodiment Ri is selected from the group consisting of butyl, trifluoromethyl, fluoro, methoxyl, ethoxyl, -O-CF<3>, -NHC(=0)CH<3>, -NHC(=0)ethyl, NHC(=0)cyclohexyl, -NHSO<2>-butyl, N(CH<3>)<2>.

[0070] According to one embodiment, R<2 >? selected from the group consisting of H, halogen, -O-C<1>-C<4 >alkyl optionally substituted with an R<6> substituent.

[0071] According to a further embodiment, R<2 >? selected from the group consisting of H, chloro, ethoxy, methoxy optionally substituted with a substituent R<6>, where R<6 >? preferably selected from the group consisting of a substituent selected from the group consisting of phenyl, fluorophenyl, pyrazine.

[0072] In one embodiment, R<3 >? selected from the group consisting of H, C<1>-C<4 >alkyl optionally substituted with an R<7> substituent, phenyl optionally substituted with an Rs substituent, C6-C<1>0 monocyclic or bicyclic aromatic heterocycle having 1 or 2 heteroatoms, preferably independently selected from S, O and N, C(=O)C5-C6 monocyclic aromatic heterocycle having 1 or 2 heteroatoms, preferably independently selected from S and N.

[0073] In one embodiment, R<3 >? selected from the group consisting of H, methyl optionally substituted with an R<7> substituent, phenyl optionally substituted with an R8 substituent, benzothiazole, benzoimidazole, benzoxazole, pyridine, pyrimidine, thiazole, thiophene, quinoxaline, quinazoline, 2-benzoxazolinone, 3,4-dihydro-1,4-benzoxazin-2-one,

[0076]

[0078] In a further embodiment R<3 >? selected from the group consisting of H, methyl optionally substituted with an R<7> substituent, phenyl optionally substituted with an R8 substituent, benzothiazole, benzoimidazole, benzoxazole, pyridine,

[0081]

[0083] In one embodiment, R<4 >? is selected from the group consisting of H,

[0084] - C<1>-C<4 >linear or branched alkyl optionally substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl, OH, -O-C<1>-C3 alkyl, halogen, COOH;

[0085] - C<4>-C<6 >cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, N?, -NHC(=0)C<1>-C<3 >alkyl;

[0086] - C<4>-C<10 >monocyclic or bicyclic heterocycloalkyl comprising a heteroatom, preferably selected from S, O and N, and optionally substituted with a linear or branched C1-C<4 >alkyl;

[0087] - C<6>-C<10 >spiro-linked heterobicycloalkyl comprising 1 or 2 heteroatoms, preferably independently selected from N, O and S.

[0088] In one embodiment, R<4 >? is selected from the group consisting of H

[0089] - C<1>-C<4 >linear alkyl optionally substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl, OH, -O-C<1>-C3 alkyl, halogen, COOH;

[0090] - C<4>-C<6 >cycloalkyl optionally substituted with a substituent selected from the group consisting of OH, N?, -NHC(=O)C<1>-C<3 >alkyl;

[0091] - C<4>-C<10 >monocyclic or bicyclic heterocycloalkyl comprising a heteroatom selected from N to O optionally substituted with a straight or branched C<1>-C<4 >alkyl;

[0092] - C1<0 >spiro-linked heterobicycloalkyl comprising a nitrogen atom.

[0093] In one embodiment, R<4 >? selected from the group consisting of methyl substituted with cyclopropyl; ethyl substituted with a substituent selected from the group consisting of OH, COOH, OCH<3 >, and CF<3>; butyl optionally substituted with a substituent selected from the group consisting of OH, and OCH<3>; cyclohexyl optionally substituted with a substituent selected from the group consisting of OH, NH<2 >, and -NHC(=0)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.

[0094] Preferably R<4 >? selected from the group consisting of methyl substituted with cyclopropyl; ethyl substituted with a substituent selected from the group consisting of OH, COOH, OCH<3 >, and CF<3>; butyl optionally substituted with a substituent selected from the group consisting of OH, and OCH<3>; cyclohexyl optionally substituted with a substituent selected from the group consisting of OH, ??, 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.

[0095] In one embodiment, R<7 >? selected from the group consisting of C3-C6 cycloalkyl, C<4>-C6 heterocycloalkyl comprising a heteroatom selected from N to O; C<5>-C<10 >monocyclic or bicyclic aromatic heterocycle having 1 to 4 heteroatoms optionally substituted with at least one Rg substituent.

[0096] In one embodiment, R<7 >? selected from the group consisting of C<5>-C<10 >monocyclic or bicyclic aromatic heterocycle having 1 to 3 heteroatoms, preferably selected from O, S and N, optionally substituted with at least one Rg substituent.

[0097] In one embodiment, R<7 >? selected from the group consisting of oxazole optionally substituted with at least one Rg substituent; oxadiazole optionally substituted with at least one Rg substituent; quinoline optionally substituted with at least one Rg substituent; thiazole optionally substituted with at least one Rg substituent; isoxazole optionally substituted with at least one Rg substituent.

[0098] In one embodiment, R<7 >? is selected from the group consisting of oxazole optionally substituted with at least one substituent

1,3,4-Oxadiazole optionally substituted with at least one Rg substituent; 1,2,4-Oxadiazole optionally substituted with at least one R9 substituent; quinoline optionally substituted with at least one R9 substituent; thiazole optionally substituted with at least one R9 substituent.

[0099] In one embodiment, R8 is selected from the group consisting of CONH<2>, CN.

[0100] In one embodiment, Rg is selected from the group consisting of halogen, N?, OH, -O-C1-C<4>alkyl, phenyl; preferably Rg is selected from the group consisting of phenyl, fluorine, chlorine, NH2, OH, OCH3.

[0101] In one embodiment, when R<3 >and R<4 >are taken together with the nitrogen to which they are bonded they form a ring having the formula

[0104]

[0106] Ra, Rb, Rc, Rd, Re and R<f >are independently selected from the group consisting of H, fluorine, OH, C(=O)NH-Rg where Rg is selected from the group consisting of:

[0107] phenyl optionally substituted with a substituent selected from the group consisting of fluorine, OCH3, SO<2>N(CH3)<2>, CN, -C(=O)NH<2>;

[0108] pyridine;

[0109] benzothiazole;

[0110] benzoimidazole;

[0111] benzoxazole;

[0112] pyrimidine;

[0113] thiazole;

[0114] oxazole;

[0115] thiophene;

[0116] quinoxaline;

[0117] quinazoline.

[0118] 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)NH<2>; pyridine and benzothiazole.

[0119] In one embodiment, when R<3 >and R<4 >taken together with the nitrogen to which they are bonded form a ring, R<1> is preferably selected from the group consisting of C<1>-C<4 >alkyl, C<1>-C3 haloalkyl, halogen, -NHSO<2>-C<1>-C<4 >alkyl, -NHC(=0)C<1>-C3 alkyl, -NHC(=O)C3-C6 cycloalkyl and R<2 >? selected from the group consisting of H, -O-C<1>-C<4 >alkyl optionally substituted with an R<6> substituent.

[0120] In a preferred embodiment:

[0121] R1 ? F;

[0122] R<2 >? H;

[0123] R<3 >and R<4 >taken together with the nitrogen to which they are bonded form a ring having the formula

[0124]

[0126] where R<a>, Rb, Rc, Rd, Re and R<f >are independently selected from the group consisting of H, fluorine, OH, C(=0)NH-Rg where Rg is selected from the group consisting of phenyl substituted with a substituent selected from the group consisting of OCH<3>, S0<2>N(CH<3>)<2>, CN, -C(=0)NH<2>; pyridine and benzothiazole.

[0127] Alternatively, in a preferred embodiment:

[0128] Ri ? selected from the group consisting of F, ethoxy;

[0129] R<2 >? H;

[0130] R<3 >? selected from the group consisting of benzothiazole, benzothiazole, phenyl substituted with CONH<2>, pyridine, benzoimidazole substituted with CH<3>, -CH<2>-thiazole, -CH<2>-thiazole-NH<2>, -CH<2>-thiazole-OH, and

[0131] R<4 >? selected from the group consisting of cyclohexyl, cyclohexyl substituted with OH, piperidine substituted with CH<3>, tetrahydrofuran, oxetane, ethyl substituted with OH.

[0132] In particular, the compound of formula (I) can be selected from the group consisting of:

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0143] Preferably, the compound of formula (I) can be selected from the group consisting of:

[0144]

[0145]

[0146]

[0148] A second aspect of the present invention relates to a pharmaceutical composition comprising a compound of Formula (I) or its salts, pharmaceutically acceptable zwitterions, enantiomers, diastereoisomers, geometric isomers, solvates and tautomers, and at least one pharmaceutically acceptable excipient. One skilled in the art is familiar with the whole variety of such excipients, such as vehicles and diluents, suitable for formulating a pharmaceutical composition.

[0149] The compounds of Formula (I), together with a conventionally employed adjuvant, vehicle, diluent, or excipient, may be formulated into pharmaceutical compositions and dosage forms thereof, and in such form may be used as solids, e.g., tablets or filled capsules, or liquids, e.g., solutions, suspensions, emulsions, elixirs, or capsules filled therewith, all for oral use, or in the form of sterile injectable solutions for parenteral administration (including subcutaneous and intravenous use). Such pharmaceutical compositions and dosage forms thereof may comprise ingredients in conventional proportions, with or without additional compounds or active ingredients, and such dosage forms may contain any suitable effective amount of the active ingredient proportionate to the dosage range intended to be employed.

[0150] Pharmaceutical compositions containing a compound of this invention may be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0151] The pharmaceutical compositions of the present invention may be administered by a variety of routes, including oral, rectal, subcutaneous, intravenous, intramuscular, intranasal, and pulmonary. Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are presented in unit dosage forms to facilitate precise dosing. The term "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 premeasured, pre-filled vials or syringes for liquid compositions, or pills, tablets, capsules, or the like for solid compositions.

[0152] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, 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, gum tragacanth, gum arabic, corn starch, or gelatin; an excipient such as starch, dicalcium phosphate, or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a slip agent such as colloidal silicon dioxide; a sweetening agent such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0153] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection or other injectable vehicles known in the art.

[0154] Pharmaceutical compositions may be in the form of tablets, pills, capsules, solutions, suspensions, emulsions, powders, suppositories and prolonged-release formulations.

[0155] If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. The amount of active compound in such therapeutically useful compositions is such as to achieve the therapeutically active dosage.

[0156] When a unit dosage form is a capsule, it may contain, in addition to materials of the type above, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. To prevent disintegration during transit through the upper portion of the gastrointestinal tract, the composition may be an enteric-coated formulation.

[0157] A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a colorant, and a flavoring agent such as cherry or orange flavor.

[0158] The active compounds can also be administered intranasally, for example as liquid drops or sprays.

[0159] Compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound of the invention and the powder of a suitable carrier and/or lubricant. Compositions for pulmonary administration may be inhaled by any dry powder inhalation device known to one skilled in the art.

[0160] The administration of the compositions is performed following a protocol and at a dosage sufficient to reduce inflammation and pain in the subject. In some embodiments, in the pharmaceutical compositions of the present invention the active ingredient or ingredients are generally formulated in dosage units.

[0161] In some embodiments, the effective amounts for a specific formulation will depend on the severity of the disease, disorder or condition, prior therapy, individual health status and response to the drug.

[0162] When used in combination with one or more 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 alone. For formulations for any variety of routes of administration, methods and formulations for drug delivery are illustrated in Remington's Pharmaceutical Sciences, 17th edition, ed., 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 Publishers, 2005; and in Loyd V. Alien and Howard C. Ansel, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th edition, Lippincott Williams & Wilkins Publishers, 2014.

[0163] The components described above for orally or injectable compositions are purely representative.

[0164] The compounds of this invention may also be administered in sustained-release forms or by sustained-release drug delivery systems.

[0165] 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.

[0166] A fourth aspect of the present invention relates to compounds of Formula (I) or their pharmaceutically acceptable salts, solvates, or isomers, for use in the prevention or treatment of a disorder associated with depolarizing GABAergic transmission.

[0167] The compounds of formula (I) may in particular be used in the prevention or treatment of a selected disorder in the group consisting of idiopathic autism, Rett syndrome, Fragile X syndrome, Asperger syndrome, DiGeorge syndrome, Angelman syndrome, 15qll.2 duplication, Tuberous sclerosis complex, Down syndrome, obsessive compulsive disorder, Prader-Willi syndrome, schizophrenia, depressive-like behaviors, 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).

[0168] Hereinafter, the present invention will be illustrated by a few examples, which are not intended to be considered limiting of the scope of the invention.

[0169] Examples

[0170] Materials and methods

[0171] All commercially available reagents and solvents were used as purchased from the suppliers without further purification. Dry solvents were purchased from . Automated column chromatographic purifications were performed using a Teledyne ISCO (CombiFlash™ Rf) or Biotage™ Selekt apparatus with prepacked columns of silica gel or basic alumina or reversed-phase C18 silica of various sizes (from 4 g to 120 g) and mixtures of increasing polarity of cyclohexane and ethyl acetate (EtOAc), cyclohexane and tert-butyl methyl ether (TBME), or dichloromethane (DCM) and methanol (MeOH), or acetonitrile (MeCN) and water (H<2>O). 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. Spectra were acquired at 300 K, using deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl<3>) as solvents. For 1H-NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet, 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 a single quadrupole detector (SQD) mass spectrometer equipped with an electrospray ionization interface and a photodiode array detector. The PDA range was 210–400 nm. Analyses were performed on an ACQUITY UPLC BEH C18 column (100x2.1 mmID, particle size 1.7 μm) with a VanGuard BEH C18 pre-column (5x2.1 mmID, particle size 1.7 μm). The mobile phase consisted of 10 mM NH<4>OAc in H<2>O at pH 5 adjusted with CH<3>COOH (A) and 10 mM NH<4>OAc in CH<3>CN-H<2>O (95:5) at pH 5.0. Depending on the analysis, two types of gradients were applied: gradient 1 (from 5% to 100% mobile phase B in 3 minutes), gradient 2 (from 5% to 50% mobile phase B in 3 minutes), or gradient 3 (from 50% to 100% mobile phase B in 3 minutes). Electrospray ionization was applied in positive and negative modes. Electrospray ionization was applied in positive and negative modes. ESI was applied in positive and negative modes. All tested compounds showed purity > 90% by NMR and UPLC/MS analysis.

[0172] General Procedures

[0173] Procedure A

[0174] Al: To a 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 under reflux for 5 h. The mixture was cooled to room temperature and quenched with NaHCO3 solution (pH 8-9). The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered, and evaporated. The crude product was purified on silica gel by column chromatography to yield the desired product.

[0175] A2: To the appropriate aniline solution (1 eq, 2g, 16.24 mmol) in 6M HCl (81 mL, 30 eq) was added a solution of crotonaldehyde (2 eq, 32.48 mmol) in toluene (0.75 M) and the mixture was stirred at 100°C until the reaction was complete. The reaction mixture was cooled to rt and basified with 2N aqueous NaOH to pH 10. The mixture was extracted with ethylene and then extracted with ethylene. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na<2>SO<4>, filtered, and evaporated. Purification by column chromatography afforded the desired product.

[0176] Procedure B

[0177] To a 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 benzoyl peroxide (0.2 eq, 1.24 mmol, 300 mg), and the reaction mixture was stirred at reflux for 1 h and then at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 (pH 8-9), extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified on silica gel by column chromatography to yield the desired product.

[0178] Procedure C

[0179] 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 through a Celite pad and washed with ethyl acetate. The filtrate was washed with saturated aqueous Na<2>CO3 solution to remove any possible presence of the quinoline N-oxide derivative as a reaction side product. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na<2>SO4, filtered, and evaporated. The crude product was It was used as such for the next step or purified on silica gel for column chromatography to obtain the desired product. Procedure D

[0180] To the solution of the appropriate halide derivative (50 mg, 0.21 mmol, 1 eq) in tetrahydrofuran (0.1 M) at room temperature, N,N-diisopropylamine (6 eq) was added followed by the addition of the appropriate amine (2 eq). The reaction mixture was stirred under 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 Na<2>SO4, filtered, and evaporated. The crude was purified on silica gel by column chromatography to afford the desired product.

[0181] Procedure E

[0182] 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 triacetoxyborohydride (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 Na<2>CO3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO4, filtered, and evaporated. If necessary, the crude product was purified by column chromatography to obtain the desired product.

[0183] Procedure F

[0184] To the solution of 2-methylquinoline-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 sulfonyl 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 NaHCO3 solution (pH 8). The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered, and evaporated. The crude product was purified on silica gel by column chromatography to yield the desired product.

[0185] Procedure I

[0186] To the solution of the appropriate hydroxyquinoline (50 mg, 0.28 mmol, 1 eq) in dry N,N-dimethylformamide, 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 hours at room temperature or heated if necessary. The reaction mixture was quenched with saturated NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered, and evaporated. The crude product was purified on silica gel by column chromatography to afford the desired product.

[0187] Procedure K

[0188] K1: To a solution of aniline (0.13 mmol, 1 eq) in dry dichloromethane (0.1 M, 1.3 mL) at room temperature, trimethylaluminum (3 eq, 0.38 mmol) was added. Gas evolution was observed. The mixture was stirred for 15 min. Then the appropriate ester (1 eq, 0.13 mmol) was carefully added, and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was carefully diluted with ethyl acetate and filtered through a Celite pad to remove aluminum salts. The filtrate was washed with aqueous NaHCO<3>. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO<4>, filtered, and evaporated. Purification by column chromatography allowed obtaining the pure product.

[0189] 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 at 60% in mineral oil (8 eq) was added and the mixture refluxed for 30 minutes. Then the ester (1 eq, 0.16 mmol) was added and the mixture refluxed for 30–60 minutes. The reaction mixture was allowed to cool to room temperature and carefully quenched with water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO<4>, filtered, and evaporated. Purification by column chromatography afforded the pure product.

[0190] Procedure L

[0191] To a solution of suitable 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 sulfate 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 saturated aqueous Na<2>CO<3> solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO<4>, filtered, and evaporated. The crude product was was purified on silica gel by column chromatography to obtain the desired product.

[0192] Procedure M

[0193] 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.

[0194] Phenylsilane (3 eq) was then added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was capped with aqueous solution of saturated Na<2>CO<3 >. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered and evaporated. Purification by column chromatography afforded the desired product.

[0195] Procedure N

[0196] To the solution of the appropriate amine (1 eq) in dry acetonitrile (0.1-0.3 M), at room temperature, were added the appropriate alkyl halide (1-1.2 eq) and potassium carbonate (2.5-3 eq); 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 Na<2>SO<4 >, filtered, and evaporated. Purification by column chromatography afforded the desired product.

[0197] Procedure O

[0198] 01: A solution of 14M HCl in dioxane (8 eq.) was added to the protected N-Boc amine solution (230 mg, 0.47 mmol, 1 eq.) in 0.1 M dioxane and the mixture was stirred at room temperature overnight. The solvent was evaporated. Purification by recrystallization or column chromatography, if necessary, afforded the desired product.

[0199] 02: To the solution of the protected N-Boc amine (1 eq) in methanol (0.2 M) was added chlorotrimethylsilane (0.1 ml) and the reaction mixture was stirred at room temperature overnight. Then phenylsilane (3 eq) was added and the reaction mixture was allowed to stir 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.

[0200] Procedure P

[0201] To the solution of the appropriate acetal-protected ketone (1 eq, 230 mg, 0.51 mmol) in 1:4 TFA/DCM (0.1 M, 5.11 mL) was added water (100 μL) and the mixture was stirred at room temperature overnight. The reaction was quenched with a saturated aqueous Na<2>CO<3> solution. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na<2>SO<4>, filtered, and evaporated. The product was used as such for the next step or, if necessary, purified by column chromatography to yield the desired product.

[0202] Procedure Q

[0203] To the solution of the appropriate ketone (1 eq) in methanol/ethanol (0.2M) was added sodium borohydride (1.2 - 6 eq) and the mixture was stirred at room temperature until the starting material disappeared. The reaction mixture was quenched with water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered and evaporated. Purification by column chromatography afforded the desired product.

[0204] Procedure W

[0205] 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 saturated Na<2>CO<3 >aqueous solution. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered, and evaporated. Purification by silica gel column chromatography afforded the pure compound.

[0206] Preparation of compounds 1.4-1.15 (Scheme 1, Figure 1) 6-fluoro-2-methylquinoline (compound 1.4, Scheme 1)

[0207]

[0209] The titrated compound was synthesized according to the previously described procedure A1, starting from 4-fluoroaniline 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) afforded the pure titrated compound as a brownish solid in 40% yield (1758 mg). Characterization: Rt 1.82 min, generic method, MS (ESI) m/z = 162.1 [M+H]<+ >. Exact mass: 161.0641. 1H NMR (400 MHz, DMSO) ? 8.24 (d, J = 8.5 Hz, IH), 7.98 (dd, J = 9.2, 5.5 Hz, IH), 7.73 (dd, J = 9.5, 2.9 Hz, IH), 7.62 (td, J = 8.9, 2.9 Hz, IH), 7.46 (dd, J = 8.4, 0.9 Hz, 1H), 2.65 (s, 3H).

[0210] 2-methyl-6-(trifluoromethyl)quinoline (compound 1.5, scheme 1)

[0213]

[0215] The titrated compound was synthesized according to the previously described procedure A1, starting from 4-trifluoromethylaniline 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) afforded the pure titrated compound as a brownish solid in 39% yield (260 mg). Characterization: Rt 2.16 min, generic method, MS (ESI) m/z = 211.8 [M+H]<+ >. Exact mass: 211.0609. <1>H NMR (400 MHz, DMSO) ? 8.49 - 8.39 (m, 2H), 8.11 (d, J = 8.8 Hz, IH), 7.95 (dd, J = 8.9, 2.2 Hz, IH), 7.58 (d, J = 8.4 Hz, IH), 2.71 (s, 3H).

[0216] 6-Butyl-2-methylquinoline (compound 1.6, scheme 1)

[0219]

[0221] The titrated compound was synthesized according to the previously described procedure A1, starting from 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) afforded the pure titrated compound as a brownish solid in 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. ? NMR (400 MHz, CDC1<3 >) ? 8.00 (d, J = 8.4 Hz, IH), 7.96 (d, J = 9.1 Hz, IH), 7.55 (dq, J = 3.9, 2.0 Hz, 2H), 7.29 (d, J = 3.2 Hz, IH), 2.2 (d, J = 3.2 Hz, IH).2 Hz, IH), 2.83 - 2.78 (m, 2H), 2.75 (s, 3H), 1.72 (tt, J = 9.1, 6.8 Hz, 2H), 1.42 (h, J = 7.4 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H).

[0222] 2-(bromomethyl)-6-fluoroquinoline (compound 1.7, scheme 1)

[0225]

[0227] The titrated compound was synthesized according to procedure B previously described, starting from 6-fluoro-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 benzoyl peroxide (0.2 eq, 1.24 mmol, 300 mg). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 95:05) afforded the titrated pure product in 46% yield (550 mg). Characterization: Rt 2.07 min, generic method, MS (ESI) m/z = 239.8 [M+H]<+ >. Exact mass: 238.9746.). 1H NMR (400 MHz, CDC13_3mm) ? 8.13 (d, J = 8.5 Hz, IH), 8.07 (dd, J = 9.2, 5.3 Hz, IH), 7.59 (dd, J = 8.6, 0.9 Hz, IH).6, 0.9 Hz, IH), 7.50 (ddd, J = 9.3, 8.3, 2.8 Hz, IH), 7.43 (dd, J = 8.7, 2.8 Hz, IH), 4.70 (s, 2H).

[0228] 2-(bromomethyl)-6-(trifluoromethyl)quinoline (compound 1.8, scheme 1)

[0231]

[0233] The titrated compound was synthesized according to procedure B previously described, starting from 6-trifluoromethyl-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 benzoyl peroxide (0.2 eq, 0.17 mmol, 41 mg). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 95:05) afforded the pure titrated product in 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. 1H NMR (400 MHz, CDC1<3>) ? 8.27 (d, J = 8.5 Hz, IH), 8.18 (d, J = 8.9 Hz, IH), 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).

[0234] 6-fluoroquinoline-2-carbaldehyde (compound 1.9, Scheme 1)

[0237]

[0239] The titrated compound was synthesized according to the procedure C described above, starting from 6-fluoro-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 2 h. 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. 1H NMR (400 MHz, DMSO) ? 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).

[0240] 6-Butylquinoline-2-carbaldehyde (compound 1.10, Scheme 1)

[0243]

[0245] The titrated compound was synthesized according to the procedure C described above, starting from 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 2 h. The titrated product was obtained pure without column chromatography purification (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. 1H NMR (400 MHz, CDC1<3>) ? 10.21 (d, J = 0.8 Hz, IH), 8.23 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.5 Hz, IH), 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).

[0246] 2-((3,3-difluoropiperidin-l-yl)methyl)-6-fluoroquinoline (Compound 1.11, Scheme 1)

[0249]

[0251] The titrated compound was synthesized according to procedure D previously described, starting from 2-(bromomethyl)-6-fluoroquinoline 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-difluoropiperidin-1-ium chloride (2 eq, 66 mg). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 60:40) afforded the pure titrated compound as a white solid in 78% yield (46 mg). Characterization: Rt 2.16 min, generic method, MS (ESI) m/z = 281.1 [M+H]<+ >, exact mass: 280.1187. ? NMR (400 MHz, DMSO) ? 8.34 (d, J = 8.5 Hz, IH), 8.03 (dd, J = 9.2, 5.4 Hz, IH), 7.75 (dt, J = 9.5, 2.7 Hz, IH), 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).

[0252] 2-((4,4-difluoropiperidin-l-yl)methyl)-6-fluoroquinoline (Compound 1.12, Scheme 1)

[0255]

[0257] The titrated compound was synthesized according to procedure D described above, starting from 2-(bromomethyl)-6-fluoroquinoline 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-difluoropiperidin-1-ium chloride (2 eq, 66 mg). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 60:40) afforded the pure titrated compound as a white solid in 75% yield (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) ? 8.35 (d, J = 8.5 Hz, IH), 8.04 (dd, J = 9.2, 5.5 Hz, IH), 7.78 (dd, J = 9.4, 2.9 Hz, IH), 7.70 (dd, J = 8.5, 0.9 Hz, IH).5, 0.9 Hz, IH), 7.65 (td, J = 8.9, 2.9 Hz, IH), 3.83 (s, 2H), 2.58 (t, J = 5.7 Hz, 4H), 1.99 (tt, J = 14.1, 5.7 Hz, 4H).

[0258] 1-((6-(trifluoromethyl)quinolin-2-yl)methyl)piperidin-3-ol (compound 1.13, scheme 1)

[0261]

[0263] The titrated compound was synthesized according to procedure D previously described, starting from 2-(bromomethyl)-6-trifluoromethylquinoline 1,8 (50 mg, 0.17 mmol, 1 eq) in THF (0.1 M, 1.7 mL), N,N-diisopropylamine (6 eq, 1.25 mmol, 0.15 mL), and 3,3-difluoropiperidin-l-ium chloride (2 eq, 47 mg). Purification by silica gel column chromatography (ethyl acetate/methanol 95:05) afforded the pure titrated compound as a yellowish oil in 89% yield (48 mg). Characterization: Rt 1.63 min, generic method, MS (ESI) m/z = 311.1 [M+H]<+>. Exact mass: 310.1293. ? NMR (400 MHz, DMSO) ? 8.52 (dd, J = 8.7, 2.2 Hz, IH), 8.47 (s, IH), 8.16 (d, J = 8.8 Hz, IH), 7.96 (dt, J = 8.9, 2.1 Hz, IH).9, 2.1 Hz, IH), 7.77 (dd, J = 8.6, 1.9 Hz, IH), 4.66 (q, J = 5.1 Hz, IH), 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, IH), 2.80 (dd, J = 10.8, 4.0 Hz, IH), 2.65 (d, J = 11.3 Hz, IH), 2.08 - 1.92 (m, IH), 1.91 - 1.73 (m, IH). 91 - 1. 73 (m, 2H) , 1 . 63 (dt, J = 12 . 6, 3 . 9 Hz , IH) , 1 . 45 ( q, J = 12 .2 Hz , IH) , 1 . 14 - 0. 94 (m, IH) .

[0264] 1-((6-butylquinolin-2-yl)methyl)piperidin-3-ol (compound 1.14, scheme 1)

[0267]

[0269] To a solution of 3-hydroxypiperidin-1-ium chloride (39 mg, 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. Gas evolution was observed. The mixture was stirred for 5 min to yield the free amine, which was reacted with 6-butylquinoline-2-carbaldehyde 1.10 (1 eq, 0.23 mmol, 50 mg), acetic acid (10 eq, 2.34 mmol, 0.1 mL), and sodium triacetoxybohydride (4 eq, 0.94 mmol, 199 mg), according to procedure E previously described. Purification by silica gel column chromatography (dichloromethane/methanol 95:05) afforded the compound as a yellow oil in 74% yield (52 mg). Characterization: Rt 2.00 min generic method, MS (ESI) m/z = 299.5 [M+H]<+>. Exact mass: 298.2045. H NMR (400 MHz, DMSO) ? 8.22 (d, J = 8.5 Hz, IH), 7.88 (d, J = 8.6 Hz, IH), 7.70 (d, J = 2.0 Hz, IH), 7.60 - 7. 55 (m, 2H), 7.5 (m, 2H).55 (m, 2H), 4.61 (dd, J = 5.0, 2.2 Hz, IH), 3.75 (d, J = 13.6 Hz, IH), 3.67 (d, J = 13.6 Hz, IH), 3.49 (tt, J = 9.0, 4.5 Hz, IH), 2.5 (tt, J = 9.0, 4.5 Hz, IH).5 Hz, IH), 2.84 - 2.72 (m, 3H), 2.69 - 2.62 (m, IH), 1.97 (td, J = 11.2, 2.8 Hz, IH), 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, IH), 1.38 (s, IH), 1.08 (tdd, J = 12.1, 10.1, 4.2 Hz, IH), 0.91 (t, J = 7.3 Hz, 3H).

[0270] N-((6-fluoroquinolin-2-yl)methyl)cyclohexanamine (compound 1.15, scheme 1)

[0273]

[0275] The titrated compound was synthesized according to the procedure E described above, starting from cyclohexylamine (391 μL, 1.2 eq, 3.43 mmol) in dry dichloromethane (0.2 M, 2.3 mL), 6-fluoroquinoline-2-carbaldehyde 1,9 (1 eq, 2.85 mmol, 500 mg), acetic acid (10 eq, 28.55 mmol, 326 μL), and sodium triacetoxyboride (4 eq, 11.42 mmol, 2.419 g), with stirring for 18 h. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 40:60 to 0:100) afforded the pure titrated compound as a beige solid in 63% yield (472 mg). Characterization: Rt 1.71 min, generic method. MS (ESI) m/z = 259.7 [M+H]<+>. Exact mass: 258.1532. ? NMR (400 MHz, DMSO) ? 8.29 (d, J = 8.5 Hz, IH), 8.01 (dd, J = 9.2, 5.5 Hz, IH), 7.74 (dd, J = 9.4, 2.9 Hz, IH), 7.69-7.59 (m, 2H), 3.98 (s, 2H), 2.44 - 2.34 (m, IH), 1.84 (d, J = 11.7 Hz, 2H), 1.65 (t, J = 6.3 Hz, 2H), 1.53 (s, IH), 1.23 - 0.99 (m, 5H).

[0276] N-(2-methylquinolin-6-yl)acetamide (compound 2.2, scheme 2)

[0279]

[0281] The titrated compound was synthesized according to the previously described procedure F, starting from 2-methylquinoline-6-amine 2.1 (60 mg, 0.38 mmol, 1 eq) in dichloromethane (0.2 M, 1.9 mL), acetyl chloride (30 µL, 1.1 eq, 0.42 mmol), and triethylamine (158 µL, 3 eq, 1.14 mmol), with stirring for 2 h. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 60:40) afforded 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. <1>H NMR (400 MHz, CDC1<3>) ? 8.32 (d, J = 2.4 Hz, IH), 8.00 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 9.0 Hz, IH), 7.53 (dd, J = 9.0, 2.5 Hz, IH), 7.28 (d, J = 1.9 Hz, IH), 2.73 (s, 3H), 2.24 (s, 3H).

[0282] N-(2-methylquinolin-6-yl)propionamide (compound 2.3, scheme 2)

[0285]

[0287] The titrated compound was synthesized according to the previously described procedure F, starting from 2-methylquinoline-6-amine 2.1 (50 mg, 0.32 mmol, 1 eq) in dichloromethane (0.2 M, 1.6 mL), propionyl chloride (30 µL, 1.1 eq, 0.35 mmol), and triethylamine (132 µL, 3 eq, 0.95 mmol), stirred for 18 h. Purification by silica gel column chromatography (dichloromethane/methanol 95:05) afforded 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. <1>H NMR (400 MHz, CDC1<3>) ? 8.33 (d, J = 2.4 Hz, IH), 7.99 (d, J = 8.4 Hz, IH), 7.93 (d, J = 9.0 Hz, IH), 7.58 -7.45 (m, J = 9.0 Hz, IH).58 - 7.45 (m, 2H), 7.29 - 7.22 (m, IH), 2.71 (s, 3H), 2.45 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).

[0288] N-(2-methylquinolin-6-yl)cyclohexanecarboxamide (compound 2.4, Scheme 2)

[0291]

[0293] The titrated compound was synthesized according to the previously described procedure F, starting from 2-methylquinolin-6-amine 2.1 (50 mg, 0.32 mmol, 1 eq) in dichloromethane (0.2 M, 1.6 mL), cyclohexanecarbonyl chloride (47 µL, 1.1 eq, 0.35 mmol), and triethylamine (132 µL, 3 eq, 0.95 mmol), stirring for 18 hours. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 60:40) afforded the pure titrated compound as a white solid in 93% yield (80 mg). Characterization: Rt = 1.96 min, MS (ESI) m/z =

[0294] 267.2

Exact mass: 268.1576. ? NMR (400 MHz, CDC1<3>

[0295] ) ? 8.38 (d, J = 2.4 Hz, IH), 8.00 (d, J = 8.5 Hz, IH), 7.95 (d, J = 9.0 Hz, IH), 7.57 - 7.48 (m, 2H), 7.28 (d, J = 1.0 Hz, IH), 2.73 (s, 3H), 2.31 (tt, J = 11.0 Hz, 2H).31 (tt, J = 11.7, 3.5 Hz, IH), 2.01 (d, J = 12.9 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.77 (d, J = 13.8 Hz, 2H), 1.60 (q, J == 12.5 Hz, 2H), 1.32 (q, J = 12.8 Hz, 4H).

[0296] N-(2-methylquinolin-6-yl)butane-1-sulfonamide (compound 2.5, Scheme 2)

[0299]

[0301] To the solution of 2-methylquinoline-6-amine 2.1 (50 mg, 0.32 mmol, 1 eq) in dry dichloromethane (0.2 M, 1.6 mL) at 0°C, butyl sulfonyl chloride (1.5 eq, 0.47 mmol, 61 μL) and triethylamine (3 eq, 0.95 mmol, 132 μL) were added and the mixture was stirred at room temperature overnight. Then, aqueous 2M NaOH (4.5 eq, 0.72 mL) and methanol (1.3 mL) were added to destroy the bisulfonamide 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 Na<2>SO<4>, filtered, and evaporated. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 70:30) afforded the pure titrated compound as a clear oil in 83% yield (74 mg). Characterization: Rt = 1.79 min, MS (ESI) m/z = 277.1 [M-H]-. Exact mass: 278.1089. H NMR (400 MHz, CDC1<3>) ? 8.00 (dd, J = 8.7, 2.1 Hz, 2H), 7.67 (d, J = 2.5 Hz, IH), 7.46 (dd, J = 9.0, 2.5 Hz, IH), 7.30 (d, J = 8.5 Hz, IH), 6.5 (d, J = 8.5 Hz, IH).5 Hz, IH), 6.92 (s, IH), 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).

[0302] N-(2-formylquinolin-6-yl)acetamide (compound 2.6, scheme 2)

[0305]

[0307] The titrated compound was synthesized according to the procedure C described above, starting from 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 2 h. 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. H NMR (400 MHz, CDC1<3>) ? 10.19 (d, J = 0.9 Hz, IH), 8.45 (s, IH), 8.26 (d, J = 8.5 Hz, IH), 8.19 (d, J = 9.0 Hz, IH), 8.02 (d, J 8.5 Hz, IH) , 7.65 (dd, J 9.1, 2.4 Hz, IH) , 7.45 (s, IH), 2.29 (s, 3H).

[0308] N-(2-formylquinolin-6-yl)propionamide (compound 2.7, scheme 2)

[0311]

[0313] The titrated compound was synthesized according to the procedure C described above, starting from N-(2-methylquinolin-6-yl)propionamide 2,3 (65 mg, 0.30 mmol, 1 eq) in dry 1,4-dioxane (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 2 h. 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. H NMR (400 MHz, CDC13 3 mm) ? 10.19 (s, IH) , 8.48 (d, J = 2.3 Hz, IH) , 8.25 (d, J = 8.5 Hz, IH) 8.18 (d, J = 9.1 Hz, IH), 8.01 (d, J = 8.1 Hz, IH).01 (d, J 8.4 Hz, IH) , 7.66 (dd, J = 9.1, 2.4 Hz, IH), 7.45 (s, IH) 2.48 (dq, J = 14.8, 7.5 Hz, 3H), 1.31 (t, J = 7.5 Hz, 3H). N-(2-formylquinolin-6-yl)cyclohexanecarboxamide (compound 2.8, Scheme 2)

[0316]

[0317] The titrated compound was synthesized according to the procedure C described above, starting from 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 2 h. 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, CDC1<3>) ? 10.21 (d, J = 0.9 Hz, IH), 8.53 (d, J = 2.4 Hz, IH), 8.26 (d, J = 8.3 Hz, IH), 8.20 (d, J = 9.1 Hz, IH), 8.02 (d, J = 8.5 Hz, IH), 7.68 (dd, J = 9.1, 2.4 Hz, IH), 7.56 - 7.47 (m, IH), 2.35 (tt, J = 11.7, 3.5 Hz, IH), 2.04 (d, J = 13.0 Hz, 2H), 1.95 - 1.86 (m, 3H), 1.76 (d, J = 9.7 Hz, IH), 1.72-1.58 (m, IH), 1.44 - 1.24 (m, 3H).

[0318] N-(2-formylquinolin-6-yl)butane-l-sulfonamide (compound 2.9, scheme 2)

[0321]

[0323] The titrated compound was synthesized according to the procedure C described above, starting from N-(2-methylquinolin-6-yl)butane-1-sulfonamide 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 2 h. 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. ? NMR (400 MHz, CDCl<3>_3mm) ? 10.20 (d, J =:0.9 Hz, IH), 8.24 (dd, J = 8.8, 6.0 Hz, 2H), 8.04 (d, J = 8.5 Hz, IH), 7.75 (d, J = 2.6 Hz, IH), 7.58 (dd, J = 9.6 Hz, IH).58 (dd, J = 9.1, 2.5 Hz, IH), 6.97 (s, IH), 3.27 - 3.19 (m, 2H), 1.92 - 1.80 (m, 2H), 1.44 (h, J = 7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H).

[0324] N-(2-((3-hydroxypiperidin-l-yl)methyl)quinolin-6-yl)acetamide (Compound 2.10, Scheme 2)

[0327]

[0329] To a solution of 3-hydroxypiperidin-1-ium chloride (31 mg, 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. Gas evolution was observed. The mixture was stirred for 5 min to yield 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 triacetoxyboride (4 eq, 0.75 mmol, 158 mg), according to procedure E previously described. Purification by silica gel column chromatography (ethyl acetate/methanol 95:05) yielded the compound as a white, foamy solid in 85% yield (48 mg). Characterization: Rt 0.87 min generic method, MS (ESI) m/z = 300.1 [M+H]<+>. Exact mass: 299.1634. ? NMR (400 MHz, DMSO) ? 10.24 (s, IH), 8.32 (d, J = 2.3 Hz, IH), 8.22 (d, J = 8.5 Hz, IH), 7.90 (d, J = 9.0 Hz, IH), 7.74 (dd, J = 9.0 Hz, IH).74 (dd, J = 9.1, 2.4 Hz, IH), 7.55 (d, J= 8.5 Hz, IH), 4.59 (s, IH), 3.74 (d, J = 13.6 Hz, IH), 3.66 (d, J = 13.6 Hz, IH), 3.66 (d, J = 13.6 Hz, IH).6 Hz, IH), 3.48 (dt, J = 9.5, 4.7 Hz, IH), 2.80 (dd, J = 10.5, 4.0 Hz, IH), 2.71 - 2.61 (m, IH), 2.12 (s, 3H), 2.03 - 1.93 (m, IH), 3H (s, IH).93 (m, IH), 1.87 - 1.77 (m, 2H), 1.63 (dt, J = 13.4, 3.6 Hz, IH), 1.45 (q, J = 12.3 Hz, IH), 1.13 - 1.03 (m, IH). N-(2-((3-hydroxypiperidin-l-yl)methyl)quinolin-6-yl)propionamide (compound 2.11, scheme 2)

[0332]

[0334] To a solution of 3-hydroxypiperidin-1-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. Gas evolution was observed. The mixture was stirred for 5 minutes to yield 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 triacetoxyboride (4 eq, 0.70 mmol, 149 mg) according to procedure F previously described. Purification by silica gel column chromatography (dichloromethane/methanol 100:0 to 90:10) afforded the compound as a white solid in 58% yield (32 mg). Characterization: Rt 1.16 min, generic method, MS (ESI) m/z = 312.1 [M+H]<+>. Exact mass: Exact mass: 313.1790. <!>H NMR (400 MHz, DMSO) ? 10.18 (s, IH), 8.34 (d, J = 2.3 Hz, IH), 8.21 (d, J = 8.5 Hz, IH), 7.89 (d, J = 9.0 Hz, IH), 7.75 (dd, J = 9.0 Hz, IH).75 (dd, J = 9.1, 2.4 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 4.62 (d, J = 4.9 Hz, IH), 3.74 (d, J = 13.6 Hz, IH), 3.65 (d, J = 13.6 Hz, IH), 3.65 (d, J = 13.6 Hz, IH).6 Hz, IH), 3.53 - 3.43 (m, IH), 2.80 (d, J = 10.4 Hz, IH), 2.66 (d, J = 11.1 Hz, IH), 2.39 (q, J = 7.5 Hz, 2H), 2.02 - 1.92 (m, J = 4.9 Hz, IH).02 - 1.92 (m, IH), 1.82 (t, J = 9.8 Hz, 2H), 1.70 - 1.57 (m, IH), 1.45 (q, J = 12.2 Hz, IH), 1.12 (t, J = 7.5 Hz, 4H).

[0335] N-(2-((3-hydroxypiperidin-l-yl)methyl)quinolin-6-yl)cyclohexanecarboxamide (compound 2.12, scheme 2)

[0338]

[0340] To a solution of 3-hydroxypiperidin-1-ium chloride (41 mg, 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. Gas evolution was observed. The mixture was stirred for 5 minutes 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 triacetoxyboride (4 eq, 0.99 mmol, 210 mg), according to procedure E previously described. Purification by silica gel column chromatography (dichloromethane/methanol 100:0 to 95:05) afforded the compound as a white solid in 46% yield (42 mg). Characterization: Rt 1.69 min, generic method, MS (ESI) m/z = 368.1 [M+H]<+>. Exact mass: 367.2260. ? NMR (400 MHz, DMSO) ? 10.11 (s, IH), 8.36 (d, J = 2.3 Hz, IH), 8.20 (d, J = 8.5 Hz, IH), 7.88 (d, J = 9.0 Hz, IH), 7.76 (dd, J = 9.0 Hz, IH).1, 2.4 Hz, IH), 7.55 (d, J = 8.5 Hz, IH), 4.61 (d, J = 4.9 Hz, IH), 3.74 (d, J = 13.6 Hz, IH), 3.65 (d, J = 13.6 Hz, IH), 3.54 - 3.42 (m, IH), 3.5 - 3.5 (m, IH).42 (m, IH), 2.80 (dd, J = 10.7, 4.0 Hz, IH), 2.66 (d, J = 11.0 Hz, OH), 2.40 (tt, J = 11.6, 3.5 Hz, IH), 2.01 - 1.92 (m, IH), 1.88 - 1.73 (m, IH).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, IH).

[0341] N-(2-((3-hydroxypiperidin-l-yl)methyl)quinolin-6-yl)butane-1-sulfonamide (compound 2.13, scheme 2)

[0344]

[0345] To a solution of 3-hydroxypiperidin-1-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. Gas evolution was observed. The mixture was stirred for 5 min to afford the free amine, which was reacted with N-(2-formylquinolin-6-yl)butane-1-sulfonamide 2,9 (1 eq, 0.24 mmol, 70 mg), acetic acid (10 eq, 2.39 mmol, 0.14 mL), and sodium triacetoxyboride (4 eq, 0.96 mmol, 203 mg), according to procedure E previously described. Purification by silica gel column chromatography (dichloromethane/methanol 100:0 to 90:10) afforded the compound as a white solid in 57% yield (52 mg). Characterization: Rt 1.47 min, generic method, MS (ESI) m/z = 378.9 [M+H]<+>. Exact mass: 377.1773. ? NMR (400 MHz, DMSO) ? 8.24 (d, J = 8.5 Hz, IH), 7.92 (d, J = 9.0 Hz, IH), 7.67 (s, IH), 7.57 (d, J = 8.5 Hz, IH), 4.60 (d, J = 5.5 Hz, IH).60 (d, J = 5.0 Hz, IH), 3.74 (d, J = 13.6 Hz, IH), 3.66 (d, J = 13.7 Hz, IH), 3.23 - 3.11 (m, 2H), 2.80 (d, J = 10.5 Hz, IH), 2.80 (d, J = 10.5 Hz, IH).5 Hz, IH), 2.69 - 2.66 (m, IH), 1.97 (t, J = 9.4 Hz, IH), 1.83 (t, J = 9.8 Hz, IH), 1.65 (td, J = 14.5, 6.5 Hz, 3H), 1.53 - 1.38 (m, IH), 1.33 (dt, J = 14.4, 7.2 Hz, 2H), 1.09 (d, J = 10.7 Hz, IH), 0.81 (t, J = 7.4 Hz, 3H).

[0346] 6-fluoro-2-methylquinolin-4-ol (compound 3.1, scheme 3)

[0347]

[0349] 4-Fluoroaniline 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 µL, 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 min. 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 the eluent to afford the compound as a white solid in 51% yield. (3295 mg). Characterization: Rt 1.08 min, generic method, MS (ESI) m/z = 177.8 [M+H]<+>. Exact mass: 177.0590. <!>H NMR (400 MHz, DMSO) ? 7.68 (dd, J = 9.4, 2.9 Hz, IH), 7.62 - 7.48 (m, 2H), 5.94 (s, IH), 2.35 ( , 3H 4-(benzyloxy)-6-fluoro-2-methylquinoline (compound 3.2, scheme 3)

[0352]

[0354] The titrated compound was synthesized according to Procedure I described above, starting from 4-fluoro2-hydroxyquinoline 3.1 (50 mg, 0.28 mmol, 1 eq), potassium carbonate (2 eq, 0.56 mmol, 79 mg), and benzyl bromide (1.2 eq, 0.34 mmol, 40 µL) in dry N,N-dimethylformamide (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) afforded the compound as a white solid in 85% yield (65 mg). Characterization: Rt 2.39 min, generic method. MS (ESI) m/z = 268.0 [M+H]<+>. Exact mass: 267.1059. ? NMR (400 MHz, CDC1<3>) ? 7.94 (dd, J = 9.2, 5.2 Hz, IH), 7.79 (dd, J = 9.5, 2.9 Hz, IH), 7.49 (ddd, J = 10.1 7.8, 1.6 Hz, 3H), 7.46 - 7.36 (m, 3H), 6.72 (s, IH), 5.26 (s, 2H), 2.68 (s, 3H).

[0355] 6-fluoro-4-((4-fluorobenzyl)oxy)-2-methylquinoline (compound 3.3, scheme 3)

[0358]

[0360] The titrated compound was synthesized according to Procedure I previously described, starting from 4-fluoro-2-hydroxyquinoline 3.1 (60 mg, 1 eq, 0.34 mmol) in dry N,N-dimethylformamide (0.3 M, 1.1 mL), potassium carbonate (2 eq, 0.68 mmol, 94 mg), and 4-fluorobenzylbromide (1.2 eq, 0.41 mmol, 51 µL). The reaction mixture was stirred at room temperature for 20 hours. Purification by silica gel column chromatography (cyclohexane/ethyl acetate from 90:10 to 60:40) afforded the compound as a gray solid in 88% yield (85 mg). Characterization: Rt 2.44 min, generic method. MS (ESI) m/z = 285.6, 287.0 [M+H]<+>. Exact mass: 285.0965. ? NMR (400 MHz, CDC13_3mm) ? 7.96 (dd, J = 9.2, 5.2 Hz, IH), 7.77 (dd, J = 9.4, 2.9 Hz, IH), 7.53 - 7.40 (m, 3H), 7.21 -7.10 (m, 2H), 5.24 (s, 2H), 2.70 (s, 3H).

[0361] Pyrazine-2-methyl methanesulfonate (compound 3.4a, Scheme 3)

[0364]

[0366] To the solution of pyrazin-2-ylmethanol (100 mg, 0.91 mmol, 1 eq) in dry dichloromethane (1M, 0.9 mL) at 0°C, methanesulfonyl chloride (1.8 eq, 1.63 mmol, 126 µL) and triethylamine (1.8 eq, 1.63 mmol, 227 µL) 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.

[0367] 6-fluoro-2-methyl-4-(pyrazine-2-methoxy)quinoline (compound 3.4, Scheme 3)

[0370]

[0372] The titrated compound was synthesized according to procedure I described above, starting from 4-fluoro-2-hydroxyquinoline 3.1 (50 mg, 1 eq, 0.28 mmol) in dry N,N-dimethylformamide (0.15 M, 1.9 mL), potassium carbonate (3 eq, 0.85 mmol, 117 mg), and pyrazin-2-methyl methanesulfonate 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 methanesulfonate 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 was stirred at room temperature for 20 h, then heated to 70?C for 5 h. Purification by silica gel column chromatography (100:0 to 90:10 dichloromethane/methanol) afforded the compound as a white solid in 43% yield (33 mg). Characterization: Rt 1.74 min, generic method. MS (ESI) m/z = 270.0 [M+H]<+>. Exact mass: 269.0964. H NMR (400 MHz, DMSO) ? 9.00 (d, J = 1.5 Hz, IH), 8.72 (dd, J = 2.6, 1.5 Hz, IH), 8.70 (d, J = 2.5 Hz, IH), 7.94 (dd, J = 9.2, 5.4 Hz, IH).2, 5.4 Hz, IH), 7.82 (dd, J = 9.7, 2.9 Hz, IH), 7.62 (td, J = 8.8, 3.0 Hz, IH), 7.18 (s, IH), 5.55 (s, 2H), 2.61 (s, 3H).

[0373] 4-(benzyloxy)-6-fluoroquinoline-2-carbaldehyde (compound 3.5, Scheme 3)

[0376]

[0378] The titrated compound was synthesized according to the procedure C described above, starting from 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 2 h. 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. ? NMR (400 MHz, CDC1<3>) ? 10.13 (s, IH), 8.20 (dd, J = 9.2, 5.3 Hz, IH), 7.90 (dd, J = 9.3, 2.9 Hz, IH), 7.56 (ddd, J = 9.3, 8.0, 2.9 Hz, IH), 7.53 - 7.38 (m, 6H), 5.36 (s, 2H).

[0379] 6-fluoro-4-((4-fluorobenzyl)oxy)quinoline-2-carbaldehyde (compound 3.6, scheme 3)

[0382]

[0384] The titrated compound was synthesized according to the procedure C described above, starting from 6-fluoro-4-((4-fluorobenzyl)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. ? NMR (400 MHz, CDC133mm) ? 10.15 (s, IH), 8.22 (dd, J = 9.2, 5.3 Hz, IH), 7.89 (dd, J = 9.2, 2.9 Hz, IH), 7.64 - 7.52 (m, 2H), 7.52 (s, IH), 7.22 - 7.12 (m, 2H), 5.35 (s, 2H).

[0385] 6-fluoro-4-(pyrazin-2-ylmethoxy)quinoline-2-carbaldehyde (compound 3.7, Scheme 3)

[0388]

[0390] The titrated compound was synthesized according to the procedure C described above, starting from 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) afforded the titrated pure compound in a 29% yield (13 mg). Characterization: Rt 1.84 min, MS (ESI) m/z = 283.9 [M+H]<+>. Exact mass: 283.0757. H NMR (400 MHz, CDC1<3>) ? 10.16 (s, IH), 8.92 (d, J = 1.5 Hz, IH), 8.71 - 8.64 (m, 2H), 8.25 (dd, J = 9.2, 5.3 Hz, IH), 7.94 (dd, J = 9.2, 2.9 Hz, IH), 7.62 (ddd, J = 9.2, 8.0, 2.9 Hz, 1H), 7.55 (s, IH), 5.57 (s, 2H).

[0391] 1-((4-(benzyloxy)-6-fluoroquinolin-2-yl)methyl)piperidin-3-ol (compound 3.8, scheme 3)

[0392]

[0394] To a solution of 3-hydroxypiperidin-1-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. Gas evolution was observed. The mixture was stirred for 5 min to afford the free amine, which was reacted with 4-(benzyloxy)-6-fluoroquinoline-2-carbaldehyde 3.5 (1 eq, 0.23 mmol, 65 mg), acetic acid (10 eq, 2.31 mmol, 0.13 mL), and sodium triacetoxybohydride (4 eq, 0.92 mmol, 196 mg), according to Procedure E previously described. Purification by silica gel column chromatography (dichloromethane/methanol 100:0 to 90:10) afforded the compound as a white solid in 57% yield (49 mg). Characterization: Rt 2.05 min, generic method, MS (ESI) m/z = 367.0 [M+H]<+>. Exact mass: 366.1744. H NMR (400 MHz, DMSO) ? 7.97 (dd, J = 9.2, 5.3 Hz, IH), 7.76 (dd, J = 9.6, 2.9 Hz, IH), 7.63 (td, J = 8.8, 3.0 Hz, IH), 7.60 - 7.55 (m, J = 8.0 Hz, IH).60 - 7.55 (m, 2H), 7.48 - 7.42 (m, 2H), 7.41 - 7.35 (m, IH), 7.25 (s, IH), 5.41 (s, 2H), 4.61 (s, IH), 3.74 - 3.60 (m, 2H), 7.60 (td, J = 9.8, 3.0 Hz, IH).60 (m, 2H), 3.50 (bs, IH, superimposed on the signal of solvent), 2.78 (dd, J 10.4, 3.9 Hz, IH), 2.60 (d, J 11.2 Hz, IH), 2.02 - 1.90 (m, IH), 1.90 - 1.74 (m, 2H), 1.62 (dd, J = 13.4, 3.9 Hz, IH), 1.43 (q, J = 11.8 Hz, IH), 1.09 (qd, J = 12.1, 4.0 Hz, IH).

[0395] 1-((6-fluoro-4- ((4-fluorobenzyl)oxy)quinolin-2-yl)methyl) piperidin-3-ol (compound 3.9, scheme 3)

[0398]

[0400] To a 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 µL) was added. Gas evolution was observed. The mixture was stirred for 5 min to yield the free amine, which was reacted with 6-fluoro-4-((4-fluorobenzyl)oxy)quinoline-2-carbaldehyde 3,6 (1 eq, 0.25 mmol, 75 mg), acetic acid (10 eq, 2.51 mmol, 143 µL), and sodium triacetoxyboride (4 eq, 1 mmol, 212 mg) according to procedure E previously described. Purification by silica gel column chromatography (dichloromethane/methanol 95:05) afforded the compound as a pale yellow solid in 58% yield (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. <1>H NMR (400 MHz, DMSO) ? 7.96 (dd, J = 9.2, 5.3 Hz, IH), 7.74 (dd, J = 9.6, 2.9 Hz, IH), 7.61 (dddd, J = 10.3, 7.0, 4.9 Hz, IH).3, 7.0, 4.1, 2.2 Hz, 3H), 7.30 - 7.20 (m, 3H), 5.38 (s, 2H), 4.69 (s, IH), 3.72 - 3.60 (m, 2H), 2.7 (dd, J = 10.6, 2.9 Hz, IH), 2.7 (dd, J = 10.3 Hz, 2H).77 (dd, J = 10.7, 4.0 Hz, IH), 2.58 (d, J = 11.1 Hz, IH), 1.96 (td, J = 11.1, 2.8 Hz, IH), 1.91 - 1.82 (m, IH), 1.82 - 1.74 (m, IH), 1.61 (dt, J = 13.1, 3.8 Hz, IH), 1.43 (qd, J = 12.3, 7.5 Hz, IH), 1.16 - 1.03 (m, IH).

[0401] 1-((6-fluoro-4-(pyrazin-2-ylmethoxy)quinolin-2-yl)methyl)piperidin-3-ol (compound 3.10, scheme 3)

[0404]

[0406] To a 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 µL) was added. Gas evolution was observed. The mixture was stirred for 5 min to obtain the free amine, which was reacted with 6-fluoro-4-(pyrazin-2-ylmethoxy)quinolin-2-carbaldehyde 3,7 (1 eq, 0.04 mmol, 12 mg), acetic acid (10 eq, 0.42 mmol, 24 µL), and sodium triacetoxyborohydride (4 eq, 0.17 mmol, 36 mg) according to Procedure E previously described. Purification by silica gel column chromatography (dichloromethane/methanol from 100:0 to 90:10) yielded the compound as a white solid in 63% yield (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) ? 8.97 (d, J = 1.5 Hz, IH), 8.74 - 8.66 (m, 2H), 7.99 (dd, J = 9.2, 5.3 Hz, IH), 7.85 (dd, J = 9.6, 3.0 Hz, IH), 7.65 (td, J = 8.8, 3.0 Hz, IH), 7.26 (s, IH), 5.58 (s, 2H), 4.61 (d, J = 5.1 Hz, IH), 3.76- 3.57 (m, 3H).76- 3.57 (m, 2H), 3.54 - 3.47 (m, IH), 2.76 (d, J = 10.5 Hz, IH), 2.57 (s, IH), 1.96 (t, J = 11.6 Hz, IH), 1.82 (dt, J = 19.5 Hz, IH).82 (dt, J = 19.3, 10.5 Hz, 2H), 1.61 (d, J = 12.9 Hz, IH), 1.41 (d, J = 12.6 Hz, IH), 1.13 - 1.03 (m, IH).

[0407] 2-(Ethoxycarbonyl)piperidin-l-ium chloride (compound 4.2, scheme 4)

[0410]

[0412] Thionyl chloride (1.2 eq, 9.3 mmol, 0.67 mL) was added to a solution of pipecolinic acid 4.1 (1 g, 7.74 mmol, 1 eq) in absolute ethanol (0.5 M, 16 mL). 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. H NMR (400 MHz, DMSO) ? 9.50 (s, IH), 4.23 (q, J = 7.1 Hz, 2H), 4.06 (d, J = 10.9 Hz, IH), 3.24 (d, J = 12.7 Hz, IH), 2.89 (t, J = 11.5 Hz, IH), 2.12 - 2.01 (m, IH), 1.80 - 1.46 (m, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0413] ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate (compound 4.3, Scheme 4)

[0416]

[0418] To a solution of 2-(ethoxycarbonyl)piperidin-1-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. Gas evolution was observed. The mixture was stirred for 5 minutes to obtain the free amine, which was was reacted with 6-fluoroquinolin-2-carbaldehyde 1,9 (1 eq, 3.65 mmol, 640 mg), acetic acid (10 eq, 36.54 mmol, 2.09 mL), and sodium triacetoxybohydride (4 eq, 14.62 mmol, 3.097 g), stirring overnight according to procedure E previously described. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 95:05) afforded the product as a yellow solid in quantitative yield (1.215 g).

[0419] Characterization: Rt 2.43 min, generic method. MS (ESI) m/z = 317.1 [M+H. Exact mass: 316.1587. H NMR (400 MHz, CDC1<3 >) ? 8.09 - 8.01 (m, 2H), 7.78 (dd, J = 8.5 0.9 Hz, IH), 7.47 - 7.36 (m, 2H), 4.20 (qd, J = 7.5, 0.9 Hz IH).20 (qd, J = 7.1, 1.7 Hz, 2H), 4.06 (d, J = 14.1 Hz, IH), 3.69 (d, J = 14.1 Hz, IH), 3.26 (dd, J = 8.3 4.0 Hz, IH).3, 4.0 Hz, IH), 2.94 (dt, J = 11.6, 4.8 Hz, IH) 2.27 (dt J = 12.0, 6.2 Hz, 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).

[0420] 1-((6-fluoroquinolin-2-yl)methyl)-N-phenylpiperidin-2-carboxamide (compound 4.4, scheme 4)

[0423]

[0425] The titrated compound was synthesized according to the K1 procedure, starting from ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4.3 (40 mg, 0.13 mmol, 1 eq), aniline (1 eq, 0.13 mmol, 11 μL), and 2M trimethylaluminum 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) afforded 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) ? 9.95 (s, IH), 8.35 (d, J = 8.5 Hz, IH), 8.02 (dd, J = 9.3, 5.4 Hz, IH), 7.84 (d, J = 8.6 Hz, IH), 7.84 (d, J = 8.6 Hz, IH).6 Hz, IH), 7.76 (dd, J = 9.4, 2.9 Hz, IH), 7.70 - 7.60 (m, 3H), 7.34 - 7.25 (m, 2H), 7.06 (tt, J = 7.4, 1.2 Hz, IH), 3.99 (d, J = 13.9 Hz, IH), 3.55 (d, J = 13.9 Hz, IH), 3.11 (dd, J = 9.6, 3.4Hz, IH), 2.84 (d, J = 11.6 Hz, OH), 2.23 - 2.13 (m, 2H).23 -2.13 (m, IH), 1.93 - 1.82 (m, IH), 1.75 (q, J = 10.1 Hz, 2H), 1.59 - 1.41 (m, 2H), 1.33 (d, J = 11.8 Hz, IH).

[0426] 1-((6-fluoroquinolin-2-yl)methyl)-N-(pyridin-3-yl)piperidin-2-carboxamide (compound 4.5, scheme 4)

[0429]

[0431] The titrated compound was synthesized according to the K1 procedure, starting from ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4.3 (50 mg, 0.16 mmol, 1 eq), 3-aminopyrine (1 eq, 0.16 mmol, 15 mg), and 2M trimethylaluminum 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 100:0 to 90:10) gained the pure titrated compound as a white solid in a 62% yield (36 mg). Characterization: Rt 2.00 min, generic method, MS (ESI) m/z = 363.1 [M-H]-.Exact mass: 364.1699. ? NMR (400 MHz, DMSO) ? 10.17 (s, IH), 8.80 (dd, J = 2.6, 0.8 Hz, IH), 8.35 (d, J = 8.5 Hz, IH), 8.25 (dd, J = 4.7, 1.5 Hz, IH), 8.10 (ddd, J = 8.5 Hz, IH).10 (ddd, J = 8.4, 2.6, 1.5 Hz, IH), 8.00 (dd, J = 9.2, 5.4 Hz, IH), 7.83 (d, J = 8.5 Hz, IH), 7.76 (dd, J = 9.4, 2.9 Hz, IH), 7.64 (td, J = 8.5 Hz, IH).64 (td, J = 8.9, 2.9 Hz, IH), 3.99 (d, J = 13.9 Hz, IH), 3.57 (d, J = 13.9 Hz, IH), 3.13 (dd, J = 9.6, 3.6 Hz, IH), 2.89-2.82 (m, IH), 2.24 - 2.14 (m, IH), 1.93 - 1.84 (m, IH), 1.75 (q, J = 10.3 Hz, 2H), 1.61 - 1.44 (m, 2H), 1.35 (t, J = 11.8 Hz, IH).

[0432] N-(benzo[d]thiazol-6-yl)-1-((6-fluoroquinolin-2-yl)methyl)piperidin-2-carboxamide (compound 4.6, scheme 4)

[0435]

[0437] The titled compound was synthesized according to the K1 procedure, starting from ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4,3 (50 mg, 0.16 mmol, 1 eq), benzo[d]thiazole-6-amine (1 eq, 0.16 mmol, 24 mg), and 2M trimethylaluminum in toluene (3 eq, 0.47 mmol, 0.24 mL), stirring the reaction at room temperature overnight.

[0438] Purification by silica gel column chromatography (cyclohexane/ethyl acetate 80:20 to 70:30) afforded the pure titrated compound as a white solid in 55% yield (36 mg). Characterization: Rt 2.27 min, generic method, MS (ESI) m/z = 421.0 [M+H]<+>. Exact mass: 420.1420. H NMR (400 MHz, DMSO) ? 10.24 (s, IH), 9.25 (s, IH), 8.56 (d, J = 2.1 Hz, IH), 8.35 (d, J = 8.5 Hz, IH), 8.00 (dd, J = 9.0, 4.4 Hz, 2H).0, 4.4 Hz, 2H), 7.84 (d, J = 8.6 Hz, IH), 7.75 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (dd, J = 8.8, 2.1 Hz, IH), 7.62 (td, J = 8.9, 2.9 Hz, IH), 4.5 (td, J = 8.9, 2.9 Hz, IH).9 Hz, IH), 4.00 (d, J = 13.9 Hz, IH), 3.59 (d, J = 13.9 Hz, IH), 3.15 (dd, J = 9.5, 3.4 Hz, IH), 2.86 (d, J = 11.5 Hz, IH), 2.21 (t, J = 9.8, 2.1 Hz, IH).21 (t, J = 9.3 Hz, IH), 1.90 (d, J = 12.5 Hz, IH), 1.82 - 1.69 (m, 2H), 1.58 - 1.44 (m, 2H), 1.36 (t, J = 11.6 Hz, IH). N-(3-fluorophenyl)-1-((6-fluoroquinolin-2-yl)methyl)piperidin-2-carboxamide (compound 4.7, scheme 4)

[0441]

[0443] The titrated compound was synthesized according to the K1 procedure, starting from ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4.3 (50 mg, 0.16 mmol, 1 eq), 3-fluoroaniline (1 eq, 0.16 mmol, 15 μL), and 2M trimethylaluminum 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 70:30) afforded the pure titrated compound as a white, foamy solid in 33% yield (20 mg). Characterization: Rt 2.50 min, generic method, MS (ESI) m/z = 380.1 [M-H]-.Exact mass: 381.1653. H NMR (400 MHz, DMSO) ? 10.17 (s, IH), 8.35 (d, J = 8.5 Hz, IH), 8.00 (dd, J = 9.2, 5.4 Hz, IH), 7.82 (d, J = 8.5 Hz, IH), 7.75 (dd, J = 9.5 Hz, IH).75 (dd, J = 9.4, 2.9 Hz, IH), 7.68 - 7.58 (m, 2H), 7.41 (dt, J = 8.3, 1.2 Hz, IH), 7.33 (td, J = 8.2, 6.7 Hz, IH), 6.92 -6.82 (m, IH), 7.9 (dt, J = 8.5 Hz, IH), 7.9 (dt, J = 8.5 Hz, IH).82 (m, IH), 3.96 (d, J = 13.9 Hz, IH), 3.62 - 3.53 (m, IH), 3.10 (dd, J = 9.6, 3.4 Hz, IH), 2.87 - 2.78 (m, IH), 2.24 - 2.13 (m, IH).24 - 2.13 (m, IH), 1.87 (d, J = 12.6 Hz, IH), 1.73 (q, J = 9.9 Hz, 2H), 1.50 (d, J = 23.0 Hz, 2H), 1.35 (t, J = 15.5 Hz, IH).

[0444] 1-((6-fluoroquinolin-2-yl)methyl)-N-(3-methoxyphenyl)piperidin-2-carboxamide (compound 4.8, scheme 4)

[0447]

[0448] The titrated compound was synthesized according to the K1 procedure, starting from ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4,3 (50 mg, 0.16 mmol, 1 eq), 3-methoxyaniline (1 eq, 0.16 mmol, 17 μL), and 2M trimethylaluminum in toluene (3 eq, 0.47 mmol, 0.24 mL), with stirring overnight at room temperature. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 80:20 to 60:40) afforded the pure titrated compound as a white solid in 32% yield (20 mg). Characterization: Rt 2.45 min, generic method, MS (ESI) m/z = 394.0 [M+H]<+>. Exact mass: 393.1853. <!>H NMR (400 MHz, DMSO) ? 9.93 (s, IH), 8.35 (d, J = 8.5 Hz, IH), 8.01 (dd, J = 9.3, 5.4 Hz, IH), 7.83 (d, J = 8.5 Hz, IH), 7.77 - 7.71 (m, J = 8.5 Hz, IH).77 - 7.71 (m, IH), 7.63 (td, J = 8.9, 2.9 Hz, IH), 7.36 (t, J = 2.2 Hz, IH), 7.21 (dt, J = 15.9, 8.1 Hz, 2H), 6.62 (dd, J = 7.7, 2.3 Hz, IH), 3.98 (d, J = 14.0 Hz, IH), 3.72 (s, 3H), 3.55 (d, J = 13.8 Hz, IH), 3.10 (d, J = 9.3 Hz, IH), 2.84 (d, J = 11.4 Hz, IH), 2.16 (d, J = 11.4 Hz, IH), 2.5 (d, J = 11.5 Hz, IH), 2.6 (d, J = 11.5 Hz, 2H).16 (d, J = 11.7 Hz, IH), 1.88 (d, J = 12.4 Hz, IH), 1.74 (d, J = 10.4 Hz, 2H), 1.64 - 1.40 (m, 2H), 1.38 - 1.16 (m, IH).

[0449] 1-((6-fluoroquinolin-2-yl)methyl)-N-(pyridin-2-yl)piperidin-2-carboxamide (compound 4.9, scheme 4)

[0450]

[0452] The titrated compound was synthesized according to the K2 procedure, starting from 2-aminopyridine (15 mg, 0.16 mmol, 1 eq) in dry tetrahydrofuran (0.1 M, 1.6 mL), sodium hydride dispersed at 60% in mineral oil (8 eq, 1.26 mmol, 50 mg), and ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4,3 (1 eq, 0.16 mmol, 50 mg). Purification by silica gel column chromatography (100:0 to 95:05 dichloromethane/methanol) afforded the product as a yellow, foamy solid in 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) ? 10.43 (s, IH), 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, IH), 7.11 (ddd, J = 7.3, 4.9, 1.1 Hz, IH), 4.02 (d, J = 14.1 Hz, IH), 3.2 (d, J = 14.1 Hz, IH).1 Hz, IH), 3.66 (d, J = 14.1 Hz, IH), 3.28 (dd, J = 8.8, 3.8 Hz, IH), 2.90 - 2.82 (m, IH), 2.32 - 2.22 (m, IH), 1.93 - 1.86 (m, IH), 1.80 - 1.65 (m, 2H), 1.54 (s, IH), 1.51 - 1.33 (m, 2H).

[0453] N-(2-(?,?-dimethylsulfamoyl)phenyl)-1-((6-fluoroquinolin-2-yl)methyl)piperidin-2-carboxamide (compound 4.10, scheme 4)

[0454]

[0456] The titrated compound was synthesized according to the K2 procedure, starting from 2-amino-N,N-dimethylbenzenesulfonamide (22 mg, 0.11 mmol, 1 eq) in dry tetrahydrofuran (0.1 M, 1.1 mL), sodium hydride dispersed at 60% in mineral oil (8 eq, 0.89 mmol, 35 mg), and ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4,3 (1 eq, 0.11 mmol, 35 mg). Purification by silica gel column chromatography (dichloromethane/methanol 95:05) afforded the product as a white solid in 29% yield (15 mg). Characterization: Rt 2.53 min, generic method. MS (ESI) m/z = 471.1 [M+H]<+>. 470.1788. ? NMR (400 MHz, DMSO) ? 10.53 (s, IH), 8.50 (d, J = 8.4 Hz, IH), 8.34 (d, J = 8.6 Hz, IH), 8.00 (dd, J = 9.2, 5.4 Hz, IH).2, 5.4 Hz, IH), 7.85 (d, J = 8.6 Hz, IH), 7.78 - 7.70 (m, 2H), 7.70 - 7.56 (m, 2H), 7.35 - 7.27 (m, IH), 4. (d, J = 13.5 Hz, IH).12 (d, J = 13.9 Hz, IH), 3.78 (d, J = 14.0 Hz, IH), 3.21 (dd, J = 8.6, 3.9 Hz, IH), 2.83 (d, J = 11.9 Hz, IH), 2.70 (s, 5H), 2.30 (t, J = 10.5 Hz, IH), 1.93 (d, J = 12.9 Hz, IH), 1.70 (d, J = 45.5 Hz, 2H), 1.47 - 1.29 (m, 2H).

[0457] N-(3-cyanophenyl)-1-((6-fluoroquinolin-2-yl)methyl)piperidin2-carboxamide (compound 4.11, scheme 4)

[0460]

[0462] The titrated compound was synthesized according to the K1 procedure, starting from ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4,3 (50 mg, 0.16 mmol, 1 eq), 3-aminobenzonitrile (1 eq, 0.16 mmol, 18 mg), and 2M trimethylaluminum 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) afforded the product as a blank in 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) ? 10.27 (s, IH), 8.34 (d, J = 8.5 Hz, IH), 8.14 (q, J = 1.3 Hz, IH), 7.98 (dd, J = 9.2, 5.4 Hz, IH), 7.90 (dt, J = 7.5 Hz, IH).90 (dt, J = 7.0, 2.4 Hz, IH), 7.82 (d, J = 8.5 Hz, IH), 7.74 (dd, J = 9.5, 2.9 Hz, IH), 7.61 (td, J = 8.9, 2.9 Hz, IH), 7.55 - 7.45 (m, 2H), 3.98 (d, J = 13.9 Hz, IH), 3.58 (d, J = 13.9 Hz, IH), 3.12 (dd, J = 9.5, 3.5 Hz, IH), 2.87 (dt, J = 11.6, 4.1 Hz, IH), 2.25 -2.14 (m, J = 8.9, 2.9 Hz, IH).25 - 2.14 (m, IH), 1.88 (dd, J = 13.2, 4.2 Hz, IH), 1.81 - 1.67 (m, 2H), 1.58 - 1.43 (m, 2H), 1.34 (t, J = 11.7 Hz, IH).

[0463] N-(4-(N,?-dlmethylsulfamoyl)phenyl)-1-((6-fluoroquinolin-2-yl)methyl)piperidin-2-carboxamide (compound 4.12, scheme 4)

[0466]

[0468] The titled compound was synthesized according to the K2 procedure, starting from 4-amino-N,N-dimethylbenzenesulfonamide (32 mg, 0.16 mmol, 1 eq) in dry tetrahydrofuran (0.1 M, 1.6 mL), sodium hydride dispersed at 60% in mineral oil (8 eq, 1.26 mmol, 51 mg), and ethyl 1-((6-fluoroquinolin-2-yl)methyl)pyrolyzed.6 mL), sodium hydride dispersed at 60% in mineral oil (8 eq, 1.26 mmol, 51 mg), and ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4.3 (1 eq, 0.16 mmol, 50 mg). Purification by silica gel column chromatography (dichloromethane/methanol 100:0 to 96:04) afforded the product as a white, foamy solid in 27% yield (20 mg). Characterization: Rt 2.35 min, generic method. MS (ESI) m/z = 469.2 [M-H]-. 470.1788. H NMR (400 MHz, DMSO) ? 10.37 (s, IH), 8.34 (d, J = 8.5 Hz, IH), 8.00 (dd, J = 9.2, 5.4 Hz, IH), 7.92 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H).82 (d, J = 8.5 Hz, IH), 7.75 (dd, J = 9.4, 2.9 Hz, IH), 7.68 (d, J = 8.8 Hz, 2H), 7.63 (td, J = 8.9, 2.9 Hz, IH), 3.98 (d, J = 14..0 Hz, IH), 3.59 (d, J = 13.9 Hz, IH), 3.16 (dd, J = 9.2, 3.5 Hz, IH), 2.87 (d, J = 11.7 Hz, IH), 2.57 (s, 6H), 2.21 (t, J = 10.5 Hz IH), IH).5 Hz, IH), 1.89 (d, J = 12.5 Hz, IH), 1.75 (q, J 11.3 Hz, 2H), 1.53 (d, J = 11.5 Hz, 2H), 1.34 (d, J = 11.6 Hz, IH).

[0469] N-(3-carbamophenyl)-1-((6-fluoroquinolin-2-yl)methyl)piperidin-2-carboxamide (compound 4.13, scheme 4)

[0472]

[0474] The titled compound was synthesized according to the K1 procedure, starting from ethyl 1-((6-fluoroquinolin-2-yl)methyl)piperidine-2-carboxylate 4,3 (50 mg, 0.16 mmol, 1 eq), 3-aminobenzamide (1 eq, 0.16 mmol, 22 mg), and 2M trimethylaluminum in toluene (3 eq, 0.47 mmol, 0.24 mL), stirring the reaction at room temperature overnight. The crude was purified by silica gel column chromatography, using dichloromethane/methanol from 100:0 to 80:20 as the eluent. A second column chromatography on silica gel, using cyclohexane/ethyl acetate from 60:40 to 0:100 as the eluent, yielded the pure titrated compound as a white, foamy solid in a 31% yield (20 mg). Characterization: Rt 1.88 min, generic method. MS (ESI) m/z = 405.1 [M-H]. Exact mass: 406.1805. H NMR (400 MHz, DMSO) ? 10.10 (s, IH), 8.35 (d, J = 8.5 Hz, IH), 8.14 (t, J = 1.9 Hz, IH), 8.04 (dd, J = 9.2, 5.4 Hz, IH), 7.93 (s, IH), 7.86 - 7.79 (m, 2H), 7.76 (dd, J = 9.4, 2.9 Hz, IH), 7.63 (td, J = 8.9, 2.9 Hz, IH), 7.54 (dt, J = 8.0, 1.3 Hz, IH), 7.41 - 7.29 (m, IH), 7.29 (s, IH).41 - 7.29 (m, 2H), 4.00 (d, J = 13.9 Hz, IH), 3.63 - 3.53 (m, IH), 3.17 (dd, J = 33.2, 11.9 Hz, IH), 2.84 (d, J = 11.6 Hz, IH), 2.19 (t, J = 10.2 Hz, IH).19 (t, J = 10.7 Hz, IH), 1.90 (d, J = 14.0 Hz, IH), 1.75 (q, J = 10.9 Hz, 2H), 1.65 - 1.41 (m, 2H), 1.34 (d, J = 11.9 Hz, IH).

[0475] 6-methoxy-2-methylquinoline (compound 5.3, scheme 5)

[0478]

[0480] The title compound was synthesized according to procedure A2, starting from 4-methoxyaniline 5.1 (1 eq, 2 g, 16.24 mmol) dissolved in 16M HCl (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 at 100°C for 48 h. Purification of the crude product by silica gel column chromatography afforded the pure title compound as a brownish solid in 74% yield (2.1 g). Characterization: Rt 1.69 min, generic method, MS (ESI) m/z = 173.8 [M+H]<+>. Exact mass 173.0841. H NMR (400 MHz, DMSO) ? 8.14 (d, J = 8.4 Hz, IH), 7.82 (d, J = 9.0 Hz, IH), 7.39 - 7.29 (m, 3H), 3.88 (s, 3H), 2.61 (s, 3H).

[0481] 2-methyl-6-(trifluoromethoxy)quinoline (compound 5.4, scheme 5)

[0484]

[0486] The titrated compound was synthesized according to procedure A1, starting from 4-trifluoromethoxyaniline 5,2 (500 mg, 2.82 mmol, 1 eq) in toluene (0.2 M, 14 mL), ethylvinyl ether (2 eq, 5.65 mmol, 540 μL), and catalytic iodine (0.1 eq, 0.28 mmol, 72 mg), with stirring at 80°C for 6 h. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 90:10) afforded the pure titrated product as a brownish oil in 47% yield (307 mg). Characterization: Rt 2.24 min, generic method, MS (ESI) m/z = 227.8 [M+H]<+>. Exact mass: 227.0558. H NMR (400 MHz, CDCI<3>) ? 8.04 (dd, J = 8.8, 3.7 Hz, 2H), 7.60 (s, IH), 7.53 (dd, J = 9.1, 2.7 Hz, IH), 7.34 (d, J = 8.4 Hz, IH), 2.75 (s, 3H).

[0487] 6-fluoro-2-(iodomethyl)quinoline (compound 5.6, scheme 5)

[0490]

[0492] The titrated compound was synthesized according to Procedure L, starting from 6-fluoro-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 sulfate pentahydrate (0.4 eq, 2.48 mmol, 620 mg), stirring the reaction at 70°C for 5 h. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 90:10) afforded the pure titrated product as a light brown solid in 64% yield (870 mg). Characterization: Rt 2.20 min, generic method. MS (ESI) m/z = 287.9 [M+H]<+>. Exact mass: 286.9607. ? NMR (400 MHz, DMSO) ? 8.33 (d, J = 8.5 Hz, IH), 8.03 (dd, J = 9.3, 5.4 Hz, IH), 7.78 (dd, J = 9.4, 2.9 Hz, IH), 7.72 - 7.64 (m, 2H), 4.76 (s, 2H).

[0493] 6-(trifluoromethyl)quinoline-2-carbaldehyde (compound 5.7, Scheme 5)

[0496]

[0498] The titrated compound was synthesized according to procedure C, starting from a solution of 6-trifluoromethyl-2-methylquinoline 1.5 (100 mg, 0.47 mmol, 1 eq) in dry 1,4-dioxane (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 column chromatography purification as a brown solid. Yield: 91%, 98 mg. Characterization: Rt 2.25 min, generic method, MS (ESI) m/z = 225.7 [M+H]<+>. H NMR (400 MHz, DMSO) ? 10.16 (d, J = 0.8 Hz, IH), 8.83 (d, J = 8.5 Hz IH), 8.69 (d, J 2.1 Hz, IH), 8.43 (d, J 8.8 Hz, IH) 8.19 8.11 (m, 2H).

[0499] 2-(iodomethyl)-6-(trifluoromethoxy)quinoline (compound 5.8, scheme 5)

[0502]

[0504] The titrated compound was synthesized according to Procedure L, starting from 2-methyl-6-trifluoromethoxyquinoline 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 sulfate pentahydrate (0.4 eq, 0.26 mmol, 66 mg), with stirring at 70°C overnight. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 80:20) afforded the pure titrated product as a brownish solid in 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) ? 8.44 (d, J = 8.5 Hz, IH), 8.09 (d, J = 9.2 Hz, IH), 8.06 - 7.99 (m, IH), 7.77 - 7.72 (m, 2H), 4.77 (s, 2H).

[0505] 6-methoxyquinoline-2-carbaldehyde (compound 5.9, Scheme 5)

[0508]

[0510] The titrated compound was synthesized according to procedure C, starting from 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 2 h. 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) ? 10.08 (s, IH), 8.41 (dd, J = 9.3, 5.4 Hz, IH), 8.03 (dd, J = 9.5, 2.8 Hz, IH), 7.97 (ddd, J = 9.2, 8.3, 2.8 Hz, IH).

[0511] 6-Ethoxyquinoline-2-carbaldehyde (compound 5.10, scheme 5)

[0514]

[0516] The product was synthesized according to Procedure C, starting from 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 2 h. The compound was obtained pure without purification by column chromatography as a brownish solid in 97% yield. Characterization: Rt 2.06 min, generic method, MS = 201.8 [M+H]<+>. Exact mass: 201.0790. ? NMR (400 MHz, DMSO) ? 10.08 (d, J = 0.8 Hz, IH), 8.50 - 8.41 (m, IH), 8.12 (d, J = 9.1 Hz, IH), 7.95 (d, J = 8.4 Hz, IH), 7.54 (dd, J = 9.1, 2.8 Hz, IH), 7.51 (d, J 2.7 Hz, IH), 4.23 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz 3H).

[0517] N-cyclohexylaniline (compound 5.11, scheme 5)

[0518]

[0520] The titrated compound was synthesized according to procedure E, starting from cyclohexanone (105 µL, 1.02 mmol, 1 eq) in dry dichloromethane (0.2 M, 5 mL), aniline (1.2 eq, 1.22 mmol, 111 µL), acetic acid (10 eq, 10.2 mmol, 583 µL), and sodium triacetoxybohydride (4 eq, 4.08 mmol, 583 µL). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 99:01) afforded the pure titrated compound as a white solid in 85% yield (155 mg). Characterization: Rt 2.60 min, generic method, MS (ESI) m/z = 176.1 [M+H]<+>. Exact mass: 175.1361. H NMR (400 MHz, CDC1<3 >) ? 7.11 - 7.03 (m, 2H), 6.58 (tt, J = 7.3, 1.1 Hz, IH), 6.53 - 6.49 (m, 2H) 3.42 ( , 1H), 3.18 (tt, J = 10.1, 3.7 Hz, IH), 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, IH), 1.36 1.21 (m, 2H), 1.21 1.00 (m, 3H). N-cyclohexylbenzo [d]thiazol-6-amine (compound 5.12, scheme 5)

[0523]

[0525] The titrated compound was synthesized according to Procedure E, starting from cyclohexanone (1 eq, 2.27 mmol, 234 μL), 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 triacetoxyboride (4 eq, 9.07 mmol, 1.92 g) in dry dichloromethane, with stirring at room temperature overnight. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 90:10) afforded the pure titrated compound as a white solid in 94% yield (500 mg). Characterization: Rt 2.36 min, generic method, MS (ESI) m/z = 232.9 [M+H]<+>. Exact mass: 232.1034. ? NMR (400 MHz, DMSO) ? 8.86 (s, IH), 7.72 (d, J = 8.8 Hz, IH), 7.11 (d, J = 2.2 Hz, IH), 6.84 (dd, J = 8.9, 2.3 Hz, IH), 5.80-5.74 (m, IH), 4.41 (d, J = 4.2 Hz, IH), 3.31 - 3.19 (m, IH), 2.02 - 1.92 (m, 2H), 1.67 (ddt, J = 46.4, 12.2, 3.9 Hz, 6H), 1.44 - 1.28 (m, 2H).

[0526] 4-(cyclohexylamino)benzamide (compound 5.13, scheme 5)

[0529]

[0531] The titrated compound was synthesized according to procedure E, starting from cyclohexanone (263 µL, 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 triacetoxybohydride (4 eq, 10.19 mmol, 1.46 mL). Stirring the reaction at room temperature overnight. The compound was 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. ? NMR (400 MHz, DMSO) ? 7.68 - 7.57 (m, 2H), 7.53 (s, IH), 6.80 (s, IH), 6.57 - 6.49 (m, 2H), 5.97 (d, J = 7.9 Hz, IH), 3.26 - 3.14 (m, IH), 3.5 (m, IH).14 (m, IH), 1.95 - 1.86 (m, 2H), 1.71 (dt, J = 13.0, 3.7 Hz, 2H), 1.64 - 1.54 (m, IH), 1.34 (qd, J = 12.3, 3.3 Hz, 2H), 1.24 - 1.05 (m, 3H).

[0532] N-cyclohexylpyridine-3-amine (compound 5.14, scheme 5)

[0535]

[0537] The titrated compound was synthesized according to Procedure E, starting from cyclohexanone (317 μL, 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 triacetoxyboride (4 eq, 12.23 mmol, 2.591 g). Purification by silica gel column chromatography (100:0 to 98:02 dichloromethane/methanol) afforded the pure titrated compound as white crystals in 62% yield (336 mg). Characterization: Rt 1.84 min, generic method, MS (ESI) m/z = 177.9 [M+H]<+>. Exact mass: 176.1313. H NMR (400 MHz, CDCl3 ) ? 7.99 (d, J = 2.9 Hz, IH), 7.90 (dd, J = 4.7, 1.4 Hz, IH), 7.05 (dd, J = 8.3, 4.7 Hz, IH), 6.84 (ddd, J = 8.3 2.9, 1.4 Hz, IH), 3.55 (s, IH), 3.24 (s, IH), 3.5 (s, IH).24 (s, IH), 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, IH), 1.43 - 1.31 (m, 2H), 1.29 1.07 (m, 3H).

[0538] 4-(cyclohexylamino)benzonitrile (compound 5.15, scheme 5)

[0541]

[0543] The titrated compound was synthesized according to procedure E, starting from cyclohexanone (1 eq, 2.04 mmol, 211 µL) in dry dichloromethane (0.3 M, 6.8 mL), 4-aminobenzonitrile (1 eq, 2.04 mmol, 241 mg), acetic acid (10 eq, 20.4 mmol, 1.166 mL), and sodium triacetoxybohydride (4 eq, 8.15 mmol, 1.166 mL). 4-aminobenzonitrile (1 eq, 2.04 mmol, 241 mg), acetic acid (10 eq, 20.4 mmol, 1.166 mL), and sodium triacetoxybohydride (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) afforded the pure titrated compound as white crystals in 59% yield (243 mg). Characterization: Rt 2.48 min, generic method, MS = 200.9 [M+H]<+>. Exact mass: 200.1313. <1>H NMR (400 MHz, CDC1<3>) ? 7.43 - 7.35 (m, 2H), 6.56 6.48 (m, 2H), 4.10 (dd, J = 13.9, 7.4 Hz, IH), 3.29 (tdt J = 10.9, 7.8, 3.8 Hz, IH), 2.01 (d, J = 4.2 Hz, 2H), 1.81 1.75 (m, 2H), 1.67 (dt, J = 12.8, 3.8 Hz, IH), 1.45 - 1.31 (m, 2H), 1.29 1.11 (m, 3H).

[0544] N-cyclohexyl-l-methyl-1H-benzo[d]imidazole-6-amine (compound 5.16, scheme 5)

[0547]

[0549] The titrated compound was synthesized according to procedure E, starting from cyclohexanone (140 µL, 1.36 mmol, 1 eq) in dry dichloromethane (4.5 mL, 0.3 M), 1-methyl-1H-benzo[d]imidazole-6-amine (1 eq, 1.36 mmol, 200 mg), acetic acid (10 eq, 13.6 mmol, 775 µL), and sodium triacetoxybohydride (4 eq, 5.42 mmol, 775 µL). Purification by silica gel column chromatography (100:0 to 95:05 dichloromethane/methanol) afforded the pure titrated compound as a purple foamy solid in 68% yield (212 mg). Characterization: Rt 1.90 min, generic method, MS = 230.0 [M+H]<+>. Exact mass: 229.1579. <1>H NMR (400 MHz, DMSO) ? 7.80 (s, IH), 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).

[0550] N-cyclohexylbenzo[d]oxazole-6-amine (compound 5.17, scheme 5)

[0553]

[0555] The titrated compound was synthesized according to procedure E, starting from cyclohexanone (153 μL, 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 μL), and sodium triacetoxybohydride (4 eq, 5.91 mmol, 1.25 mg).48 mmol, 198 mg), (10 eq, 14.77 mmol, 845 μL), and sodium triacetoxybohydride (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) afforded the pure titrated compound as the purple oil in 53% yield (171 mg). Characterization: Rt 2.31 min, generic method, MS (ESI) m/z = 216.9 [M+H]<+>. Exact mass: 216.1263. <!>H NMR (400 MHz, CDC1<3 >) ? 7.88 (s, IH), 7.51 (d, J = 8.6 Hz, IH), 6.75 (d, J = 2.2 Hz, IH), 6.63 (dd, J = 8.6, 2.2 Hz, IH), 3.76 (s, IH), 3.29 (tt, J = 10.2, 3.8 Hz, IH).2, 3.8 Hz, IH), 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, IH), 1.50 - 1.34 (m, 2H), 1.34 - 1.14 (m, 2H).

[0556] N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)cyclohexanamine (compound 5.18, scheme 5)

[0557]

[0559] The titled compound? was synthesized according to procedure F, starting from cyclohexanone (263 μL, 2.55 mmol, 1 eq) in dry dichloromethane (0.8 M, 3.2 mL), (3-phenyl-1,2,4-oxadiazole-5-yl)methanamine (1 eq, 2.55 mmol, 446.73 mg), acetic acid (10 eq, 25.47 mmol, 1.46 mL), sodium triacetoxybohydride (4 eq, 10.47 mmol, 1.46 mL).55 mmol, 446.73 mg), acetic acid (10 eq, 25.47 mmol, 1.46 mL), sodium triacetoxybohydride (4 eq, 10.19 mmol, 2.16 g), stirring the reaction at room temperature overnight. The compound was was obtained pure without purification by column chromatography (100% yield, white solid, 655 mg). Characterization: Rt 1.93 min, generic method, MS = 258.1 [M+H]<+>. Exact mass: 257.15.

[0560] N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)cyclohexanamine (compound 5.19, scheme 5)

[0563]

[0565] The titled compound? It was synthesized according to Procedure E, starting from cyclohexanone (263 µL, 2.55 mmol, 1 eq) in dry dichloromethane (0.8 M, 3.2 mL), (5-phenyl-1,3,4-oxadiazole-2-yl)methanamine (1 eq, 2.55 mmol, 446 mg), acetic acid (10 eq, 25.47 mmol, 1.46 mL), sodium triacetoxybohydride (4 eq, 10.19 mmol, 1.46 mL). 55 mmol, 446 mg), acetic acid (10 eq, 25.47 mmol, 1.46 mL), sodium triacetoxybohydride (4 eq, 10.19 mmol, 2.16 g), stirring the reaction at room temperature overnight. The compound was 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.

[0566] N-((2-phenyloxazole-5-yl)methyl)cyclohexanamine (compound 5.20, scheme 5)

[0569]

[0571] The titrated compound was synthesized according to procedure E, starting from cyclohexanone (263 μL, 2.55 mmol, 1 eq) in dry dichloromethane (0.8 M, 3.2 mL), (2-phenyloxazole-5-yl)methanamine (1 eq, 2.55 mmol, 445 mg), acetic acid (10 eq, 25.47 mmol, 1.46 mL), sodium triacetoxybohydride (4 eq, 10.19 mmol, 1.46 mL). (2-phenyloxazole-5-yl)methanamine (1 eq, 2.55 mmol, 445 mg), acetic acid (10 eq, 25.47 mmol, 1.46 mL), sodium triacetoxybohydride (4 eq, 10.19 mmol, 2.16 g), stirring the reaction at room temperature overnight. The compound was It 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. N-(pyridin-3-ylmethyl)cyclohexanamine (compound 5.21, Scheme 5)

[0574]

[0576] The titrated compound was synthesized according to procedure E, starting from cyclohexanone (263 μL, 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, 1.46 mL), sodium triacetoxybohydride (4 eq, 10.19 mmol, 1.46 mL). 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 5.22, Scheme 5)

[0579]

[0581] The titrated compound was synthesized according to the procedure E described above, starting from 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 triacetoxybohydride (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 Na<2>SO4. The solvent was evaporated by rotavapor, and the resulting crude product was was purified by silica gel column chromatography (cyclohexane/ethyl acetate 90:10) affording 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;<1 >H NMR (400 MHz, DMSO) ? 8.91 (s, IH), 7.76 (d, J = 8.8 Hz, IH), 7.13 (d, J = 2.3 Hz, IH), 6.87 (dd, J = 8.9, 2.3 Hz, IH), 6.20 (d, J = 6.3 Hz, IH), 4.03 (ddt, J = 10.0, 6.7, 3.3 Hz, IH), 3.92 (dd, J = 8.8, 5.8 Hz, IH), 3.84 (dt, J = 8.4, 7.3 Hz, IH), 3.74 (td, J = 8.2, 5.4 Hz, IH), 3.56 (dd, J = 8.2, 5.4 Hz, IH).56 (dd, J = 8.8, 3.6 Hz, IH), 2.28 - 2.15 (m, IH), 1.79 (dddd, J = 12.6, 7.3, 5.5, 3.6 Hz, IH).

[0582] N-(oxetan-3-yl)benzo[d]thiazol-6-amine (compound 5.23, scheme 5)

[0585]

[0587] The titrated compound was synthesized according to the procedure E described above, starting from 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 triacetoxybohydride (4 eq, 11.48 mmol, 2.43 g), stirring overnight at room temperature. The reaction was quenched by adding sodium bicarbonate, extracted with ethyl acetate, washed with brine, and dried over Na<2>SO<4>. The solvent was evaporated by rotavapor, and the resulting crude product was was purified by silica gel column chromatography (cyclohexane/ethyl acetate 90:10) affording the pure compound titrated 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;<1 >H NMR (400 MHz, DMSO) ? 8.93 (s, IH), 7.78 (d, J = 8.8 Hz, IH), 6.98 (d, J = 2.4 Hz, IH), 6.82 (dd, J = 8.8, 2.3 Hz, IH), 6.71 (d, J = 6.3 Hz, IH), 4.88 (t, J = 6.5 Hz, 2H), 4.58 (h, J = 6.4 Hz, IH), 4.43 (t, J = 6.0 Hz, 2H).

[0588] N-(cyclopropylmethyl)benzo[d]thiazole-6-amine (compound 5.24, scheme 5)

[0590] The titrated compound was synthesized according to general procedure 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 μL, 0.40 mmol, 1 eq), acetic acid (10 eq, 4.00 mmol, 228 μL), and sodium triacetoxyborohydride (4 eq, 1.60 mmol, 338 mg). Purification by flash chromatography on silica gel (cyclohexane/EtOAc 85:15) afforded the pure titrated compound as a white solid (39.3 mg, 48% yield). Characterization: Rt = 2.02 min; MS (ESI) m/z: 205.3 [M+H]<+>. Exact mass: 204.0721.<1 >H NMR (400 MHz, CDC1<3 >) ? 8.64 (s, IH), 7.87 (d, J = 8.8 Hz, IH), 7.01 (d, J = 2.0 Hz, IH), 6.81 (ddd, J = 8.9, 2.4, 1.0 Hz, IH), 4.04 (s, IH), 3.00 (dd, J = 7.0, 1.1 Hz, 2H), 1.17 - 1.07 (m, IH), 0.63 - 0.52 (m, 2H), 0.27 (qd, J = 4.8, 2.5 Hz, 2H).

[0591] tert-butyl 4-((benzo[d]thiazol-6-ylamino)methyl)piperidine-1-carboxylate (compound 5.25, Scheme 5)

[0594]

[0596] The titrated compound was synthesized according to the general procedure E from benzo[d]thiazol-6-amine 6.1 (100 mg, 0.67 mmol) in dry DCM (0.3 M, 2 mL), 1-Bocpiperidin-4-carboxaldehyde (142 mg, 0.67 mmol), acetic acid (10 eq, 6.66 mmol, 380 μL), and sodium triacetoxyboride (4 eq, 2.66 mmol, 565 mg). Purification by flash chromatography on silica gel (cyclohexane/EtOAc 85:15) afforded the pure titrated compound as a white foam (134.6 mg, 58% yield). Characterization: Rt = 2.33 min; MS (ESI) m/z: 348.0 [M+H]<+>. Exact mass: 347.1667. H NMR (400 MHz, CDCI<3 >) ? 8.65 (s, IH), 7.87 (d, J = 8.8 Hz, IH), 7.02 (d, J = 2.4 Hz, IH), 6.79 (dd, J = 8.8, 2.4 Hz, IH), 4.21 - 4.07 (m, IH), 3.96 (bs, IH), 3.09 (d, J = 6.3 Hz, 2H), 2.82 - 2.41 (m, 2H) 1.87 1.73 (m, 3H), 1.46 (s, 9H), 1.29 1.13 (m, 2H).

[0597] tert-butyl 3-(benzo[d]thiazol-6-ylamino)pyrrolidine-1-carboxylate (compound 5.26, Scheme 5)

[0600]

[0602] The titrated compound was synthesized according to general procedure E from benzo[d]thiazol-6-amine 6.1 (100 mg, 0.67 mmol) in dry DCM (0.3 M, 2 mL), tert-butyl-3-oxopyrrolidine-l-carboxylate (112 μL, 0.67 mmol), acetic acid (10 eq, 6.66 mmol), and sodium triacetoxybohydrate (4 eq, 2.66 mmol, 565 mg). Purification by flash chromatography on silica gel (cyclohexane/EtOAc 80:20) afforded the titrated compound as a pure white oil (143.8 mg, 68% yield). Characterization: Rt = 2.09 min; MS (ESI) m/z: 320.0 [M+H]<+>. Exact mass: 319.1354. <1>H NMR (400 MHz, CDC1<3 >) ? 8.68 (s, IH), 7.89 (d, J = 8.8 Hz, IH), 7.05 (d, J = 2.4 Hz, IH), 6.80 (dd, J 8.8, 2.4 Hz, 1H), 4.29 3.96 (m, IH), 3.9 (m, IH).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), 1.99-1.86 (m IH), 1.47 (s, 9H).

[0603] tert-butyl 4-(benzo[d]thiazol-6-ylamino)azepane-1-carboxylate (compound 5.27, Scheme 5)

[0604]

[0606] The titrated compound was synthesized according to the general procedure 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-l-carboxylate (142 mg, 0.67 mmol), acetic acid (10 eq, 6.66 mmol, 380 μL), and sodium triacetoxyboride (4 eq, 2.66 mmol, 565 mg). Purification by flash chromatography on silica gel (cyclohexane/EtOAc 75:25) afforded the pure titrated compound as a white foam (171.4 mg, 74% yield). Characterization: Rt = 2.32 min; MS (ESI) m/z: 347.9 [M+H]<+>. Exact mass: 347.1667. ? NMR (400 MHz, DMSO-d6) ? 8.87 (s, IH), 7.73 (d, J = 8.8 Hz, IH), 7.05 (d, J = 2.3 Hz, 1H) 6.81 (dt, J = 9.0, 2.2 Hz, IH), 5.90 (t, J = 6.5 Hz, 1H) 3.59 3.44 (m, 3H).59 3.44 (m, IH), 3.41 3.34 (m, 3H) 3.22 (dt, J = 8.7, 4.9 Hz, IH), 2.09 - 1.92 (m, 2H), 1.94 1.71 (m, 2H), 1.70 1.49 (m, 2H), 1.42 (s, 9H).

[0607] tert-butyl 4-(benzo[d]thiazol-6-ylamino)piperidine-1-carboxylate (compound 5.28, Scheme 5)

[0610]

[0612] The titled compound? It was synthesized according to procedure E, starting from benzo[d]thiazol-6-amine 6.1 (528 mg, 1 eq, 3.52 mmol) in dry dichloromethane (0.3 M, 11.7 mL), l-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) afforded the pure titrated compound as a yellowish oil in a 67% yield (800 mg). Characterization: Rt 2.24 min, generic method, MS (ESI) m/z = 333.9 M+H]<+>; 392.2 [M+CH<3>COO-]- . Exact mass: 333.1511. ? NMR (400 MHz, DMSO) ? 8.89 (s, IH), 7.74 (d, J = 8.9 Hz, IH), 7.18 (d, J = 2.3 Hz, IH), 6.85 (dd, J = 8.9, 2.3 Hz, IH), 5.87 (d, J = 8.1 Hz, IH), 3.2 (d, J = 8.1 Hz, IH).1 Hz, IH), 3.89 (d, J = 13.2 Hz, 2H), 3.56 - 3.42 (m, IH), 2.93 (s, 2H), 1.93 (dd, J = 12.3, 3.7 Hz, 2H), 1.41 (s, 9H), 1.30 - 1.16 (m, 2H).

[0613] N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-6-amine (compound 5.29, scheme 5)

[0616]

[0618] The titrated compound was synthesized according to procedure E, starting from 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 triacetoxyborohydride (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) afforded the pure titrated product as white crystals in 30% yield (140 mg). Characterization: Rt 1.60 min, generic method, MS (ESI) m/z = 234.9 [M+H]+. Exact mass: 234.0827. ? NMR (400 MHz, DMSO) ? 8.88 (s, IH), 7.74 (d, J = 8.8 Hz, IH), 7.19 (d, J = 2.2 Hz, IH), 6.86 (dd, J = 8.9, 2.4 Hz, IH), 5.89 (d, J = 8.0 Hz, IH), 3.0.1 (d, J = 8.0 Hz, 1H).0 Hz, IH), 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). N-(thiazol-5-ylmethyl)cyclopentanamine (compound 5.30, scheme 5)

[0621]

[0623] The titrated compound was synthesized according to procedure E, starting from cyclopentamine (1 eq, 26 µL, 0.265 mmol) in dry dichloromethane (900 µL), aldehyde 13,12 (1 eq, 20 µL, 0.265 mmol), sodium triacetoxybohydride (4 eq, 225 mg, 1.06 mmol), with stirring at room temperature overnight. The crude was directly subjected to the subsequent reaction without further purification.

[0624] N-(4-(benzo[d]thiazol-6-ylamino)cyclohexyl)acetamide (compound 5.31, scheme 5)

[0625]

[0627] The titrated compound was synthesized according to Procedure E, starting from N-(4-oxocyclohexyl)acetamide (155 mg, 1 mmol, 1 eq), benzo[d]thiazole-6-amine 6.1 (1 eq, 150 mg, 1.0 mmol), glacial acetic acid (1 eq, 1 mmol, 59 μL), 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) afforded the pure titrated product in 87% yield (250 mg). Characterization: LCMS only, MS (ESI): m/z = 290.1 [M+H]<+ >. Exact mass: 289.1249.

[0628] N-cyclohexyl-N-((6-fluoroquinolin-2-yl)methyl)aniline (compound 5.32, scheme 5)

[0631]

[0633] The titrated compound was synthesized according to Procedure E, starting from N-6-fluoroquinoline-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 μL), and sodium triacetoxyboride (4 eq, 2.85 mmol), stirring the reaction mixture at room temperature overnight. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 95:05) afforded the pure titrated compound as a white solid in 20% yield (20 mg). Characterization: Rt 2.40 min, apolar method, MS (ESI) m/z = 335.0 [M+H]<+>. Exact mass: 334.1845. <1>H NMR (400 MHz, DMSO) ? 8.25 (d, J = 8.6 Hz, IH), 8.05 (dd, J = 9.2, 5.4 Hz, IH), 7.73 (dd, J = 9.3, 2.9 Hz, IH), 7.66 (td, J = 8.9, 2.9 Hz, IH), 7.44 (d, J = 8.6 Hz, IH), 7.10 (dd, J = 8.6, 7.1 Hz, 2H), 6.71 (d, J = 8.2, 5.4 Hz, IH).71 (d, J = 8.3 Hz, 2H), 6.59 (t, J = 7.2 Hz, IH), 4.65 (s, 2H), 3.85 (s, IH), 1.79 (dd, J = 28.3, 10.3Hz, 4H), 1.61 (d, J = 13.0 Hz, IH), 1.44 (h, J = 12.5 Hz, 4H), 1.15 (dd, J = 21.3, 9.5 Hz, IH).

[0634] N-cyclohexyl-N-((6-fluoroquinolin-2-yl)methyl)benzo[d]thiazol-6-amine (compound 5.33, scheme 5)

[0637]

[0639] The titrated compound was synthesized according to the N procedure, starting from 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). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 95:05) afforded the pure titrated compound as a white solid in 55% yield (70 mg). Characterization: Rt 1.99 min, generic method, MS (ESI) m/z = 392.3 [M+H]<+>. Exact mass: 391.1518. ? NMR (400 MHz, DMSO) ? 8.94 (s, IH), 8.25 (d, J = 8.6 Hz, IH), 8.06 (dd, J = 9.2, 5.4 Hz, IH), 7.79 (d, J = 9.1 Hz, IH), 7.73 (dd, J = 9.4, 2.9 Hz, IH), 7.66 (td, J = 8.9, 2.9 Hz, IH), 7.49 -7.41 (m, 2H), 6.97 (dd, J = 9.2, 2.6 Hz, IH), 4.76 (s, 2H), 4.02 - 3.89 (m, IH), 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, IH), 1.47 (q, J = 11.7 Hz, 4H), 1.26 - 1.04 (m, 2H).

[0640] 4-(cyclohexyl ((6-fluoroquinolin-2-yl)methyl)animino)benzamide (compound 5.34, scheme 5)

[0643]

[0645] The titled compound was synthesized according to procedure M, starting from fluoroquinoline-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 THF (0.2 M, 0.9 mL), trifluoroacetic acid (3 eq, 0.55 mmol, 42 μL), phenylsilane (3 eq, 0.55 mmol, 69 μL). The crude was purified on silica gel by column chromatography using dichloromethane/methanol from 100:0 to 90:10 as eluent to obtain the not sufficiently pure compound. The compound was was further purified by silica gel column chromatography using dichloromethane/ethyl acetate as eluent from 100:0 to 90:10 to afford the pure compound titrated as a white solid in 16% yield (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) ? 8.27 (d, J = 8.6 Hz, IH), 8.04 (dd, J = 9.3, 5.4 Hz, IH), 7.73 (dd, J = 9.4, 2.9 Hz, IH), 7.70 - 7.53 (m, 3H), 7.38 (d, J = 8.6 Hz, IH), 6.88 (s, IH), 6H (s, IH).88 (s, IH), 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, IH), 1.45 (q, J = 11.7 Hz, 4H), 1.27 - 1.09 (m, IH).

[0646] N-cyclohexyl-N-((6-fluoroquinolin-2-yl)methyl)pyridin-3-amine (compound 5.35, scheme 5)

[0649]

[0651] The titled compound was synthesized according to procedure M, starting from fluoroquinoline-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 μL), phenylsilane (3 eq, 0.68 mmol, 85 μL). The crude was purified on silica gel by column chromatography using dichloromethane/methanol from 100:0 to 90:10 as eluent to obtain the not sufficiently pure compound. The compound was was further purified by a second silica gel column chromatography using cyclohexane/isopropanol from 100:0 to 90:10 as the eluent to afford the compound as a white, foamy solid in 23% yield (18 mg). Characterization: Rt 2.57 min, generic method, MS = 335.8 [M+H]<+>. Exact mass: 335.1798. H NMR (400 MHz, DMSO) ? 8.28 (d, J = 8.6 Hz, IH), 8.07 - 8.00 (m, 2H), 7.80 (dd, J = 3.9, 1.8 Hz, IH), 7.73 (dd, J = 9.4, 2.9 Hz, IH), 7.66 (td, J = 8.9, 2.9 Hz, IH), 7.44 (d, J = 8.6 Hz, IH), 7.15 - 7.05 (m, IH).15 - 7.05 (m, 2H), 4.69 (s, 2H), 3.88 (d, J = 9.5 Hz, IH), 1.82 (d, J = 10.5 Hz, 2H), 1.75 (d, J = 11.5 Hz, 2H), 1.60 (d, J = 13.1 Hz, IH), 1.45 (h, J = 12.7 Hz, 4H), 1.14 (t, J = 12.3 Hz, IH).

[0652] 4-(cyclohexyl ((6-fluoroquinolin-2-yl)methyl)animino) benzonitrile (compound 5.36, scheme 5)

[0655]

[0657] The titrated compound was synthesized according to procedure M, starting from fluoroquinoline-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 gL), and phenylsilane (3 eq, 0.75 mmol, 94 gL). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 90:10) afforded the pure titrated compound as a beige solid in 45% yield (41 mg). Characterization: Rt 2.06 min, apolar method, MS (ESI) m/z = 358.1 [M-H]-.Exact mass: 359.1798. H NMR (400 MHz, DMSO) ? 8.29 (d, J = 8.6 Hz, IH), 8.03 (dd, J = 9.2, 5.4 Hz, IH), 7.76 (dd, J = 9.4, 2.9 Hz, IH), 7.66 (td, J = 8.9, 2.9 Hz, IH), 7.56-7.48 (m, 2H), 7.39 (d, J = 8.6 Hz, IH), 6.85 - 6.76 (m, 2H), 4.79 (s, 2H), 4.05 - 3.90 (m, IH), 1.86 - 1.70 (m, 4H), 1.64 - 1.36 (m, 5H), 1.19 -1.03 (m, 1H).

[0658] N-cyclohexyl-N-((6-fluoroquinolin-2-yl)methyl)-1-methyl-1H-benzo[d]imidazole-6-amine (compound 5.37, scheme 5)

[0661]

[0663] The titrated compound was synthesized according to procedure M, starting from fluoroquinoline-2-carbaldehyde 1.9 (2 eq, 0.44 mmol, 76 mg) and N-cyclohexyl-1-methyl-1H-benzo[d]imidazole-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 μL), and phenylsilane (3 eq, 0.65 mmol, 82 μL). Purification by silica gel column chromatography (dichloromethane/methanol 100:0 to 90:10) afforded the pure titrated product as a foamy yellow solid in 46% yield (39 mg). Characterization: Rt 2.59 min, generic method, MS = 389.0 [M+H]<+>. Exact mass: 388.2063. <!>H NMR (400 MHz, DMSO) ? 8.22 (d, J = 8.6 Hz, 1H), 8.06 (dd, J = 9.2, 5.4 Hz, IH), 7.87 (s, IH), 7.71 (dd, J = 9.4, 2.9 Hz, IH).4, 2.9 Hz, IH), 7.65 (td, J = 8.9, 2.9 Hz, IH), 7.50 (d, J = 8.6 Hz, IH), 7.37 (d, J = 8.9 Hz, IH), 6.87 (d, J = 2..4 Hz, IH), 6.76 (dd, J = 8.9, 2.4 Hz, IH), 4.70 (s, 2H), 3.95 - 3.77 (m, IH), 3.64 (s, 3H), 1.89 (d, J = 10.6 Hz, 2H), 1.89 (d, J = 10.6 Hz, 2H), 1.5 (d, 2H).6 Hz, 2H), 1.77 (d, J = 11.6 Hz, 2H), 1.61 (d, J = 13.0 Hz, IH), 1.55 - 1.34 (m, 4H), 1.20 - 1.01 (m, IH).

[0664] N-cyclohexyl-N-((6-fluoroquinolin-2-yl)methyl)benzo[d]oxazole-6-amine (compound 5.38, scheme 5)

[0667]

[0669] The titled compound was synthesized according to procedure M, starting from N-cyclohexylbenzo[d]oxazole-6-amine 5.17 (50 mg, 0.23 mmol, 1 eq), fluoroquinoline-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 gL), phenylsilane (3 eq, 0.69 mmol, 53 gL). The crude was purified on silica gel by column chromatography using cyclohexane/ethyl acetate from 80:20 to 50:50 as eluent to obtain the not sufficiently pure product. The compound was was further purified by a second column chromatography on silica gel using dichloromethane/ethyl acetate as eluent from 100:0 to 90:10 to afford the pure compound titrated as a foamy yellow solid in 40% yield. Characterization: Rt 1.95 min, apolar method, MS (ESI) m/z = 376.0 [M+H]<+>. H NMR (400 MHz, DMSO) ? 8.38 (s, IH), 8.26 (d, J = 8.6 Hz, IH), 8.06 (dd, J = 9.2, 5.4 Hz, IH), 7.74 (dd, J = 9.2, 5.4 Hz, IH).74 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (td, J = 8.9, 2.9 Hz, IH), 7.47 (dd, J = 11.2, 8.7 Hz, 2H), 7.03 (d, J = 2.4 Hz, IH), 6.83 (dd, J = 9.0, 2.5 Hz, IH), 4.73 (s, 2H), 3.92 (t, J = 9.8 Hz, IH), 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, IH), 1.48 (q, J = 12.1 Hz, 4H), 1.21 - 1.08 (m, IH).

[0670] N-((6-fluoroquinolin-2-yl)methyl)-N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)cyclohexanamine (Compound 5.39, Scheme 5)

[0671]

[0673] The titled compound was synthesized according to the procedure M described previously. 6-Fluoroquinolin-2-carbaldehyde 1,9 (350 mg, 2 mmol) is dissolved in 14 mL of THF, TFA (3 mmol, 235 µL), and N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)cyclohexanamine 5,19 (1 mmol, 258 mg) are added, and the mixture is stirred for 1 h. Phenylsilane (2.25 mmol, 273 µL) 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 sulfate. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10) afforded the pure titrated compound as a white solid in 45% yield (187 mg). Characterization: Rt 2.41 min, generic method, MS (ESI) m/z = 417 [M+H]<+>. Exact mass: 416.50. H NMR (400 MHz, DMSO) ? 8.26 (d, J = 8.5 Hz, IH), 7.98 (dd, J = 9.2, 5.4 Hz, IH), 7.86 - 7.82 (m, 2H), 7.73 (d, J = 8.5 Hz, IH), 7.66 (dd, J = 9.4, 2.9 Hz, IH), 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, IH), 1.88 (d, J = 12.0 Hz, 2H), 1.74 (d, J = 12.1 Hz, 2H), 1.55 (d, J = 11.6 Hz, IH), 1.33 (q, J = 11.8 Hz, 2H), 1.14 (dq, J = 26.0 12.4 Hz, 3H).

[0674] N-((6-fluoroquinolin-2-yl)methyl)-N-((2-phenyloxazole-5-yl)methyl)cyclohexanamine (Compound 5.40, Scheme 5)

[0677]

[0679] The titled compound was synthesized according to the procedure M described previously. 6-Fluoroquinoline-2-carbaldehyde 1,9 (350 mg, 2 mmol) is dissolved in 14 mL of THF, TFA (3 mmol, 235 µL) and N-((2-phenyloxazol-5-yl)methyl)cyclohexanamine 5,20 (1 mmol, 2.56 mg) are added, and the reaction is prestiged for 1 h. Phenylsilane (2.25 mmol, 273 µL) 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 sulfate. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10) afforded the pure titrated compound as a white solid in 74% yield (307 mg). Characterization: Rt 2.28 min, generic method, MS (ESI) m/z = 416 [M+H]<+>. Exact mass: 415.21.

[0680] <1>H NMR (400 MHz, DMSO) ? 8.25 (d, J = 8.6 Hz, IH), 8.03 (s IH) , 7.99 (dd, J = 9.2, 5.5 Hz, IH) , 7.92 - 7.87 (m, 2H) , 7.80 (d, J = 8.6 Hz, IH) , 7.69 (dd, J = 9.5, 2.9 Hz, IH) , 7.59 (td, J = 8.9, 2.9 Hz, IH) .9, 2.9 Hz, IH) , 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, IH) , 1.42 - 1.00 (m, 5H) .

[0681] N-((6-fluoroquinolin-2-yl)methyl)-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)cyclohexanamine (Compound 5.41, Scheme 5)

[0684]

[0686] The titled compound was synthesized according to the procedure M described previously. 6-Fluoroquinolin-2-carbaldehyde 1,9 (350 mg, 2 mmol) is dissolved in 14 mL of THF, TFA (3 mmol, 235 µL) and N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)cyclohexanamine 5,18 (1 mmol, 2.57 mg) are added, and the mixture is stirred for 1 h. Phenyl silane (2.25 mmol, 273 µL) 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 sulfate. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10) yielded the pure titrated compound as a white solid in a 52% yield (216 mg). Characterization: Rt 2.44 min, generic method, MS (ESI) m/z = 417 [M+H]<+>. Exact mass: 416.20. NMR (400 MHz, DMSO) ? 8.26 (d, J = 8.5 Hz, IH), 7.98 (dd, J = 9.2, 5.4 Hz, IH), 7.87 - 7.82 (m, 2H), 7.73 (d, J = 8.5 Hz, IH), 7.66 (dd, J = 9.4, 2.9 Hz, IH), 7.62 - 7.47 (m, 2H). 62 - 7.47 (m, 4H), 4.18 (s, 2H), 4.12 (s, 2H), 2.74 - 2.60 (m, IH), 1.88 (d, J = 12.0 Hz, 2H), 1.74 (d, J = 12.1 Hz, 2H), 1.55 (d, 11.6 Hz, IH), 1.42 - 1.01 (m, 5H).

[0687] ?,?-bis((6-fluoroquinolin-2-yl)methyl)cyclohexanamine (compound 5.42, scheme 5)

[0690]

[0692] The titrated compound was synthesized according to the procedure M described above; 6-fluoroquinoline-2-carbaldehyde 1.9 (350 mg, 2 mmol) is dissolved in 14 mL of THF, TFA (3 mmol 235 µL) and N-(pyridin-3-ylmethyl)cyclohexanamine 5.21 (1 mmol, 190 mg) are added and the reaction is prestiged for 1 hour.

[0693] Phenyl silane (2.25 mmol, 273 µL) is added by gravity, and the mixture is stirred overnight. The reaction is quenched with sodium carbonate, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10) afforded the pure titrated compound as a white solid in a 57% yield (238 mg). Characterization: Rt 2.12 min, generic method, MS (ESI) m/z = 418 [M+H]. Exact mass: 417.20. H NMR (400 MHz, CDC1 _<33 >mm) ? 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, IH), 2.02 (d, J = 12.3 Hz, 2H), 1.79 (d, J = 11.6 Hz, 2H), 1.63 (s, 2H), 1.47 - 1.34 (m, 2H), 1.20 -1.09 (m, 2H).

[0694] N-cyclohexyl-N-((6-methoxyquinolin-2-yl)methyl)benzo[d]thiazol-6-amine (compound 5.43, scheme 5)

[0697]

[0699] The titrated compound was synthesized according to procedure M, starting from N-cyclohexylbenzo[d]thiazol-6-amine 5.12 (62 mg, 0.27 mmol, 1 eq) and 6-methoxyquinoline-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 µL), phenylsilane (3 eq, 0.8 mmol, 100 µL). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 90:10) afforded the pure titrated product as a white solid in 49% yield. Characterization: Rt 1.92 min, generic method, MS (ESI) m/z = 403.9 [M+H]<+>. ? NMR (400 MHz, DMSO) ? 8.94 (s, IH), 8.15 (d, J = 8.5 Hz, IH), 7.90 (d, J = 9.2 Hz, IH), 7.78 (d, J = 9.1 Hz, IH), 7.45 - 7.34 (m, 3H), 7.32 (d, J = 2.8 Hz, IH), 6.98 (dd, J = 9.2, 2.6 Hz, IH), 4.73 (s, 2H), 3.94 (d, J = 11.0 Hz, IH), 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, IH), 1.48 (q, J = 13.0 Hz, 4H), 1.19 - 1.11 (m, IH).

[0700] N-cyclohexyl-N-((6-ethoxyquinolin-2-yl)methyl)benzo[d]thiazol-6-amine (compound 5.44, scheme 5)

[0703]

[0705] The product was synthesized according to procedure M, starting from cyclohexylbenzo[d]thiazole-6-amine 5.12 (1 eq, 43 mg, 0.19 mmol) and 6-ethoxyquinoline-2-carbaldehyde 5.10 (2 eq, 0.37 mmol, 74 mg), trifluoroacetic acid (3 eq, 0.56 mmol, 42 µL), phenylsilane (3 eq, 0.56 mmol, 70 µL) in dry tetrahydrofuran (0.2 M, 0.9 mL). Purification by silica gel column chromatography (cyclohexane/ethyl acetate from 100:0 to 80:20) afforded the pure product titrated as a white solid in a 45% yield (35 mg). Characterization: Rt 2.19 min, generic method, MS (ESI) m/z = 418.0 [M+H]<+>. Exact mass: 417.1875. ? NMR (400 MHz, DMSO) ? 8.94 (s, IH), 8.13 (d, J = 8.6 Hz, IH), 7.89 (d, J = 9.2 Hz, IH), 7.78 (d, J = 9.1 Hz, IH), 7.42 (d, J = 2.6 Hz, IH), 7.41 - 7.33 (m, 2H), 7.30 (d, J = 2.8 Hz, IH), 6.98 (dd, J = 9.2, 2.6 Hz, IH), 6.98 (d, J = 9.2, 2.6 Hz, IH).2, 2.6 Hz, IH), 4.72 (s, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.91 (d, J = 28.3 Hz, IH), 1.87 (d, J = 9.7 Hz, 2H), 1.77 (d, J = 10.7 Hz, 2H), 1.62 (d, J = 12.9 Hz, IH), 1.59 - 1.33 (m, 7H), 1.22 - 1.07 (m, IH).

[0706] N-cyclohexyl-N-((6-(trifluoromethyl)quinolin-2-yl)methyl)benzo[d]thiazol-6-amine (compound 5.45, scheme 5)

[0709]

[0711] The titrated compound was synthesized according to procedure M, starting from cyclohexylbenzo[d]thiazole-6-amine 5.12 (50 mg, 0.22 mmol, 1 eq) and 6-(trifluoromethyl)quinoline-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 µL), and phenylsilane (3 eq, 0.65 mmol, 81 µL). The crude product was purified on silica gel by column chromatography using cyclohexane/ethyl acetate from 100:0 to 90:10 as the eluent. The product was was further purified by a second silica gel column chromatography using cyclohexane/dichloromethane from 100:0 to 90:10 as eluent. The product was further triturated with t-butyl methyl ether to afford the pure title product as a pale yellow solid in 10% yield (10 mg). Characterization: Rt 2.41 min, generic method, MS (ESI) m/z = 441.9 [M+H]<+ >. H NMR (400 MHz, DMSO) ? 8.95 (s, IH), 8.50 - 8.45 (m, 2H), 8.19 (d, J = 8.8 Hz, IH), 8.04 - 7.97 (m, IH), 7.79 (d, J = 9.0 Hz, IH), 7.58 (d, J = 8.6 Hz, IH), 7.45 (d, J = 2.6 Hz, IH), 6.99 (dd, J = 9.0 Hz, IH).99 (dd, J = 9.2, 2.6 Hz, IH), 4.83 (s, 2H), 3.97 (s, IH), 1.88 (d, J = 9.6 Hz, 2H), 1.77 (d, J = 10.8 Hz, 2H), 1.63 (d, J = 12.8 Hz, IH), 1.49 (q, J = 12.0 Hz, 4H), 1.21 - 1.09 (m, IH).

[0712] N-cyclohexyl-N-((6-(trifluoromethoxy)quinolin-2-yl)methyl)benzo[d]thiazol-6-amine (compound 5.46, scheme 5)

[0715]

[0717] The title compound was synthesized according to the N procedure, starting from 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 under reflux overnight. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 95:05) afforded the pure title as a pale yellow solid in 68% yield (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. <1>H NMR (400 MHz, DMSO) ? 8.95 (s, IH), 8.37 (d, J = 8.6 Hz, IH), 8.12 (d, J = 9.2 Hz, IH), 8.00 (s, IH), 7.79 (d, J = 9.1 Hz, IH), 7.77 - 7.71 (m, IH), 7.51 (d, J = 8.6 Hz, IH), 7.44 (d, J = 2. 10.6Hz, 2H).77 (d, J = 10.7 Hz, 2H), 1.63 (d, J = 12.9 Hz, IH), 1.48 (q, J = 11.5 Hz, 4H), 1.15 (d, J = 12.6 Hz, IH).

[0718] N-(benzo [d]thiazol-6-ylmethyl)-N-((6-fluoroquinolin-2-yl)methyl)tetrahydrofuran-3-amine (compound 5.47, scheme 5)

[0721]

[0723] The titrated compound was synthesized according to the N procedure, starting from 6-fluoro-2-(iodomethyl)quinoline 5.6 (350 mg, 2 mmol) in 20 mL of ACN, potassium carbonate (3 mmol, 414 mg), and N-(tetrahydrofuran-3-yl)benzo[d]thiazole-6-amine 5.22 (1.6 mmol, 352.4 mg). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10-10:90) afforded the pure titrated compound as a white solid in 53% yield (314 mg). Characterization: Rt 0.93 min, generic method, MS (ESI) m/z = 394 [M+H]<+>. Exact mass: 393.13. <1 >H NMR (400 MHz, DMSO) ? 8.98 (s, IH), 8.29 (d, J = 8.6 Hz, IH), 8.04 (dd, J = 9.3, 5.4 Hz, IH), 7.83 - 7.71 (m, 2H), 7.66 (td, J = 9.0, 2.9 Hz, IH), 7.51 - 7.43 (m, 2H), 6.99 (dd, J = 9.0, 2H).99 (dd, J = 9.1, 2.6 Hz, IH), 4.79 (q, J = 18.3 Hz, 3H), 4.01 - 3.85 (m, 2H), 3.78 (dd, J = 9.7, 4.1 Hz, IH), 3.66 (q, J = 8.0 Hz, IH), 2.40 (h, J = 7.9 Hz, IH), 1.94 (dq, J = 13.1, 7.7 Hz, IH).

[0724] N-(benzo[d]thiazol-6-ylmethyl)-N-((6-fluoroquinolin-2-yl)methyl)oxetane-3-amine (Compound 5.48, Scheme 5)

[0727]

[0729] The titrated compound was synthesized according to the N procedure, starting from 6-fluoro-2-(iodomethyl)quinoline 5.6 (350 mg, 2 mmol) in 20 mL of ACN, potassium carbonate (3 mmol, 414 mg), and N-(oxetane-3-yl)benzo[d]thiazole-6-amine 5.23 (1.6 mmol, 343.7 mg). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10-10:90) afforded the pure titrated compound as a white solid in 57% yield (345 mg). Characterization: Rt 1.00 min, generic method, MS (ESI) m/z = 380 [M+H]<+>. Exact mass: 379.12.<1 >H NMR (400 MHz, CDC1<3>) ? 8.73 (s, IH), 8.12 - 7.99 (m, 2H), 7.94 (d, J = 9.0 Hz, IH), 7.55 - 7.45 (m, 2H), 7.42 (dd, J = 8.7, 2.8 Hz, IH).7, 2.8 Hz, IH), 7.02 (d, J = 2.5 Hz, IH), 6.89 (dd, J = 9.0, 2.5 Hz, IH), 5.05 - 4.91 (m, 3H), 4.86 (s, 2H), 4.83 - 4.73 (m, 2H).

[0730] N-(cyclopropylmethyl)-N-((6-fluoroquinolin-2-yl)methyl)benzo[d]thiazole-6-amine (compound 5.49, scheme 5)

[0733]

[0735] The titrated compound was synthesized according to the general procedure M, starting from intermediate 5.24 (39 mg, 0.19 mmol), fluoroquinoline-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 µL), and phenylsilane (3 eq, 0.57 mmol, 71 µL). Purification by reversed-phase flash chromatography (H2O/MeCN 35:65) afforded the pure titrated compound as a brown solid (9.1 mg, 13% yield). Characterization: Rt = 1.50 min; MS (ESI) m/z: 364.1 [M+H]<+>. Exact mass: 363.1205. H NMR (400 MHz, DMS0-d6) ? 8.93 (s, IH), 8.26 (d, J = 8.6 Hz, IH), 8.05 (dd, J = 9.2, 5.4 Hz, IH), 7.79 (d, J = 9.2, 5.4 Hz, IH).79 (d, J = 9.1 Hz, IH), 7.74 (dd, J = 9.4, 2.9 Hz, IH), 7.66 (td, J = 8.9, 2.9 Hz, IH), 7.45 (d, J = 8.6 Hz, IH), 7.45 (d, J = 8.6 Hz, IH).6 Hz, IH), 7.42 (d, J = 2.5 Hz, IH), 7.02 (dd, J = 9.1, 2.6 Hz, IH), 4.94 (s, 2H), 3.53 (d, J = 6.6 Hz, 2H), 1.20 (dq, J = 13.2, 6.2 Hz, IH), 0.59 - 0.39 (m, 2H), 0.29 (dd, J = 4.9, 1.6 Hz, 2H).

[0736] tert-butyl 4-((benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl) methyl) amino ) me ti 1) piperidin-1-carboxylate (compound 5.50 , scheme 5)

[0739]

[0740] The titrated compound was synthesized according to the general N procedure, starting from 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 (H<2>O/MeCN 30:70) afforded the pure titrated compound as a yellow foam (104.9 mg, 54% yield). Characterization: Rt = 1.80 min; MS (ESI) m/z: 507.1 [M+H]<+>. Exact mass: 506.2152. <1>H NMR (400 MHz, DMSO-d6) ? 8.91 (s, IH), 8.25 (d J = 8.6 Hz, IH), 8.03 (dd, J = 9.2, 5.4 Hz, IH), 7.76 (d, J = 9.0 Hz, IH), 7.76 (d, J = 9.0 Hz, 1H).0 Hz, IH), 7.73 (dd, J = 9.4, 2.9 Hz, IH), 7.65 (td, J = 8.9, 2.9 Hz, IH), 7.38 (d, J = 2.6 Hz, IH), 7.36 (d, J = 8.2, 5.4 Hz, IH).36 (d, J = 8.6 Hz, IH), 6.97 (dd, J = 9.1, 2.6 Hz, IH), 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).1 Hz, 2H), 2.72 - 2.56 (m, 2H), 2.08 - 1.86 (m, IH), 1.73 (d, J = 12.7 Hz, 2H), 1.38 (s, 9H) 1.27 - 0.94 (m, 2H).

[0741] tert-butyl3-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl) methyl) amino)pyrrolidine-1-carboxylate (compound 5.51, Scheme 5)

[0744]

[0746] The titrated compound was synthesized according to the general N procedure, starting from 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 (H<2>O/MeCN 40:60) afforded the pure titrated compound as a brown oil (38.7 mg, 18% yield). Characterization: Rt 1.51 min; MS (ESI ) m/z : 479.2 [M+H] <+ >. Exact mass: 478, 1839. H NMR (400 MHz, DMSO-d6) ? 8.99 (s, IH), 8.30 (d, J = 8.6 Hz, IH), 8.03 (dd, J = 9.3, 5.4 Hz, IH), 7.80 (d, J = 9.0 Hz, IH), 7.76 (dd, J = 9.4, 2.9 Hz, IH), 7.66 (td, J = 8.9, 2.9 Hz, IH), 7.57 (d, J = 2.9 Hz, IH).57 (d, J = 2.5 Hz, IH), 7.46 (d, J = 8.6 Hz, IH), 7.04 (dd, J = 9.1, 2.6 Hz, IH), 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).

[0747] tert-butyl 4-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl)methyl) animino) azepan-l-carboxylate (compound 5.52 , Scheme 5)

[0750]

[0752] The titrated compound was synthesized according to the general N procedure, starting from 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 (H<2>O/MeCN 25:75) afforded the pure titrated compound as a brown foam (38.9 mg, 16% yield). Characterization: Rt = 1.80 min; MS (ESI) m/z: 507.2 [M+H]<+>. Exact mass: 506.2152. H NMR (400 MHz, DMSO-d6) ? 8.12 (d, J = 2.3 Hz, IH), 7.43 (d, J = 8.6 Hz, IH) , 7.21 (dd, J = 9.2, 5.4 Hz IH), 6.95 (dd, J = 9.2, 5.4 Hz, IH).95 (dd, J = 9.1, 5.6 Hz IH) , 6.90 (dd, J = 9.4, 2.9 Hz, IH) , 6.82 (td, J = 8.9, 2.9 Hz, IH), 6.64 (d, J = 8.6 Hz, IH), 6.6 (d, J = 8.6 Hz, IH).6 Hz, IH), 6.57 (d, J = 7.5 Hz, IH), 6.12 (t, J = 9.4 Hz, IH) 3.87 (s, 2H), 3.26 - 3.09 (m, IH), 2.76 - 2.56 (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) animino) piperidin-l-carboxylate (compound 5.53, Scheme 5)

[0755]

[0757] The title compound was synthesized according to the N procedure, starting from 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), with the reaction mixture refluxing overnight. The crude was purified on silica gel using cyclohexane/ethyl acetate 100:0 to 50:50 as the eluent to obtain a mixture of the product and the starting material. The mixture ? was further purified on reversed-phase silica gel using water/acetonitrile from 90:10 to 50:50 as eluent to afford the compound as a white solid in 26% yield (230 mg). Characterization: Rt 1.72 min, nonpolar method, MS = 493.0 [M+H]<+>. Exact mass: 492.1995. H NMR (400 MHz, DMSO) ? 8.97 (s, IH), 8.27 (d, J = 8.6 Hz, IH), 8.05 (dd, J = 9.2, 5.4 Hz, IH), 7.80 (d, J = 9.2, 5.4 Hz, IH).80 (d, J = 9.1 Hz, IH), 7.75 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (td, J = 8.9, 2.9 Hz, IH), 7.52 (d, J = 2.5 Hz, IH), 7.48 (d, J = 8.6 Hz, IH), 7.04 (dd, J = 9.2, 2.6 Hz, IH), 4.75 (s, 2H), 4.18 (t, J = 11.7 Hz, IH), 4.07 (d, J = 26.5 Hz, IH).07 (d, J = 26.0 Hz, 2H), 2.93 (s, 3H), 1.85 (d, J = 12.1 Hz, 2H), 1.66 - 1.51 (m, 2H), 1.38 (s, 9H).

[0758] N-(4-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl) methyl) animino) cyclohexyl) acetamide (compound 5.54, scheme 5)

[0761]

[0763] The titrated compound was synthesized according to procedure M, starting from N-(4-(benzo[d]thiazol-6-ylamino)cyclohexyl)acetamide 5.31 (1 eq, 245 mg, 0.84 mmol), 6-fluoroquinoline-2-carbaldehyde 1.9 (297 mg, 1.7 mmol, 2 eq), trifluoroacetic acid (3 eq, 2.5 mmol, 191 μL), phenylsilane (3 eq, 2.5 mmol, 308 μL), in dry tetrahydrofuran THF (0.07 M, 12 mL) at room temperature. The crude product was was purified first by silica gel column chromatography (hexane(s) -PrOH from 99:1 to 80:20) and then by C18 reversed-phase silica gel column chromatography (water/acetonitrile from 90:10 to 50:50) to afford the pure titrated product as a light yellow solid in 10% yield (37 mg). Characterization: MS (ESI) m/z = 449.2 [M+H]<+>. Exact mass: 448.1733. H NMR (400 MHz, dmso) ? 8.94 (s, IH), 8.26 (d, J = 8.5 Hz, IH), 8.05 (dd, J = 9.2, 5.4 Hz, IH), 7.80 - 7.70 (m, 3H), 7.66 (td, J = 8.9, 2.9 Hz, IH), 7.48 - 7.42 (m, 2H), 6. (dd, J = 9.9, 2H).97 (dd, J = 9.2, 2.5 Hz, IH), 4.76 (s, 2H), 3.95 (d, J = 12.1 Hz, IH), 3.50 (d, J = 11.6 Hz, 2H), 1.84 (d, J = 10.8 Hz, 5H), 1.77 (s, 3H), 1.64 (q, J = 12.3 Hz, 2H), 1.40 (q, J = 12.1 Hz, 2H).

[0764] N-((6-fluoroquinolin-2-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-6-amine (compound 5.55, scheme 5)

[0767]

[0769] The title compound was synthesized according to the N procedure, starting from N-(tetrahydro-2H-pyrano-4-yl)benzo[d]thiazole-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 was purified on silica gel using cyclohexane/ethyl acetate from 100:0 to 60:40 as the eluent. The compound was further purified by a mixture of eluents. The compound was was further purified by reversed-phase silica gel column chromatography, using 90:10 to 60:40 water/acetonitrile eluent to afford the compound as a white solid in 50% yield (110 mg). Characterization: Rt 1.00 min, nonpolar method, MS (ESI) m/z = 393.9 [M+H]<+ >, exact mass: 393.1311. ? NMR (400 MHz, DMSO) ? 8.97 (s, 1H), 8.27 (d, J = 8.6 Hz, IH), 8.06 (dd, J = 9.2, 5.4 Hz, IH), 7.80 (d, J = 9.2, 5.4 Hz, IH).80 (d, J = 9.1 Hz, IH), 7.75 (dd, J = 9.4, 2.9 Hz, 1H), 7.67 (td, J = 8.9, 3.0 Hz, IH), 7.54 (d, J = 2.6 Hz, 1H), 7.54 (d, J = 2.6 Hz, IH), 7.5 (d, J = 2.6 Hz, IH).6 Hz, 1H), 7.49 (d, J = 8.6 Hz, IH), 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).

[0770] N-((6-ethoxyquinolin-2-yl)methyl)-N-(thiazol-5-methyl)cyclopentanamine (compound 5.56, scheme 5)

[0771]

[0773] The titrated compound was synthesized according to procedure E, starting from intermediate 5.30 (0.265 mmol, 1 eq) in dry dichloromethane (900 μL), aldehyde 5.10 (153 mg, 0.265 mmol), acetic acid (catalytic), and sodium triacetoxybohydride (4 eq, 225 mg, 1.06 mmol), with stirring at room temperature overnight. Purification by flash chromatography on silica gel (cyclohexane/EtOAc 70:30) afforded the pure titrated compound (25 mg, 25% yield). Characterization: Rt = 1.61 min; MS (ESI) m/z: 368.5 [M+H]<+>, exact mass: 353.1562. H NMR (400 MHz, DMSO) ? 8.97 (d, J = 0.8 Hz, IH), 8.18 (d, J = 8.5 Hz, IH), 7.84 (d, J = 9.0 Hz, IH), 7.77 (s, 1H), 7.58 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 9.0, 2.8 Hz, 1H), 7.30 (d, J = 2.8 Hz, IH), 4.5 (d, J = 2.8 Hz, IH).8 Hz, IH), 4.15 (q, J = 7.0 Hz, 2H), 3.92 (s, 2H), 3.83 (s, 2H), 3.07 (t, J = 7.7 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) .

[0774] 2-((benzo[d]thiazol-6-yl(piperidin-1-io-4-ylmethyl)ammonium) methyl)-6-fluoroquinolin-1-ium chloride (compound 5.57, scheme 5)

[0775]

[0777] The compound was synthesized according to general procedure 01 using intermediate 5.50 (104 mg, 0.21 mmol) in dioxane (0.1 M, 2 mL) and HC14M in dioxane (8 eq, 1.64 mmol, 410 μL), stirring the reaction mixture at room temperature for 6 h. The solvent was evaporated to afford 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. H NMR (400 MHz, DMSO-d6) ? 8.95 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 8.7 Hz, IH), 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).01 (dd, J = 9.2, 2.6 Hz, IH), 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, IH), 1.92 (d, J = 13.1 Hz, 2H), 1.52 - 1.32 (m, 2H).

[0778] 2-((benzo[d]thiazol-6-yl(pyrrolidin-l-io-3-yl)ammonium)methyl)-6-fluoroquinolin-l-io chloride (compound 5.58, scheme 5)

[0781]

[0782] The titled compound was synthesized according to general procedure 01 using intermediate 5.51 (38 mg, 0.079 mmol) in dioxane (0.1 M, 800 µL) and HC14M in dioxane (8 eq, 0.635 mmol, 160 µL), stirring the reaction mixture at room temperature for 6 hours. The solvent was evaporated to afford 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. H NMR (400 MHz, DMSO-d6) ? 9.17 (b, IH), 9.08 (b, IH), 9.04 (s, IH), 8.37 (d, J = 8.6 Hz, IH), 8.08 (dd, J = 9.6 Hz, IH).08 (dd, J = 9.3, 5.4 Hz, IH), 7.84 (d, J = 9.0 Hz, IH), 7.80 (dd, J = 9.4, 2.9 Hz, IH), 7.70 (td, J = 8.9, 2.9 Hz, IH), 7.62 - 7.43 (m, 2H), 7.06 (dd, J = 9.1, 2.5 Hz, IH), 5.04 - 4.62 (m, 3H), 3.70 - 3.57 (m, IH), 3.5 (td, J = 9.4, 2.9 Hz, IH).57 (m, IH), 3.46 - 3.36 (m, IH),. 3.21 -3.05 (m, 2H), 2.36 - 2.25 (m, IH), 1.99 (dt, J = 19.9, 9.2 Hz, IH).

[0783] 2-((azepan-1-io-4-yl (benzo[d]thiazol-6-yl)ammonium)methyl)-6-fluoroquinolin-1-ium chloride (compound 5.59, scheme 5)

[0786]

[0788] The titled compound was synthesized according to general procedure 01 using intermediate 5.52 (38 mg, 0.075 mmol) in dioxane (0.1 M, 750 μL) and HC14M in dioxane (8 eq, 0.600 mmol, 150 μL), stirring the reaction mixture at room temperature for 4 hours. The solvent was evaporated to afford 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) ? 9.39 (b, IH), 9.26 (b, IH), 9.03 (s, IH), 8.65 (d, J = 8.7 Hz, IH), 8.36 (dd, J = 9.7 Hz, IH).36 (dd, J = 9.3, 5.1 Hz, IH), 7.98 (dd, J = 9.1, 2.9 Hz, IH), 7.89 (td, J = 8.9, 2.8 Hz, IH), 7.71 (d, J = 8.7 Hz, IH), 7.7 (s, IH).7.59 (d, J = 2.5 Hz, IH), 7.09 (dd, J = 9.1, 2.6 Hz, IH), 5.00 (d, J = 6.2 Hz, 2H), 4.36 (s, IH), 3.30 - 3.15 (m, 3H), 3.13 - 3.00 (m, IH), 2.26 - 2.09 (m, 2H), 2.06 - 1.66 (m, 4H).

[0789] 2-((benzo[d]thiazol-6-yl(piperidin-1-io-4-yl)ammonium) methyl)-6-fluoroquinolin-l-io chloride (compound 5.60, scheme 5)

[0792]

[0794] The titled compound was synthesized according to Procedure 01, starting from tert-butyl 4-(benzo[d]thiazol-6-yl ((6-fluoroquinolin-2-yl)methyl)amino)piperidine-1-carboxylate 5.53 (230 mg, 0.47 mmol, 1 eq) in dioxane (0.1 M), 4M HCl 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. ? NMR (400 MHz, DMSO) ? 9.03 (s, IH), 8.96 (s, IH), 8.73 (s, IH), 8.46 (d, J = 8.6 Hz, IH), 8.18 (dd, J = 9.3, 5.2 Hz, IH), 7.89 - 7.82 (m, 2H), 7.77 (td, J = 8.9, 2.9 Hz, IH), 7.64 - 7.56 (m, 2H), 7.10 (dd, J = 9.2, 2.6 Hz, IH), 4.85 (s, 2H), 4.35 (d, J = 9.6 Hz, IH), 3.35 (d, J = 12.4 Hz, 2H), 3.10 (s, 2H), 2.00 (d, J = 8.5 Hz, 4H).

[0795] N-(1,4-dioxaspiro[4,5]decan-8-yl)benzo[d]thiazol-6-amine (compound 6.3, scheme 6)

[0798]

[0800] The titrated compound? was synthesized according to procedure E, starting from 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 monoethylene acetal 6.2 (1 eq, 1.28 mmol, 200 mg), acetic acid (10 eq, 12.8 mmol, 732 μL), and sodium triacetoxybohydride (4 eq, 12.8 mmol, 732 μL).2 (1 eq, 1.28 mmol, 200 mg), acetic acid (10 eq, 12.8 mmol, 732 μL), and sodium triacetoxybohydride (4 eq, 1.085 g, 5.12 mmol), and the mixture ? was stirred at room temperature overnight. Purification by silica gel column chromatography (cyclohexane/ethyl acetate from 90:10 to 50:50) yielded the pure titrated product as a white, foamy solid in 77% yield (408 mg). Characterization: Rt 1.86 min, generic method, MS (ESI) m/z = 290.9 [M+H]<+>. Exact mass: 290.1089. H NMR (400 MHz, DMSO) ? 8.87 (s, IH), 7.72 (d, J = 8.8 Hz, IH), 7.15 (d, J = 2.3 Hz, IH), 6.85 (dd, J = 8.9, 2.3 Hz, IH), 5.85 (d, J = 8.0 Hz, IH), 3.87 (d, J = 2.0 Hz, IH).87 (d, J = 2.0 Hz, 4H), 3.84 - 3.82 (m, IH), 1.91 (dd, J = 12.6, 4.1 Hz, 2H), 1.73 (d, J = 12.9 Hz, IH), 1.69 - 1.55 (m, 2H), 1.52 - 1.40 (m, 3H).

[0801] 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)

[0804]

[0806] The titrated compound was synthesized according to the N procedure, starting from N-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d]thiazole-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 under reflux overnight. Purification on a silica gel column (100:0 to 95:05 dichloromethane/methanol) afforded the desired product as a white, foamy solid in 47% yield (75 mg). Characterization: Rt 2.44 min, generic method, MS (ESI) m/z = 450.0 [M+H]<+>. Exact mass: 449.1573. ? NMR (400 MHz, DMSO) ? 8.96 (s, IH), 8.27 (d, J = 8.6 Hz, IH), 8.06 (dd, J = 9.3, 5.4 Hz, IH), 7.80 (d, J = 9.1 Hz, IH), 7.75 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (td, J = 8.9, 2.9 Hz, IH).9, 2.9 Hz, IH), 7.51 (d, J = 2.6 Hz, IH), 7.46 (d, J = 8.6 Hz, IH), 7.02 (dd, J = 9.1, 2.6 Hz, IH), 4.72 (s, 2H), 4.10 (s, IH), 3.85 (s, 4H), 1.76 (td, J = 23.7, 12.9 Hz, 8H).

[0807] 4-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl)methyl)animino)cyclohexan-1-one (compound 6.5, scheme 6)

[0810]

[0812] The titrated compound was synthesized according to procedure P, starting from ((6-fluoroquinolin-2-yl)methyl)-N-(1,4-dioxaspiro[4.5]decane-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 µL), 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. ? NMR (400 MHz, DMSO) ? 8.98 (s, IH), 8.28 (d, J = 8.4 Hz, IH), 8.05 (dd, J = 9.2, 5.4 Hz, IH), 7.82 (d, J = 9.1 Hz, IH), 7.75 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (td, J = 8.9, 3.0 Hz, IH), 7.57 (d, J = 2.9, 3.0 Hz, IH).57 (d, J = 2.6 Hz, IH), 7.50 (d, J = 8.6 Hz, IH), 7.07 (dd, J = 9.1, 2.6 Hz, IH), 4.79 (s, 2H), 4.58 (t, J = 11.6 Hz, IH), 2.80 - 2.67 (m, 2H), 2.26 (d, J = 14.5 Hz, 2H), 2.12 (s, 2H), 1.99 (s, 2H).

[0813] 4-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl)methyl)amino)cyclohexan-1-ol (compound 6.6, scheme 6)

[0816]

[0818] The titrated product was synthesized according to the Q procedure, starting from 4-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl)methyl)amino)cyclohexan-1-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), with stirring for 1 h. Purification by silica gel column chromatography (100:0 to 90:10 dichloromethane/methanol) afforded the pure titrated product as a white, foamy solid in 91% yield (180 mg). Characterization: Rt 2.03 min, generic method, MS (ESI) m/z = 408.2 [M+H]<+>. Exact mass: 407.1468. H NMR (400 MHz, DMSO) ? 8.95 (s, IH), 8.26 (d, J 8.6 Hz, IH), 8.06 (dd, J = 9.2, 5.4 Hz, IH), 7.78 (d, J = 9.1 Hz, IH), 7.69 - 7.63 (m, 1H), 7.48 - 7.42 (m, 2H), 6.97 (dd, J = 9.1, 2.6 Hz, IH).1, 2.6 Hz, IH), 4.74 (s, 2H), 4.58 (d, J = 4.3 Hz, IH), 3.96 (t, J = 11.5 Hz, IH), 3.47 - 3.38 (m, IH), 1.85 (t, J = 15.4 Hz, 5H), 1.60 (q, J = 12.1 Hz, 2H), 1.42 (q, J = 11.5 Hz, 2H).

[0819] N-((6-fluoroquinolin-2-yl)methyl)-N-(1-methylpiperidin-4-yl)benzo[d]thiazol-6-amine (compound 7.1, scheme 7)

[0822]

[0824] To a solution of 2-((benzo[d]thiazol-6-yl(piperidin-1-io-4-yl)ammonium)methyl)-6-fluoroquinolin-1-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 μL) was added. Evolution of gas was observed. The mixture was stirred for 5 minutes to obtain the free amine, which was was reacted with paraformaldehyde in water (36%) (1.2 eq, 0.12 mmol, 8 μL), acetic acid (10 eq, 1.0 mmol, 57 μL), and sodium triacetoxybohydride (4 eq, 0.75 mmol, 84 mg), according to procedure E previously described. The crude was purified on silica gel using dichloromethane/methanol/ammonia from 100:0 to 80:19:1 as the 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. H NMR (400 MHz, DMSO) ? 8.96 (s, IH), 8.27 (d, J = 8.6 Hz, IH), 8.06 (dd, J = 9.2, 5.4 Hz, IH), 7.79 (d, J = 9.1 Hz, IH), 7.75 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (td, J = 8.9, 3.0 Hz, IH), 7.51- 7.44 (m, J = 8.9, 3.0 Hz, IH).51 - 7.44 (m, 2H), 7.00 (dd, J = 9.2, 2.6 Hz, IH), 4.76 (s, 2H), 3.93 (dt, J = 11.2, 6.4 Hz, IH), 2.81 (t, J = 9.9 Hz, 2H), 2.17 (s, 3H), 2.14 - 2.04 (m, 2H), 1.86 - 1.67 (m, 4H).

[0825] N-(1-butylpiperidin-4-yl)-N-((6-fluoroquinolin-2-yl) methyl)benzo[d]thiazol-6-amine (compound 7.2, scheme 7)

[0828]

[0830] To the solution of the raw material To the solution of 2-((benzo[d]thiazol-6-yl(piperidin-1-io-4-yl)ammonium)methyl)-6-fluoroquinolin-1-io 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 μL) was added. Evolution of gas was observed. The mixture was stirred for 5 minutes to obtain the free amine, which was was reacted with butyraldehyde (3 eq, 0.3 mmol, 27 µL), acetic acid (10 eq, 1.0 mmol, 57 µL), and sodium triacetoxyborohydride (4 eq, 0.75 mmol, 84 mg), according to procedure E previously described. The crude was purified on silica gel using dichloromethane/methanol/ammonia from 100:0 to 80:19:1 as the eluent to afford 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. <1>H NMR (400 MHz, DMSO) ? 8.96 (s, IH), 8.27 (d, J = 8.6 Hz, IH), 8.06 (dd, J = 9.3, 5.4 Hz, IH), 7.79 (d, J = 9.1 Hz, IH), 7.75 (dd, J = 9.1 Hz, IH).75 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (td, J = 8.9, 2.9 Hz, IH), 7.52 -7.44 (m, 2H), 7.01 (dd, J = 9.1, 2.6 Hz, IH), 4.76 (s, 2H), 4.00 - 3.85 (m, 2H), 3.85 (m, 2H).00 - 3.85 (m, IH), 2.92 (d, J = 11.1 Hz, 2H), 2.27 (dd, J = 8.2, 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), 1.38 (p, J = 7.1 Hz, 2H), 1.27 (dq, J = 14.7, 7.1 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0831] N-((6-fluoroquinolin-2-yl)methyl)-N-(1-isopropylpiperidin 4-yl)benzo[d]thiazol-6-amine (compound 7.3, scheme 7)

[0834]

[0836] To a solution of 2-((benzo[d]thiazol-6-yl(piperidin-1-io-4-yl)ammonium)methyl)-6-fluoroquinolin-1-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 µL) was added. Gas evolution was observed. The mixture was stirred for 5 minutes to obtain the free amine, which was was reacted with acetone (2 eq, 0.2 mmol, 15 μL), acetic acid (10 eq, 1.0 mmol, 57 μL), and sodium triacetoxybohydride (4 eq, 0.75 mmol, 84 mg), according to procedure E previously described. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 50:50) afforded the pure titrated product as a white, foamy solid in 64% yield (29 mg). Characterization: Rt 1.82 min, generic method, MS (ESI) m/z = 435.3 [M+H]<+>. H NMR (400 MHz, DMSO) ? 8.96 (s, IH), 8.27 (d, J = 8.6 Hz, IH), 8.06 (dd, J = 9.2, 5.4 Hz, IH), 7.79 (d, J = 9.2, 5.4 Hz, IH).79 (d, J = 9.1 Hz, IH), 7.75 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (td, J = 8.9, 2.9 Hz, IH), 7.50 (d, J = 2.6 Hz, IH), 7.50 (d, J = 2.6 Hz, IH).6 Hz, IH), 7.47 (d, J = 8.6 Hz, IH), 4.76 (s, 2H), 3.93 (s, IH), 2.85 (d, J = 10.9 Hz, 2H), 2.36 (d, J = 15.0 Hz, 2H), 1.84 (d, J = 11.8 Hz, 2H), 1.68 (q, J = 11.7 Hz, 2H), 0.97 (d, J = 6.5 Hz, 6H).

[0837] N-((6-fluoroquinolin-2-yl)methyl)-N-(1-isobutylpiperidin-4-yl)benzo[d]thiazole-6-amine (compound 7.4, scheme 7)

[0838]

[0840] To the solution of 2-((benzo[d]thiazol-6-yl(piperidin-1-io-4-yl)ammonium)methyl)-6-fluoroquinolin-1-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 μL) was added. Evolution of gas was observed. The mixture was stirred for 5 minutes to obtain the free amine, which was was reacted with isobutyraldehyde (2 eq, 0.2 mmol, 18 µL), acetic acid (10 eq, 1.0 mmol, 57 µL), and sodium triacetoxybohydride (4 eq, 0.75 mmol, 84 mg), according to procedure E previously described. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 50:50) afforded the pure titrated product as a white, foamy solid in 66% yield (30 mg). Characterization: Rt 1.96 min, MS (ESI) m/z = 449.3 [M+H] <+>. Exact mass: 448.2097. <1>H NMR (400 MHz, DMSO) ? 8.96 (s, IH), 8.27 (d, J = 8.6 Hz, IH), 8.06 (dd, J = 9.3, 5.4 Hz, IH), 7.80 (d, J = 9.1 Hz, IH), 7.74 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (td, J = 8.9, 2.9 Hz, IH), 7.51 - 7.44 (m, J = 8.9, 2.9 Hz, IH).51 -7.44 (m, 2H), 7.01 (dd, J = 9.1, 2.6 Hz, IH), 4.77 (s, 2H), 3.98 - 3.86 (m, IH), 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 8)

[0843]

[0845] The titled compound was synthesized according to Procedure E, starting from benzo[d]thiazol-6-amine 6.1 (150 mg, 1.0 mmol, 1.0 eq) in dry dichloromethane (0.3 M, 3.3 mL), tert-butyl 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 μL), and sodium triacetoxyboride (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) afforded the product as a light brown solid. MS (ESI) m/z = 360.1 [M+H]+. Exact mass: 359.1667.

[0846] tert-butyl 3-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl)methyl)amino )-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 8.3, Scheme 8)

[0847]

[0849] The titled compound was synthesized according to procedure M, starting from 6-fluoroquinolin-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 was purified on silica gel by column chromatography using dichloromethane/acetone from 100:0 to 90:10 as eluent to afford the compound as a beige solid. Characterization: LCMS only, MS (ESI) m/z = 519.1 [M+H]<+>. Exact mass: 518.2152.

[0850] 2-((benzo[d]thiazol-6-yl((IR,5S)-8-azabicyclo[3.2.1]octane-8-io-3-yl)ammonium)methyl)-6-fluoroquinolin-1-ium chloride (compound 8.4, scheme 8)

[0853]

[0854] The titrated compound was synthesized according to procedure 02, starting from tert-butyl 3-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl)methyl)amino)-8-azabicyclo

[0855] [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 afford the compound as an orange solid in 5% yield over three passes (30 mg). Characterization: MS (ESI) m/z = 419.2 [M+H]<+>. Exact mass: 418.1627. ? NMR (400 MHz, DMSO) ? 9.16 (d, J = 10.9 Hz, 1H), 9.06 (s, IH), 8.98 (s, IH), 8.40 (d, J = 8.7 Hz, IH), 8.15 (dd, J = 9.3, 5.3 Hz, IH), 7.88 - 7.70 (m, 3H), 7.66 (d, J = 2.5 Hz, IH), 7.47 (d, J = 8.6 Hz, IH), 7.47 (d, J = 8.5 Hz, IH).6 Hz, IH), 7.13 (dd, J = 9.1, 2.5 Hz, IH), 4.85 (s, 2H), 4.63 (t, J = 8.2 Hz, IH), 2.44 - 2.51 (m, 6H, overlapping to the solvent signal), 2.02 (t, J = 4.8 Hz, 4H), 1.79 (dd, J = 14.1, 9.3 Hz, 2H).

[0856] tert-butyl 7-(benzo[d]thiazol-6-ylamino)-2-azaspiro[3.5]nonane-2-carboxylate (compound 9.2, Scheme 9)

[0859]

[0861] The titrated product was synthesized according to Procedure E, starting from 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]nonane-2-carboxylate 9.1 (1 eq, 1.0 mmol, 239 mg), acetic acid (1 eq, 1.0 mmol, 59 μL), and sodium triacetoxyboride (2 eq, 2.0 mmol, 424 mg). The crude product was purified on silica gel using cyclohexane i-PrOH from 99:1 to 80:20 as the eluent to yield the product as a light brown solid. Characterization: LSMS only, MS (ESI) m/z = 374.0 [M+H]+. 373.1824.

[0862] tert-butyl 7-(benzo[d]thiazol-6-yl((6-fluoroquinolin-2-yl)methyl)animino)-2-azaspiro[3.5]nonane-2-carboxylate (compound 9.3, Scheme 9)

[0865]

[0867] The titrated compound was synthesized according to procedure M, starting from 6-fluoroquinolin-2-carbaldehyde 1.9 (2 eq), tert-butyl 7-(benzo[d]thiazol-6-ylamino)-2-azaspiro[3.5]nonane-2-carboxylate 9.2 (1 eq) in dry tetrahydrofuran (0.2 M), trifluoroacetic acid (3 eq), phenylsilane (3 eq). The crude was purified on silica gel by column chromatography using dichloromethane/acetone from 100:0 to 90:10 as the eluent to obtain the compound as a beige solid. Characterization: LCMS only, MS (ESI) m/z = 533, 1 [M+H] <+ >. Exact mass: 532 .2308 .

[0868] 2-((benzo[d]thiazol-6-yl(2-azaspiro[3.5]nonan-2-io-7-yl)ammonium)methyl)-6-fluoroquinolin-1-ium chloride (compound 9.4, scheme 9)

[0871]

[0873] The titled compound was synthesized according to procedure 02, starting from tert-butyl 7-(benzo[d]thiazol-6-yl ((6-fluoroquinolin-2-yl)methyl)animino)-2-azaspiro[3.5]nonane-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 afford the compound as an orange solid in 33% yield in three steps (168 mg). MS (ESI) m/z = 433.2 [M+H]<+>. Exact mass: 432.1784. H NMR (400 MHz, DMSO) ? 9.13 (s, 2H), 9.00 (s, IH), 8.58 (d, J = 8.7 Hz, IH), 8.30 (dd, J = 9.4, 5.1 Hz, IH), 7.98 - 7.91 (m, 2H).98 - 7.91 (m, IH), 7.84 (dd, J = 24.1, 9.1 Hz, 2H), 7.66 (d, J = 8.7 Hz, IH), 7.53 (d, J = 2.5 Hz, IH), 7.04 (dd, J = 9.1, 2.6 Hz, 1H).1, 2.6 Hz, IH), 4.93 (s, 2H), 3.71 (t, J = 6.2 Hz, 2H), 3.60 (t, J = 6.3 Hz, 2H), 2.50 (IH superimposed on the solvent signal), 2.10 (d, J = 12.7 Hz, 2H), 1.79 (d, J = 12.0 Hz, 2H), 1.65 (dd, J = 14.7, 11.5 Hz, 2H), 1.52 (q, J = 12.1 Hz, 2H).

[0874] 3-(benzo[d]thiazol-6-ylamino)cyclohex-2-en-1-one (compound 10.2, scheme 10)

[0877]

[0878] 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 molecular sieve 4A (0.2 g), and the mixture was heated under microwave irradiation for 4 h at 100°C. Subsequently, the reaction mixture was allowed to cool and cautiously quenched with saturated aqueous NaHCO3 solution (control pH around 8). The aqueous layer was was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered, and evaporated. Purification on a silica gel column (dichloromethane/methanol 100:0 to 90:10) afforded the pure product as a light yellow oil in 49% yield (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) ? 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, IH).7, 2.2 Hz, IH), 5.38 (s, IH) 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).

[0879] rac-(IR,3R)-3-(benzo[d]thiazol-6-ylamino)cyclohexan-1-ol (compound 10.3, scheme 10) and rac-(IR,3S)-3-(benzo[d]thiazol-6-ylamino)cyclohexan-1-ol (compound 10.4, scheme 10)

[0882]

[0884] Compound10.3 Compound10.4 The titrated compounds were obtained according to the Q procedure, starting from 3-(benzo[d]thiazol-6-ylamino)cyclohex-2-en-1-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 was purified by basic aluminum oxide column chromatography using 100:0 to 90:10 dichloromethane/methanol as eluent to afford the two separated diastereomers, fraction 1 and fraction 2, as white, foamy solids, in 12% (20 mg) and 21% (35 mg) yields, respectively. Fraction 1 was purified by chromatography using 100:0 to 90:10 dichloromethane/methanol as eluent to afford the two separated diastereomers, fraction 1 and fraction 2, as white, foamy solids, in 12% (20 mg) and 21% (35 mg) yields, respectively. was identified as rac-(IR,3R)-3-(benzo[d]thiazol-6-ylamino)cyclohexan-1-ol and fraction 2 as rac-(1R,3S)-3-(benzo[d]thiazol-6-ylamino)cyclohexan-1-ol.

[0885] rac-(IR,3R)-3-(benzo[d]thiazol-6-ylamino)cyclohexan-1-ol (compound 10.3): Characterization: Rt 1.56 min, generic method, MS (ESI) m/z 248.9 [M+H]<+>. Exact mass: 248.0983. H NMR (400 MHz, DMSO) ? 8.86 (s, 1H), 7.72 (d, J = 8.9 Hz, IH), 7.10 (d, J = 2.3 Hz, IH), 6.85 (dd, J = 8.9, 2.3 Hz, IH), 5.75 (d, J = 8.0 Hz, IH), 4.48 (d, J = 3.0 Hz, IH), 3.5 (d, J = 3.0 Hz, IH), 3.5 (d, J = 3.0 Hz, IH), 3.5 (d, J = 3.0 Hz, IH).4 Hz, IH), 3.96 (s, IH), 3.64 (dd, J = 10.9, 6.5 Hz, IH), 1.83 (s, 2H), 1.68 (dd, J = 13.1, 8.8Hz, IH), 1.49 (td, J = 16.8, 8.3 Hz, 4H), 1.26 (q, J = 9.6 Hz, IH).

[0886] rac-(IR,3S)-3-(benzo[d]thiazol-6-ylamino)cyclohexan-1-ol (compound 10.4): Characterization: Rt 1.56 min, generic method, MS (ESI) m/z = 248.9 [M+H]<+>. Exact mass: 248.0983. <1>H NMR (400 MHz, DMSO) ? 8.87 (s, IH), 7.72 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 2.3 Hz, IH), 6.82 (dd, J = 8.9, 2.3 Hz, IH), 5.81 (d, J = 8.3 Hz, IH), 4.61 (d, J = 4.6 Hz, IH), 3.54 - 3.42 (m, OH), 3.27 (d, J = 3.7 Hz, IH), 2.18 (d, J = 12.0 Hz, IH), 1.93 (d, J = 12.6 Hz, IH), 1.83 (d, J = 11.8 Hz, IH), 1.70 (dt, J = 13.5, 3.5 Hz, IH), 1.37 - 1.22 (m, IH), 1.12 - 0.92 (m, 2H).

[0887] rac-(1S,3S)-3-[1,3-benzothiazol-6-yl-[(6-fluoro-2-quinolyl)methyl]amino]cyclohexanol (compound 10.5, scheme 10)

[0890]

[0892] The titrated compound was synthesized according to procedure M, starting from rac-(IR,3R)-3-(benzo[d]thiazol-6-ylamino)cyclohexan-1-ol 10.3 (1 eq, 20 mg, 0.08 mmol) and 6-fluoroquinolin-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 µL).11 Crude ? was purified on silica gel using dichloromethane/methanol as eluent from 100:0 to 80:20 and then in reverse phase using water/acetonitrile as eluent from 90:10 to 50:50 to afford 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. <!>H NMR (400 MHz, DMSO) ? 8.87 (s, IH), 8.20 (d, J = 8.6 Hz, IH), 7.98 (dd, J = 9.2, 5.4 Hz, IH), 7.73 (d, J = 9.1 Hz, IH), 7.7 (d, J = 9.1 Hz, 1H).1 Hz, IH), 7.67 (dd, J = 9.4, 2.9 Hz, IH), 7.59 (td, J = 8.9, 2.9 Hz, IH), 7.38 (d, J = 8.6 Hz, IH), 7.31 (d, J = 2.5 Hz, IH), 6.5 (d, J = 2.5 Hz, IH), 6.5 (d, J = 2.5 Hz, IH).5 Hz, IH), 6.91 (dd, J = 9.2, 2.6 Hz, IH), 4.75 - 4.62 (m, 2H), 4.60 (s, IH), 4.30 (t, J = 12.0 Hz, IH), 4.01 (s, IH), 1.87 - 1.70 (m, 4H), 1.64 - 1.50 (m, 2H), 1.44 (d, J = 10.0 Hz, IH), 1.33 - 1.22 (m, IH).

[0893] rac-(1R,3S)-3-[1,3-benzothiazol-6-yl-[(6-fluoro-2-quinolyl)methyl]amino]cyclohexanol (compound 10.6, scheme 10)

[0894]

[0896] The titrated compound was synthesized according to procedure M, starting from rac-(IR,3S)-3-(benzo[d]thiazol-6-ylamino)cyclohexan-1-ol 10.4 (1 eq, 35 mg, 0.14 mmol) and 6-fluoroquinolin-2-carbaldehyde 1.9 (2 eq, 0.28 mmol, 50 mg), trifluoroacetic acid (3 eq, 0.42 mmol, 32 µL), phenylsilane (3 eq, 0.42 mmol, 52 µL). Purification by silica gel column chromatography (dichloromethane/methanol 100:0 to 80:20) afforded the pure titrated product as a white, foamy solid in 17% yield (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. ? NMR (400 MHz, DMSO) ? 8.88 (d, J = 1.7 Hz, IH), 8.20 (d, J = 8.6 Hz, IH), 7.99 (dd, J = 9.2, 5.4 Hz, IH), 7.72 (d, J = 9.1 Hz, IH), 7.72 (d, J = 9.1 Hz, IH).1 Hz, IH), 7.67 (dd, J = 9.4, 2.9 Hz, IH), 7.60 (td, J = 8.9, 3.0 Hz, IH), 7.41 - 7.35 (m, 2H), 6.91 (dd, J = 9.2, 2.6 Hz, IH).2, 2.6 Hz, IH), 4.69 (s, 2H), 4.58 (d, J = 5.0 Hz, IH), 3.92 (s, IH), 3.55 (dd, J = 12.6, 2.9 Hz, IH), 1.98 (d, J = 10.9 Hz, IH), 1.98 (d, J = 10.0 Hz, IH).9 Hz, IH), 1.74 (d, J = 13.2 Hz, 2H), 1.64 (d, J = 10.3 Hz, IH), 1.37 - 1.24 (m, 3H), 1.08 - 0.91 (m, IH). 2-methyl-6-nitroquinoline (compound 11.2, Scheme 11)

[0897]

[0899] The compound was synthesized according to procedure A1, starting from 4-nitroaniline 11.1 (1 eq, 2 g, 14.48 mmol) in 6 M HCl (72 mL, 30 eq) and a solution of crotonaldehyde (2 eq, 28.96 mmol, 2.4 mL) in toluene (1.5 M, 19.3 mL), and the mixture was stirred at 100°C for 5 h. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10 to 80:20) afforded the pure title product as an ochreous solid in 66% yield (1.83 g). Characterization: Rt 1.81 min, MS (ESI) m/z = 188.8 [M+H]<+>. Exact mass: 188.0586. ? NMR (400 MHz, DMSO) ? 9.02 (d, J = 2.6 Hz, IH), 8.59 (d, J = 8.5 Hz, IH), 8.43 (dd, J = 9.2, 2.7 Hz, IH), 8.11 (d, J = 9.2 Hz, IH), 7.64 (d, J = 8.5 Hz, IH), 2.73 (s, 3H).

[0900] 6-nitroquinoline-2-carbaldehyde (compound 11.3, Scheme 11)

[0903]

[0905] The titled compound was synthesized according to procedure C, starting from 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), by 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).

[0906] Characterization: Rt 1.86 min, MS (ESI) m/z = 202.9 [M+H]<+>. Exact mass: 202.0378. ? NMR (400 MHz, DMSO) ? 10.17 (d, J = 0.9 Hz, IH), 9.22 (d, J = 2.6 Hz, IH), 8.96 (d, J = 8.5 Hz, IH), 8.59 (dd, J = 9.3, 2.6 Hz, IH), 8.45 (d, J = 9.3 Hz, IH), 8.17 (d, J = 8.5 Hz, IH).

[0907] N-cyclohexyl-N-((6-nitroquinolin-2-yl)methyl)benzo[d]thiazol-6-amine (compound 11.4, scheme 11)

[0910]

[0912] The titled compound was synthesized according to procedure M, starting from N-cyclohexylbenzo[d]thiazole-6-amine 5.12 (1 eq, 440 mg, 1.896 mmol), 6-nitroquinoline-2-carbaldehyde 11.3 (2 eq, 3.79 mmol, 767 mg), trifluoroacetic acid (3 eq, 5.69 mmol, 436 µL), and phenylsilane (3 eq, 5.69 mmol, 702 µL) in dry tetrahydrofuran (0.2 M, 9.5 mL). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100:0 to 50:50) afforded the pure title product as a foamy yellow solid in 65% yield (525 mg). Characterization: Rt 1.98 min, nonpolar method, MS = 419.2 [M+H]<+>. Exact mass: 418.1463. H NMR (400 MHz, DMSO) ? 9.02 (d, J = 2.6 Hz, IH), 8.95 (s, IH), 8.61 (d, J = 8.6 Hz, IH), 8.47 (dd, J 9.3, 2.7 Hz, IH), 8.19 (d, J 9.3 Hz, IH), 7.80 (d, J = 9.1 Hz, IH), 7.62 (d, J = 8.6 Hz, IH), 7.45 (d J = 2.6 Hz, IH), 6.5 (s, IH).6 Hz, IH), 6.98 (dd, J = 9.2, 2.6 Hz, IH), 4.84 (s, 2H), 3.98 (s, IH), 1.88 (d, J = 9.4 Hz, 2H), 1.77 (d, J = 10.7 Hz, 2H), 1.63 (d, J = 13.0 Hz, IH), 1.49 (q, J = 11.6 Hz, 4H), 1.16 (t, J = 8.9 Hz, IH). N-((6-aminoquinolin-2-yl)methyl)-N-cyclohexylbenzo[d]thiazol-6-amine (compound 11.5, scheme 11)

[0915]

[0917] To a solution of N-cyclohexyl-N-((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 10% wt Pd/C (35 mg, 20% wt of the starting material) were added, followed by the careful addition of methanol (0.5 mL). Evolution of gas was observed. The mixture was stirred for 1 h until the reaction was complete. The mixture was filtered through a Celite pad, eluting 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 Na<2>SO4, filtered, and evaporated. Purification by silica gel column chromatography (dichloromethane/methanol from 100:0 to 90:10) afforded the pure titrated compound as a yellowish solid in a 48% yield (80 mg). Characterization: Rt 1.24 min, nonpolar method, MS (ESI) m/z = 389.1 [M+H]<+>. Exact mass: 388.1722. ? NMR (400 MHz, DMSO) ? 8.93 (s, IH), 7.80 (dd, J = 20.2, 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, IH), 7.40 (d, J = 2.0 Hz, IH).40 (d, J = 2.5 Hz, IH), 7.20 - 7.11 (m, 2H), 6.97 (dd, J = 9.2, 2.6 Hz, IH), 6.75 (d, J = 2.5 Hz, IH), 5. (s, 2H), 5. (s, 2H).51 (s, 2H), 4.64 (s, 2H), 3.93 (s, IH), 3.18 (d, J = 5.2 Hz, IH), 1.86 (d, J = 9.9Hz, 2H), 1.77 (d, J = 10.7 Hz, 2H), 1.63 (d, J = 12.9 Hz, IH), 1.49 (p, J = 11.9 Hz, 4H), 1.15 (d, J = 12.3 Hz).

[0918] N-cyclohexyl-N-((6-(dimethylamino)quinolin-2-yl)methyl)benzo[d]thiazol-6-amine (compound 11.6, scheme 11)

[0921]

[0923] The titrated compound was synthesized according to procedure E, starting from N-((6-aminoquinolin-2-yl)methyl)-N-cyclohexylbenzo[d]thiazol-6-amine 11.5 (1 eq, 0.154 mmol, 60 mg), 36 wt% paraformaldehyde in water (2 eq, 0.302 mmol, 15 μL), acetic acid (10 eq, 1.54 mmol, 88 μL), and sodium triacetoxyborohydride (4 eq, 0.616 mmol, 88 μL) 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 100:0 to 90:10) afforded the pure titrated product as a brown solid in 50% yield (32 mg). Characterization: Rt 2.05 min, generic method, MS = 417.2 [M+H]<+>. Exact mass: 416.2035. ? NMR (400 MHz, DMSO) ? 8.93 (s, IH), 7.98 (d, J = 8.5 Hz, IH), 7.81 (d, J = 9.3 Hz, IH), 7.78 (d, J = 9.1 Hz, IH), 7.78 (d, J = 9.1 Hz, 1H).1 Hz, IH), 7.44 (dd, J = 9.3, 2.9 Hz, IH), 7.41 (d, J = 2.6 Hz, IH), 7.25 (d, J = 8.6 Hz, IH), 6.98 (dd, J = 9.2, 2.6 Hz, IH), 6.89 (d, J = 2.8 Hz, IH), 4.68 (s, 2H), 3.94 (s, IH), 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 Hz, IH).2 Hz, 2H), 1.77 (d, J = 10.6 Hz, 2H), 1.63 (d, J = 12.8 Hz, IH), 1.48 (q, J = 12.1 Hz, 4H), 1.22-1.06 (m, IH).

[0924] 6-fluoro-4-methoxy-2-methylquinoline (compound 12.1, Scheme 12)

[0927]

[0928] The titrated compound was synthesized according to Procedure I, starting from 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 μL), stirring the reaction mixture for 20 h at room temperature. Purification by silica gel column chromatography (cyclohexane/ethyl acetate from 80:20 to 50:50) afforded the pure titrated compound, a white solid, in 46% yield (40 mg). Characterization: Rt 1.78 min, MS (ESI) m/z = 191.7 [M+H]<+>. Exact mass: 191.0746. H NMR (400 MHz, DMSO) ? 7.90 (dd, J = 9.2, 5.4 Hz, IH), 7.69 (dd, J = 9.7, 2.9 Hz, IH), 7.58 (td, J = 8.9, 3.0 Hz, IH), 6.97 (s, IH), 4.01 (s, 3H), 2.59 (s, 3H).

[0929] 4-Ethoxy-6-fluoro-2-methylquinoline (compound 12.2, Scheme 12)

[0932]

[0934] The titrated compound was synthesized according to Procedure I, starting from 6-fluoro-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 μL), by 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. H NMR (400 MHz, DMSO) ? 7.89 (dd, J = 9.2, 5.4 Hz, IH), 7.69 (dd, J = 9.7, 3.0 Hz, IH), 7.58 (td, J = 8. 8, 3.0 Hz, IH).8, 3.0 Hz, IH), 6.95 (s, IH), 4.28 (q, J = 7.0 Hz, 2H), 2.58 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H).

[0935] 4-Chloro-6-fluoro-2-methylquinoline (compound 12.3, Scheme 12)

[0938]

[0940] 6-Fluoro-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 3 h. The mixture was allowed to cool and the residue was carefully quenched with saturated Na<2>CO<3 > and ice. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous Na<2>SO4 to afford 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. H NMR (400 MHz, CDC1<3>) ? 8.02 (dd, J = 9.2, 5.3 Hz, IH), 7.79 (dd, J = 9.4, 2.9 Hz, IH), 7.49 (ddd, J 9.2, 8.1, 2.9 Hz, IH) 7.41 (d, J = 0.8 Hz, IH), 2.71 (s, 3H).

[0941] 6-fluoro-4-methoxyquinoline-2-carbaldehyde (compound 12.4, Scheme 12)

[0944]

[0946] The titrated compound was synthesized according to procedure C, starting from 6-fluoro-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 2 h. The compound was obtained pure without column chromatographic purification. Yield: 92% (40 mg, light brown solid). Characterization: Rt 2.07 min, generic method, MS (ESI) m/z = 205.8 [M+H]<+>. H NMR (400 MHz, CDCl<3>) ? 10.13 (s, 1H), 8.19 (dd, J = 9.2, 5.3 Hz, IH), 7.85 (dd, J = 9.3, 2.9 Hz, IH), 7.56 (ddd, J = 9.1, 8.0, 2.8 Hz, IH), 7.40 (s, IH), 4.13 (s, 3H).

[0947] 4-Ethoxy-6-fluoroquinoline-2-carbaldehyde (compound 12.5, Scheme 12)

[0950]

[0952] The titrated compound was synthesized according to procedure C, starting from 4-ethoxy-6-fluoro-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. ? NMR (400 MHz, DMSO) ? 10.02 (s, IH), 8.23 (dd, J = 9.2, 5.4 Hz, IH), 7.86 - 7.82 (m, IH) 7.79 (td, J 8.8, 3.0 Hz, IH), 7.38 (s, IH), 4.47 4.28 (m, 2H), 1.49 (t, J = 6.9 Hz, 3H).

[0953] 4-Chloro-6-fluoroquinoline-2-carbaldehyde (compound 12.6 Scheme 12)

[0956]

[0958] The titrated compound was synthesized according to procedure C, starting from 4-chloro-6-fluoro-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), by 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. H NMR (400 MHz, DMSO) ? 10.08 (s, IH), 8.41 (dd, J = 9.3, 5.4 Hz, 1H), 8.03 (dd, J = 9.5, 2.8 Hz, IH), 7.97 (ddd, J = 9.2 8.3, 2.8 Hz, IH).

[0959] N-cyclohexyl-N-((6-fluoro-4-methoxyquinolin-2-yl)methyl)benzo[d]thiazole-6-amine (compound 12.7, scheme 12)

[0962]

[0964] The titrated compound was synthesized according to Procedure M, starting from N-cyclohexylbenzo[d]thiazol-6-amine 5.12 (26 mg, 0.11 mmol, 1 eq) and 6-fluoro-4-methoxyquinoline-2-carbaldehyde 12.4 (1.5 eq, 0.17 mmol, 35 mg) in dry tetrahydrofuran, trifluoroacetic acid (3 eq, 0.34 mmol, 25 gL), and phenylsilane (3 eq, 0.34 mmol, 42 gL). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10 to 80:20) afforded the pure titrated product as a white solid in 65% yield (31 mg). Characterization: Rt 2.10 min, apolar method, MS (ESI) m/z = 421.9 [M+H]<+>. Exact mass: 421.1624. ? NMR (400 MHz, DMSO) ? 8.95 (s, IH), 7.99 (dd, J = 9.2, 5.4 Hz, IH), 7.80 (d, J = 9.1 Hz, IH), 7.72 (dd, J = 9.7, 2.9 Hz, IH), 7.64 (td, J = 8.8, 3.0 Hz, IH), 7.46 (d, J = 2.6 Hz, IH), 6.99 (dd, J = 9.6 Hz, IH).99 (dd, J = 9.2, 2.6 Hz, IH), 6.94 (s, IH), 4.69 bs, IH), 3.95 (s, 2H), 3.89 (s, 3H), 1.91 (s, 2H), 1.79 (d, J = 10.5 Hz, 2H), 1.64 (d, J = 13.0 Hz, IH), 1.49 (q, J = 11.2 Hz, 4H)

[0965] N-Clclohexyl-N-((4-ethoxy-6-fluoroquinolin-2-yl)methyl)benzo[d]thiazol-6-amine (compound 12.8, scheme 12)

[0968]

[0970] The titrated compound was synthesized according to procedure M, starting from N-cyclohexylbenzo[d]thiazol-6-amine 5.12 (20 mg, 0.09 mmol, 1 eq), 4-ethoxy-6-fluoroquinoline-2-carbaldehyde 12.5 (1.5 eq, 0.13 mmol, 28 mg) in dry tetrahydrofuran, trifluoroacetic acid (3 eq, 0.26 mmol, 20 gL), phenylsilane (3 eq, 0.26 mmol, 32 gL). Purification by silica gel column chromatography (cyclohexane/ethyl acetate 90:10 to 80:20) afforded the pure titrated product as a golden foamy solid in 55% yield (21 mg). Characterization: Rt 2.38 min, MS (ESI) m/z = 436.0 [M+H]<+>. Exact mass: 435.1781. H NMR (400 MHz, DMSO) ? 8.95 (s, IH), 7.98 (dd, J = 9.2, 5.4 Hz, IH), 7.79 (d, J = 9.1 Hz, IH), 7.71 (dd, J = 9.6, 2.9 Hz, IH), 7.64 (td, J = 8.8, 3.0 Hz, IH), 7.45 (d, J = 2.6 Hz, IH), 6.98 (dd, J = 9.1, 2.6 Hz, IH), 6.90 (s, IH), 4. (s, 2H), 4. (s, 2H), 4. (s, 2H).68 (s, 2H), 4.13 (q, J = 6.9 Hz, 2H), 3.96 (d, J = 10.8 Hz, IH), 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, IH), 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, IH).

[0971] N-((4-chloro-6-fluoroquinolin-2-yl)methyl)-N-cyclohexylbenzo[d]thiazol-6-amine (compound 12.9, scheme 12)

[0974]

[0976] The titrated compound was synthesized according to procedure M, starting from N-cyclohexylbenzo[d]thiazol-6-amine 5.12 (50 mg, 0.22 mmol, 1 eq), 4-chloro-6-fluoroquinoline-2-carbaldehyde 12.6 (90 mg, 0.43 mmol, 2 eq), trifluoroacetic acid (3 eq, 0.65 mmol, 50 µL), and phenylsilane (3 eq, 0.65 mmol, 80 µL). Purification by silica gel column chromatography (cyclohexane/ethyl acetate from 100:0 to 90:10) afforded the pure titrated product as a pale yellow solid in a 31% yield (30 mg). Characterization: Rt 2.63 min, apolar method, MS (ESI) m/z = 425.9, 427.9 [M+H]<+>. Exact mass: 425.1129. ? NMR (400 MHz, DMSO) ? 9.01 (s, IH), 8.20 (dd, J = 9.2, 5.4 Hz, IH), 7.90 (dd, J = 9.6, 2.8 Hz, IH), 7.88 - 7.82 (m, 2H), 7.64 (s, IH), 7.52 (d, J = 2.6 Hz, IH), 7.04 (dd, J = 9.6 Hz, IH) Hz, 4H), 1.23 - 1.15 (m, IH).

[0977] N-((6-fluoroquinolin-2-yl)methyl)cyclopentanamine (compound 13.1, scheme 13)

[0980]

[0982] The titrated compound was synthesized according to general procedure E, starting from 6-fluoroquinoline-2-carbaldehyde 1,9 (1 eq, 50 mg, 0.29 mmol), cyclopentanamine (1 eq, 28 μL, 0.29 mmol), sodium triacetoxybohydride (4 eq, 1.14 mmol, 242 mg) in dry dichloromethane (0.3 M, 1 mL), without adding acetic acid. The crude was directly subjected to the subsequent reaction without further purification. Characterization: Rt = 1.47 min; MS (ESI) m/z: 244.8 [M+H]<+>. Exact mass: 244.1376. ? NMR (400 MHz, DMSO-d6) ? 8.29 (d, J = 8.6 Hz, IH), 8.01 (dd, J = 9.2, 5.5 Hz, IH), 7.74 (dd, J = 9.4, 2.9 Hz, IH), 7.66 (d, J = 8.4, 2.9 Hz, IH).66 (d, J = 8.3 Hz, IH), 7.65 - 7.58 (m, IH), 3.94 (s, 2H), 3.07 - 2.98 (m, IH), 1.77 - 1.55 (m, 4H), 1.55 - 1.27 (m, 4H).

[0983] N-((6-ethoxyquinolin-2-yl)methyl)-4-methoxybutane-1-amine (compound 13.2, scheme 13)

[0986]

[0988] The titled compound was synthesized according to general procedure E, starting from 6-ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 80 mg, 0.40 mmol), 4-methoxybutanl-amine (1 eq, 41 mg, 0.40 mmol), sodium triacetoxybohydride (4 eq, 1.59 mmol, 337 mg) in dry dichloromethane (0.3 M, 1.3 mL), without adding acetic acid. The crude was directly subjected to the subsequent reaction without further purification. Characterization: Rt = 1.62 min; MS (ESI) m/z: 289.7 [M+H]<+>. Exact mass: 288.1838. ? NMR (400 MHz, DMSO-d6) ? 8.18 (d, J = 8.6 Hz, OH), 7.84 (d, J = 9.0 Hz, IH), 7.54 (d, J = 8.5 Hz, OH), 7.38 - 7.28 (m, IH), 6.54 (s, IH) , 4.15 (q, J = 6.5 Hz, IH) .15 (q, J = 6.9 Hz 2H) , 3.89 (d, J = 34.8 Hz, IH) , 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) . N-((6-ethoxyquinolin-2-yl)methyl)-3, 3, 3-trifluoropropan-1-amine (compound 13.3, scheme 13)

[0991]

[0993] The titled compound was synthesized according to general procedure E, starting from 6-ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 80 mg, 0.40 mmol), 3,3,3-trifluoropropan-l-amine hydrochloride (1 eq, 60 mg, 0.40 mmol), sodium triacetoxybohydride (4 eq, 1.59 mmol, 337 mg) in dry dichloromethane (0.3 M, 1.3 mL), without the addition of acetic acid. The crude was directly subjected 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) ? 8.19 (d, J = 8.4 Hz, IH), 7.84 (d, J = 9.0 Hz, IH), 7.53 (d, J = 8.5 Hz, IH), 7.35 (dd, J = 9.0, 2.8 Hz, IH), 7.32 (d, J 2.8 Hz, IH).32 (d, J = 2.8 Hz, IH), 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).

[0994] 4-(((6-ethoxyquinolin-2-yl)methyl) animino) butan-1-ol (compound 13.4, scheme 13)

[0995]

[0997] The titled compound was synthesized according to general procedure E, starting from 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 80 mg, 0.40 mmol), 4-aminobutan-1-ol (1 eq, 37 μL, 0.40 mmol), sodium triacetoxybohydride (4 eq, 1.59 mmol, 337 mg) in dry dichloromethane (0.3 M, 1.3 mL), without adding acetic acid. The crude was directly subjected to the subsequent reaction without further purification. Characterization: Rt = 1.40 min; MS (ESI) m/z: 275.6 [M+H]<+>. Exact mass: 274.1681. H NMR (400 MHz, DMSO-d6) ? 8.18 (d, J = 8.4 Hz, IH), 7.84 (d, J = 9.0 Hz, IH), 7.54 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 8.9, 2.9 Hz, IH), 7.31 (d, J = 2..7 Hz, IH), 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).

[0998] N-((6-ethoxyquinolin-2-yl)methyl)butan-1-amine (compound 13.5, scheme 13)

[1001]

[1003] The titrated compound was synthesized according to general procedure E, starting from 6-ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 80 mg, 0.40 mmol, 1 eq), butane-1-amine (1 eq, 39 μL, 0.40 mmol, 1 eq), sodium triacetoxybohydride (4 eq, 1.59 mmol, 337 mg) in dry dichloromethane (0.3 M, 1.3 mL), without adding acetic acid. The crude product was directly subjected to the subsequent reaction without further purification. Characterization: Rt = 1.71 min; MS (ESI) m/z: 259.7 [M+H]<+>. Exact mass: 258.1732. NMR (400 MHz, DMSO-d6) ? 8.18 (d, J = 8.5 Hz, IH), 7.84 (d, J = 9.0 Hz, IH), 7.55 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 9.0, 2.8 Hz, IH), 7.31 (d, J = 2.7 Hz, IH), 4.15 (q, J = 7.0, 2.8 Hz, IH).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).

[1004] (tert-butyl ((lr,4r)-4-(((6-fluoroquinolin-2-yl)methyl) amino)cyclohexyl)carbamate (Compound 13.6, Scheme 13)

[1007]

[1009] The titled compound was synthesized according to general procedure E, starting from 6-fluoroquinolin-2-carbaldehyde 1,9 (100 mg, 0.57 mmol, 1 eq), 1-N-Boc-trans-1,4-cyclohexyldiamine (122 mg, 0.57 mmol, 1 eq), sodium triacetoxybohydride (4 eq, 2.28 mmol, 484 mg) in dry dichloromethane (0.3 M, 2 mL), without adding acetic acid. The crude was directly subjected to the subsequent reaction without further purification. Characterization: Rt = 1.78 min; MS (ESI) m/z: 374.6 [M+H]<+>. Exact mass: 373.2166. H NMR (400 MHz, DMSO-d6) ? 8.29 (d, J = 8.5 Hz, IH), 8.01 (dd, J = 9.2, 5.4 Hz, IH), 7.74 (dd, J = 9.5, 2.9 Hz, IH), 7.66 (d, J = 8.5 Hz, IH), 7.64 - 7. 59 (m, IH), 7.59 (m, IH).59 (m, IH), 6.64 (d, J = 8.0 Hz, IH) 3.98 (s, 2H), 3.65 - 3.58 m, IH) 2.36 - 2.1i m, 2H) 1.7! - 1.66 (m, 3H), 1.36 (s, 9H), 1.14 - 1.04 (m, 5H).

[1010] N-((6-ethoxyquinolin-2-yl)methyl)cyclohexanamine (compound 13.7, scheme 13)

[1013]

[1015] The titrated compound was synthesized according to procedure E, starting from 6-ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 70 mg, 0.348 mmol), cyclohexylamine (1 eq, 0.348 mmol, 40 µL), sodium triacetoxybohydride (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 column chromatography purification (95% yield, 94 mg, brown oil). Characterization: Rt 1.89 min, generic method, MS (ESI) m/z = 285.2 [M+H]<+>. Exact mass: 284.1889. H NMR (400 MHz, DMSO) ? 8.17 (d, J = 8.5 Hz, IH), 7.84 (d, J = 9.0 Hz, IH) 7.56 (d, J = 8.5 Hz, IH), 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, IH), 1.86 (d, J = 12.2 Hz, 2H), 1.65 (d, J = 4.5 Hz, 2H), 1.54 (s, IH), 1.40 (t, J = 6.9 Hz, 3H), 1.26 - 1.00 (m, 5H).

[1016] 2-(((6-ethoxyquinolin-2-yl)methyl)amino)ethane-1-ol (compound 13.8, scheme 13)

[1019]

[1021] The titrated compound was synthesized according to procedure E, starting from 6-ethoxyquinolin-2-carbaldehyde 5.10 (1 eq, 70 mg, 0.348 mmol), 2-aminoethane-1-ol (1 eq, 0.348 mmol, 21 µL), sodium triacetoxybohydride (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 column chromatography purification (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) ? 8.19 (d, J = 8.3 Hz, IH), 7.85 (d, J = 9.0 Hz, IH), 7.54 (d, J = 8.5 Hz, IH), 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).

[1022] N-((6-ethoxyquinolin-2-yl)methyl)-2-methoxyethane-1-amine (compound 13.9, scheme 13)

[1025]

[1027] The titrated compound was synthesized according to procedure E, starting from 6-ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 70 mg, 0.348 mmol), 2-methoxyethane-1-amine (1 eq, 0.348 mmol, 30 µL), sodium triacetoxybohydride (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. H NMR (400 MHz, DMSO) ? 8.18 (d, J = 8.5 Hz, IH), 7.85 (d, J = 9.0 Hz, IH), 7.53 (d, J = 8.5 Hz, IH), 7.35 (dd, J = 9.0, 2.8 Hz, IH), 7.32 (d, J = 2.8 Hz, IH), 4.5 (d, J = 2.8 Hz, IH).8 Hz, IH), 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).

[1028] tert-butyl (4-(((6-ethoxyquinolin-2-yl)methyl)amino )cyclohexyl)carbamate (compound 13.10, scheme 13)

[1031]

[1033] The titrated compound was synthesized according to procedure E, starting from 6-ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 70 mg, 0.348 mmol), tert-butyl (4-aminocyclohexyl)carbamate (1 eq, 0.348 mmol, 75 mg), sodium triacetoxybohydride (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. H NMR (400 MHz, DMSO) ? 8.17 (d, J = 8.5 Hz, IH), 7.84 (d, J = 9.1 Hz, IH), 7.55 (d, J = 8.5 Hz, IH), 7.37 - 7.30 (m, 2H), 6.65 (bs, IH), 4.15 (q, J = 7.5 Hz, IH).15 (q, J = 7.0 Hz, 2H), 3.94 (s, 2H), 3.18 (bs, IH), 2.35 - 2.26 (m, IH), 1.91 (bs, 2H), 1.75 (bs, 2H), 1.44-1.32 (m, 11 H), 1.09 (q, J = 9.1 Hz, 2H).

[1034] N-((6-ethoxyquinolin-2-yl)methyl)benzo[d]thiazole-6-amine (compound 13.11, scheme 13)

[1037]

[1039] To the solution of 6-ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 2.38 mmol, 500 mg) and benzo[d]thiazole-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 µL) was added and the mixture was stirred at room temperature overnight. Subsequently, sodium borohydride (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 Na<2>CO<3 > and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na<2>SO<4> , filtered, and evaporated. The crude was purified by column chromatography over neutral aluminum oxide (cyclohexane/i-propanol from 100:0 to 90:10) to yield the pure titrated compound as a foamy yellowish 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. <J>H NMR (400 MHz, DMSO) ? 8.89 (s, IH), 8.19 (d, J = 8.5 Hz, IH), 7.92 (d, J = 9.1 Hz, IH), 7.76 (d, J = 8.9 Hz, IH), 7.50 (d, J = 8.5 Hz, IH), 7.38 (dd, J = 9.1, 2.8 Hz, IH), 7.32 (d, J = 2.8 Hz, IH).32 (d, J = 2.8 Hz, IH), 7.15 (d, J = 2.2 Hz, IH), 6.96 (dd, J = 8.9, 2.3 Hz, IH), 6.82 (t, J = 6.0 Hz, IH), 4.56 (d, J = 6.0 Hz, 2H), 4.15 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H).

[1040] N-((6-fluoroquinolin-2-yl)methyl)-N-(thiazol-5-methyl)cyclopentanamine (compound 13.13, scheme 13)

[1043]

[1045] The titrated compound was synthesized according to general procedure E using intermediate 13.1 (0.29 mmol, 1 eq), thiazole-5-carbaldehyde 13.12 (1 eq, 28 μL, 0.29 mmol), catalytic acetic acid, and sodium triacetoxybohydride (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) afforded the pure titrated compound as an orange oil (55.8 mg, 57% yield). Characterization: Rt = 1.49 min; MS (ESI) m/z: 342.6 [M+H]<+>. Exact mass: 341.1362. H NMR (400 MHz, DMSO-d6) ? 8.97 (d, J = 0.8 Hz, IH), 8.31 (d, J = 8.5 Hz, IH), 8.02 (dd, J = 9.2, 5.5 Hz, IH), 7.77 (d, J = 0.9 Hz, IH), 7.74 (dd, J = 9.4, 2.9 Hz, IH), 7.68 (dd, J = 8.4, 2.9 Hz, IH).68 (dd, J = 8.5, 0.9 Hz, IH), 7.62 (td, J = 8.9, 2.9 Hz, IH), 3.94 (s, 2H), 3.87 (s, 2H), 3.07 (p, J = 7.9 Hz, IH), 1.76 (s, 2H), 1.58 (d, J = 12.0 Hz, 2H), 1.54 - 1.28 (m, 4H).

[1046] N-((6-ethoxyquinolin-2-yl)methyl)-4-methoxy-N-(thiazol-5-methyl)butan- 1-aitimine (compound 13.14, scheme 13)

[1049]

[1051] The titrated compound was synthesized according to general procedure E using intermediate 13.2 (1 eq, 0.40 mmol), thiazole-5-carbaldehyde 13.12 (39 μL, 0.40 mmol), catalytic acetic acid, and sodium triacetoxybohydride (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) afforded the pure compound titrated as a brown oil (39.8 mg, 26% yield). Characterization: Rt = 1.08 min; MS (ESI) m/z : 386.7 [M+H]<+>. Exact mass: 385.1824. ? NMR (400 MHz, DMS0-d6) ? 9.01 (d, J = 0.9 Hz, IH) , 8.21 (d, J = 8.5 Hz, IH) , 7.85 (d, J = 9.0 Hz, IH) , 7.79 (d, J = 0.9 Hz, IH) , 7.55 (d, J = 8.5 Hz, IH) , 7.34 (dd, J = 9.0, 2.8 Hz, IH) , 7.32 (d, J = 2.8 Hz, IH) .32 (d, J = 2.8 Hz, IH) , 4.15 (q, J = 6.9 Hz, 2H) , 3.89 (s, 2H) , 3.78 (s, 2H) , 3.19 (t, J = 6.2Hz, 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 = 7.0Hz, 3H)

[1052] N-((6-ethoxyquinolin-2-yl)methyl)-3, 3, 3-trifluoro-N-(thiazol-5-methyl)propane-1-amine (compound 13.15, scheme 13)

[1055]

[1057] The titrated compound was synthesized according to general procedure E using intermediate 13.3 (1 eq, 0.084 mmol), thiazole-5-carbaldehyde 13.12 (1 eq, 8 μL, 0.084 mmol), catalytic acetic acid, and sodium triacetoxybohydride (4 eq, 0.336 mmol, 7 8 mg), in dry dichloromethane (0.2 M, 650 μL). The mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel (cyclohexane/acetone 60:40) afforded the pure titrated compound as a yellow oil (18.8 mg, 57% yield). Characterization: Rt 2.42 min; MS (ESI) m/z: 396.2 [M+H]<+>. Exact mass: 395.1279. ? NMR (400 MHz, DMSO-d6) ? 9.03 (s, IH), 8.22 (d J = 8.5 Hz, IH), 7.86 (d, J = 9.0 Hz, IH), 7.83 (s, IH) 7.55 (d, J = 8.5 Hz, IH), 7.35 (dd, J = 9.0, 2.8 Hz, IH), 7.33 (d, J = 2.8 Hz, IH).33 (d, J = 2.7 Hz, IH), 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, IH), 1.40 (t, J = 7.0Hz, 3H).

[1058] 4-(((6-ethoxyquinolin-2-yl)methyl)(thiazol-5-methyl)amino) butan-1-ol (compound 13.16, scheme 13)

[1061]

[1063] The titled compound was synthesized according to general procedure E using intermediate 13.4 (1 eq, 0.40 mmol), thiazole-5-carbaldehyde 13.12 (1 eq, 39 μL, 0.40 mmol), catalytic acetic acid, and sodium triacetoxybohydride (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) afforded the pure compound as the orange oil (59.6 mg, 44% yield). Characterization: Rt = 0.57 min; MS (ESI) m/z: 372.5 [M+H]<+>. Exact mass: 371.1667. H NMR (400 MHz, DMSO-d6) ? 9.01 (d, J = 0.8 Hz, IH), 8.21 (d, J = 8.5 Hz, IH), 7.85 (d, J = 9.1 Hz, IH), 7.79 (d, J = 0.1 Hz, IH).79 (d, J 0.9 Hz, IH) , 7.56 (d, J = 8.5 Hz, IH) , 7.34 (dd, J = 9.0, 2.8 Hz, IH) , 7.31 (d, J = 2.8 Hz, IH) , 4.36 (d, J = 5.7 Hz, IH), 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) .

[1064] N-((6-ethoxyquinolin-2-yl)methyl)-N-(thiazol-5-methyl)butan-1-amine (compound 13.17, scheme 13)

[1067]

[1069] The titrated compound was synthesized according to general procedure E using intermediate 13.5 (1 eq, 0.40 mmol), thiazole-5-carbaldehyde 13.12 (1 eq, 39 μL, 0.40 mmol), catalytic acetic acid, and sodium triacetoxybohydride (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) afforded the pure compound titrated as a brown oil (62.0 mg, 44% yield). Characterization: Rt = 1.58 min; MS (ESI) m/z: 356.7 [M+H]<+>. Exact mass: 355.1718. H NMR (400 MHz, DMSO-d6) ? 9.01 (d, J = 0.8 Hz, IH), 8.21 (d, J = 8.5 Hz, IH), 7.85 (d, J = 9.0 Hz, IH), 7.79 (d, J = 0.0 Hz, IH).79 (d, J = 0.9 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 9.0, 2.8 Hz, IH), 7.31 (d, J = 2.8 Hz, IH), 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 = 7.4 Hz, 3H) . tert-butyl ((lr,4r)-4- (((6-fluoroquinolin-2-yl)methyl) (thiazol-5-methyl)animino)cyclohexyl) carbamate (Compound 13.18, Scheme 13)

[1072]

[1074] The titrated compound was synthesized according to general procedure E using intermediate 13.6 (1 eq, 0.57 mmol), thiazole-5-carbaldehyde 13.12 (1 eq, 56 μL, 0.57 mmol), catalytic acetic acid, and sodium triacetoxybohydride (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 50:50) afforded the pure titrated compound as a yellow oil (83.7 mg, 31% yield). Characterization: Rt = 1.40 min; MS (ESI) m/z: 471.7 [M+H]<+>. Exact mass: 470.2152. ? NMR (400 MHz, DMSO-d6) ? 9.01 (d, J = 0.8 Hz, IH), 8.21 (d, J = 8.5 Hz, IH), 7.85 (d, J = 9.0 Hz, IH), 7.79 (d, J = 0.9 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 9.0, 2.8 Hz, IH), 7.31 (d, J = 2.8 Hz, IH), 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 = 7.0Hz, 3H), 1.23 (h, J = 7.3 Hz, 2H), 0.77 (t, J = 7.4 Hz, 3H).

[1075] N-((6-ethoxyquinolin-2-yl)methyl)-N-(thiazol-5-methyl)cyclohexanamine (compound 13.19, scheme 13)

[1078]

[1080] The titrated compound was synthesized according to procedure E, starting from N-((6-ethoxyquinolin-2-yl)methyl)cyclohexanamine 13.7 (1 eq, 94 mg, 0.33 mmol), thiazole-5-carbaldehyde 13.12 (1 eq, 0.33 mmol, 29 μL), 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 100:0 to 80:20) afforded the pure titrated compound as a white powder in 56% yield (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) ? 8.94 (s, IH), 8.19 (d, J = 8.5 Hz, IH), 7.83 (d, J = 9.0 Hz, IH), 7.74 (s, IH), 7.61 (d, J = 8.5 Hz, IH), 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, IH, superimposed on the solvent signal), 1.84 (d, J = 12.4 Hz, 2H), 1.72 (s, 2H), 1.54 (s, IH), 1.43-1.27 (m, 5H), 1.10 (q, J = 10.9 Hz, 3H).

[1081] 2-(((6-ethoxyquinolin-2-yl)methyl) (thiazol-5-methyl)amino ) ethane-1-ol (compound 13.19, scheme 13)

[1084]

[1086] The titled compound was synthesized according to procedure E, starting from 2-(((6-ethoxyquinolin-2-yl)methyl)animino)ethane-1-ol 13.8 (1 eq, 78 mg, 0.318 mmol), thiazole-5-carbaldehyde 13.12 (1 eq, 0.318 mmol, 27 μL), catalytic acetic acid, and sodium triacetoxybohydride (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 was purified by silica gel chromatography (dichloromethane 100:0 to 90:10). The product was was further purified by a second silica gel column chromatography using cyclohexane/i-propanol from 100:0 to 90:10 as eluent to afford the pure compound titrated as a pale yellow oil in a 27% yield (30 mg). Characterization: Rt 1.78 min, generic method, MS (ESI) m/z = 344.0 [M+H]<+>. Exact mass: 343.1354. H NMR (400 MHz, DMSO) 59.02 (d, J= 0.7 Hz, IH), 8.22 (d, J = 8.5 Hz, IH), 7.85 (d, J = 9.0 Hz, IH), 7.81 (d, J = 0.8 Hz, IH), 7.61 (d, J = 8.5 Hz, IH), 7.35 (dd, J = 9.0, 2.8 Hz, IH), 7.33 (d, J = 2.8 Hz, IH).33 (d, J = 2.7 Hz, IH), 4.56 (t, J = 5.4 Hz, IH), 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) .

[1087] N-((6-ethoxyquinolin-2-yl)methyl)-2-methoxy-N-(thiazol-5-methyl)ethane-1-amine (compound 13.21, scheme 13)

[1090]

[1092] The titled compound was synthesized according to procedure E, starting from N-((6-ethoxyquinolin-2-yl)methyl)-2-methoxyethane-1-amine 13.9 (1 eq, 70 mg, 0.269 mmol), thiazole-5-carbaldehyde 13.12 (1 eq, 0.269 mmol, 23 μL), catalytic acetic acid, and sodium triacetoxybohydride (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 silica gel chromatography (cyclohexane/acetone 80:20 to 60:40) afforded the pure titrated product as a pale yellow oil in 59% yield (57 mg). Characterization: Rt 2.11 min, generic method, MS (ESI) m/z = 357.7 [M+H]<+ >. Exact mass: 357.1511. H NMR (400 MHz, DMSO) ? 9.02 (d, J = 0.8 Hz, IH), 8.22 (d, J = 8.5 Hz, IH), 7.86 (d, J = 9.0 Hz, IH), 7.81 (d, J = 0.9 Hz, IH), 7.59 (d, J = 8.5 Hz, IH), 7.35 (dd, J = 9.0, 2.8 Hz, IH), 7.32 (d, J = 2.8 Hz, IH), 4.15 (q, J = 7.0 Hz, 2H), 3.98 (s, 2H), 3.86 (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).

[1093] tert-butyl (4-(((6-ethoxyquinolin-2-yl)methyl)(thiazol-5-methyl)animino)cyclohexyl)carbamate (compound 13.22, Scheme 13)

[1096]

[1098] The titrated compound was synthesized according to procedure E, starting from tert-butyl (4-(((6-ethoxyquinolin-2-yl)methyl)amino)cyclohexyl)carbamate 13.10 (1 eq, 140 mg, 0.348 mmol), thiazole-5-carbaldehyde 13.12 (1 eq, 0.348 mmol, 30 μL), catalytic acetic acid, and sodium triacetoxyboride (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 afforded the pure titrated compound as a white powder in 36% yield (63 mg). Characterization: Rt 1.85 min, apolar method, MS (ESI) m/z = 497.3 [M+H]<+>. Exact mass: 496.2508. H NMR (400 MHz, DMSO) ? 8.94 (d, J = 0.7 Hz, IH), 8.19 (d, J = 8.6 Hz, IH), 7.84 (d, J = 9.0 Hz, IH), 7.75 (s, IH), 7.59 (d, J = 8.5 Hz, IH), 7.38 - 7.29 (m, 2H), 6.61 (d, J = 8.1 Hz, IH), 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, IH), 2.52 (bs, IH, 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).

[1099] 2-(((4-ammoniumcyclohexyl)(thiazol-5-methyl)ammonium)methyl)-6-fluoroquinolin-1-ium chloride (compound 13.24, scheme 13)

[1102]

[1104] The compound was synthesized according to general procedure 01 using intermediate 13.18 (1 eq, 22 mg, 0.048 mmol) in dioxane (0.1 M, 500 µL) and HC14M in dioxane (8 eq, 0.389 mmol, 100 µL), stirring the reaction mixture at room temperature for 3 h. The solvent was evaporated to afford 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) ? 9.01 (d, J = 0.8 Hz, IH), 8.21 (d, J = 8.5 Hz, IH), 7.85 (d, J = 9.0 Hz, IH), 7.79 (d, J = 0.0 Hz, IH).79 (d, J = 0.9 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 9.0, 2.8 Hz, IH), 7.31 (d, J = 2.8 Hz, IH), 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 = 7.4 Hz, 3H).

[1105] N<1 >-((6-ethoxyquinolin-2-yl)methyl)-N<1 >-(thiazol-5-ylmethyl)-cyclohexane-1,4-diamine (compound 13.25, scheme 13)

[1106]

[1108] The titrated compound was synthesized according to procedure 01, starting from 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 eq, 1.3 mL) and HC14M in dioxane (8 eq, 0.253 mL), stirring the reaction mixture at room temperature for 5 h. The hydrochloric salt resulting from the deprotection was found to be unstable. After evaporation of the solvent, the crude product was dissolved in ethyl acetate and washed with 2M NaOH aqueous solution to afford the free amine. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na<2 >SO<4 >, filtered, and evaporated. Purification by silica gel column chromatography (dichloromethane/methanol/ammonia 100:0:0 to 80:19:1) afforded the pure titrated compound as a yellow oil in 42% yield (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) ? 8.95 (d, J = 0.8 Hz, IH), 8.19 (d, J = 8.6 Hz, IH), 7.84 (d, J = 9.0 Hz, IH), 7.75 (s, IH), 7.60 (d, J = 8.5 Hz, IH), 7.36 - 7.29 (m, 2H), 4.15 (q, J 6.5 Hz, IH), 4.5 (q, J 6.5 Hz, IH), 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 (IH superimposed on the D<2 >O signal), 2.50-2.45 (m, IH), 1.79 (d, J = 11.5 Hz, 4H), 1.51-1.37 (m, 5H), 0.93 (q, J = 11.8 Hz, 2H).

[1109] 1-(6-Ethoxyquinolin-2-yl)-N-(thiazol-5-methyl)methanamine (compound 14.2, scheme 14)

[1112]

[1114] To a 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. Gas evolution was observed. The mixture was stirred for 1 h to afford the free amine, which was reacted with ethoxyquinoline-2-carbaldehyde 5.10 (1 eq, 0.33 mmol, 670 mg) and sodium triacetoxybohydride (4 eq, 13.35 mmol, 2.82 g), without adding acetic acid, according to procedure E previously described. The reaction mixture was stirred overnight. Purification by silica gel column chromatography (cyclohexane/acetone 70:30) afforded the pure titrated compound as a light brown oil in 56% yield (564 mg). Characterization: Rt 1.64 min, generic method, MS (ESI) m/z = 300.2 [M+H]<+>. Exact mass: 299.1092. <1>H NMR (400 MHz, DMSO) ? 9.02 - 8.95 (m, IH), 8.20 (d, J = 8.5 Hz, IH), 7.85 (d, J = 9.0 Hz, IH), 7.76 (d, J = 1.1 Hz, IH) , 7.56 (d, J = 8.0 Hz, IH) .56 (d, J = 8.5 Hz, IH) , 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) . 3-((((6-Ethoxyquinolin-2-yl)methyl)(thiazol-5-methyl)amino)propanoic acid (compound 14.4, Scheme 14)

[1117]

[1119] 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 μL) were added, and the reaction mixture was stirred under reflux for 24 h. Then, 2 eq of 3-bromopropionic acid (51 mg) was added, and the mixture was stirred under reflux for another 24 h. The mixture was allowed to cool to room temperature and dried under vacuum to obtain the crude product, which was It was purified by silica gel column chromatography (dichloromethane/methanol from 100:0 to 90:10). The resulting residue was dissolved in i-propanol to yield a white precipitate (triethylammonium bromide), which was filtered. The filtrate was dried to yield 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) ? 9.03 (s, IH), 8.21 (d, J = 8.5 Hz, IH), 7.86 (d, J = 8.9 Hz, IH), 7.81 (s, IH), 7.56 (d, J = 8.5 Hz, IH), 7.38 - 7. 30 (m, 2H), 7.30 (m, 2H).30 (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).

[1120] N-((6-ethoxyquinolin-2-yl)methyl)-N-(thiazol-5-methyl)cyclobutanamine (compound 14.5, scheme 14)

[1123]

[1125] The titrated compound was synthesized according to procedure E, starting from 1-(6-ethoxyquinolin-2-yl)-α7-(thiazol-5-ylmethyl)methanamine 14,2 (1 eq, 50 mg, 0.168 mmol), cyclobutanone (1 eq, 0.168 mmol, 12.5 μL), catalytic acetic acid, sodium triacetoxybohydride (4 eq, 0.668 mmol, 141 mg) in dry dichloromethane (0.1 M, 1.7 mL), with stirring overnight. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 100 to 70:30) afforded the pure titrated compound as a clear oil in 51% yield (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) ? 9.00 (d, J = 0.8 Hz, IH), 8.19 (d, J = 8.5 Hz, IH), 7.87 (d, J = 9.0 Hz, IH), 7.76 (d, J = 0.0 Hz, IH).76 (d, J= 0.9 Hz, IH), 7.55 (d, J= 8.5 Hz, IH), 7.35 (dd, J = 9.0, 2.8 Hz, IH), 7.32 (d, J = 2.7 Hz, IH), 4.16 (q, J = 7.0 Hz, 2H), 3.83 (s, 2H), 3.70 (s, 2H), 3.23 - 3.10 (m, IH), 1.92 (q, J = 7.9 Hz, 2H), 1.92 (q, J = 2.5 Hz, IH).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).

[1126] N-((6-ethoxyquinolin-2-yl)methyl) -N-(thiazol-5-methyl) tetrahydrofuran-3-amine (compound 14.6, scheme 14)

[1129]

[1131] The titrated compound was synthesized according to procedure E, starting from 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 µL), catalytic acetic acid, sodium triacetoxybohydride (4 eq, 0.80 mmol, 170 mg) in dry dichloromethane (0.1 M, 2.0 mL), with stirring overnight. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 70:30 to 50:50) afforded the titrated pure compound as a yellowish oil in 53% yield (39 mg). Characterization: Rt 2.05 min, generic method, MS (ESI) m/z = 370.2 [M+H]<+>. Exact mass: 369.1511. ? NMR (400 MHz, DMSO) ? 9.00 (s, 1H), 8.21 (d, J 8.5 Hz, IH), 7.86 (d, J = 9.0 Hz, IH), 7.80 (s, 1H), 7.56 (d, J = 8.5 Hz, IH), 7.35 (dd, J = 9.0, 2.8 Hz, IH), 7.33 (d, J = 2.8 Hz, IH), 4. (q, J = 6.8 Hz, IH).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, IH), 2.01 (qd, J = 7.8, 3.9 Hz, IH), 1.93 - 1.80 (m, IH), 1.40 (t, J = 7.0 Hz, 3H).

[1132] tert-butyl 4-(((6-ethoxyquinolin-2-yl)methyl)(thiazol-5-methyl)animino)piperidin-l-carboxylate (compound 14.7, scheme 14)

[1135]

[1137] The titrated compound was synthesized according to procedure E, starting from 1-(6-ethoxyquinolin-2-yl)-N-(thiazol-5-ylmethyl)methanamine 14,2 (1 eq, 60 mg, 0.20 mmol), tert-butyl 4-oxopiperidin-1-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) afforded the pure compound titrated as a yellowish oil in 36% yield (35 mg). Characterization: Rt 2.60 min, generic method, MS (ESI) m/z = 483.4 [M+H]<+>. Exact mass: 482.2352. H NMR (400 MHz, DMSO) ? 8.94 (d, J = 0.7 Hz, 1H), 8.19 (d, J = 8.5 Hz, IH), 7.83 (d, J = 9.0 Hz, IH), 7.75 (d, J = 0.9 Hz, IH), 7.59 (d, J = 8.5 Hz, IH), 7.34 (dd, J 9.1, 2.8 Hz, IH), 7.31 (d, J = 2.8 Hz, IH), 4.15 (q, J = 7.0 Hz, 2H), 3.96 (d, J 18.8 Hz, 4H) 3.88 (s, 2H), 2.70 2.56 (m, 3H), 1.77 (d, J = 12.3 Hz, 2H), 1.48-1.32 (m,14H). N-((6-ethoxyquinolin-2-yl)methyl)-N-(thiazol-5-methyl)piperidin-4-amine (compound 14.8, scheme 14)

[1140]

[1142] The titrated compound was synthesized according to procedure 01, starting from tert-butyl 4-(((6-ethoxyquinolin-2-yl)methyl)(thiazol-5-ylmethyl)amino)piperidine-1-carboxylate 14.7 (1 eq, 30 mg, 0.062 mmol) dissolved in dioxane (1 mL) and 4M HCl in dioxane (8 eq, 0.12 mL), with stirring at room temperature for 3 h. The hydrochloric salt resulting from the deprotection was found to be unstable. After evaporation of the solvent, the crude product was dissolved in ethyl acetate and washed with 2M NaOH aqueous solution to afford the free amine. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na<2>SO<4>, filtered, and evaporated. Purification by silica gel column chromatography (dichloromethane/methanol/ammonia from 100:0:0 to 80:19:1) afforded the pure titrated compound as a white powder in a yield of 42% (10 mg). Characterization: Rt 1.71 min, generic method, MS (ESI) m/z = 383.2 [M+H]<H>-. H NMR (400 MHz, DMSO) ? 8.95 (d, J = 0.8 Hz, IH), 8.20 (d, J = 8.5 Hz, IH), 7.84 (d, J = 9.0 Hz, IH), 7.76 (s, IH), 7.60 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 9.1, 2.8 Hz, IH), 7.31 (d, J = 2.8 Hz, IH), 4.15 (q, J = 6.0 Hz, IH), 7.15 (q, J = 6.0 Hz, IH), 7.15 (q, J = 6.0 Hz, IH).15 (q, J = 6.9 Hz, 2H), 3.94 (s, 2H), 3.88 (s, 2H), 3.02 (d, J = 12.1 Hz, 2H), 2.64 - 2.54 (m, IH), 2.40 (t, J = 12.1 Hz, 2H).40 (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).

[1143] tert-butyl 1-(((6-ethoxyquinolin-2-yl)methyl)(thiazol-5-methyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate (compound 14 . 9 , Scheme 14 )

[1146]

[1148] The titrated compound was synthesized according to procedure E, starting from 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 triacetoxyboride (4 eq, 0.80 mmol, 170 mg) in dry dichloromethane (0.1 M, 2.0 mL), with stirring overnight. Purification by silica gel column chromatography (cyclohexane/ethyl acetate 80:20 to 50:50) afforded the pure titrated compound as a yellowish oil in 34% yield (35 mg). Characterization: Rt 1.84 min, apolar method, MS (ESI) m/z = 523.3 [M+H]<+>. Exact mass: 522.2665. H NMR (400 MHz, DMSO) ? 8.95 (d, J = 0.8 Hz, IH), 8.19 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 9.0 Hz, IH), 7.75 (s, IH), 7.34 (dd, J = 9.0, 2.8 Hz, IH), 7.31 (d, J = 2.8 Hz, IH), 4. (t, J = 6.0 Hz, IH).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), 2.42 (s, IH), 1.84 (d, J = 12.0 Hz, 2H), 1.73 (d, J = 11.7 Hz, 2H), 1.45-1.21 (m, 16 H).

[1149] N-((6-ethoxyquinolin-2-yl)methyl)-N-(thiazol-5-methyl)-2-azaspiro[3.5]nonan-7-aitimine (compound 14.10, scheme 14)

[1152]

[1154] The titrated product was synthesized from tert-butyl 7-(((6-ethoxyquinolin-2-yl)methyl)(thiazol-5-methyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate 14.9 (1 eq, 0.067 mmol, 35 mg) dissolved in a dry mixture of dichloromethane/trifluoroacetic acid 10:1 (2 mL), and stirring the reaction mixture for 2 h. Purification by silica gel column chromatography (dichloromethane/methanol/ammonia 100:0:0 to 80:19:1) afforded the pure titrated compound as a white, foamy solid in 70% yield (20 mg). Characterization: Rt 1.86 min, generic method, MS (ESI) m/z = 423.2 [M+H]<+>. Exact mass: 422.2140. ? NMR (400 MHz, DMSO) ? 8.94 (d, J = 0.8 Hz, IH), 8.19 (d, J = 8.6 Hz, IH), 7.83 (d, J = 9.0 Hz, IH), 7.75 (s, IH), 7.59 (d, J = 8.5 Hz, IH), 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 the D signal? 0, 3.24 (s, 2H), 3.10 (s, 2H), 2.41 (t, J = 10.2 Hz, IH), 1.97 (d, J = 12.5 Hz, 2H), 1.14 (q, J = 7.0 Hz, 2H), 1.5 (s, 2H).5 Hz, 2H), 1.71 (d, J = 12.0 Hz, 2H), 1.40 (t, J = 6.9 Hz, 3H), 1.32 (t, J = 12.2 Hz, 2H), 1.19 (t, J = 12.8 Hz, 2H).

[1155] N-((6-ethoxyquinolin-2-yl)methyl)-N-(thiazol-5-methyl)-1,4-dioxaspiro[4.5]decane-8-amine (compound 15.1, scheme 15)

[1158]

[1160] The titrated compound was synthesized according to procedure E, starting from 1-(6-ethoxyquinolin-2-yl)-α7-(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 triacetoxybohydride (4 eq, 0.8 mmol, 170 mg), stirring the reaction mixture overnight. Purification by chromatography on a silica gel column (cyclohexane/ethyl acetate from 80:20 to 50:50) yielded the pure compound, titrated as a yellow oil, in a 49% yield (43 mg). Characterization: Rt 1.09 min, nonpolar method, MS (ESI) m/z = 440.3 [M+H]<+>. Exact mass: 439.1930. ? NMR (400 MHz, DMSO) ? 8.94 (d, J = 0.8 Hz, IH), 8.19 (d, J = 8.5 Hz, IH), 7.84 (d, J = 9.1 Hz, IH), 7.75 (d, J = 0.1 Hz, IH).75 (d, J = 0.9 Hz, IH), 7.59 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 9.0, 2.8 Hz, IH), 7.30 (d, J = 2.7 Hz, IH), 4.15 (q, J = 6.5 Hz, IH).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, IH), 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).

[1161] 4-(((6-Ethoxyquinolin-2-yl)methyl) (thiazol-5-methyl)amino ) cyclohexan-1-one (compound 15.2, scheme 15)

[1164]

[1166] The titrated compound was synthesized according to procedure P, starting from N-((6-ethoxyquinolin-2-yl)methyl)-N-(thiazol-5-ylmethyl)-1,4-dioxaspiro[4.5]decane-8-amine 15.1 (1 eq, 43 mg, 0.098 mmol) in DCM/TFA (4:1, 2 mL) and water (50 µL), 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. ? NMR (400 MHz, DMSO) ? 8.96 (d, J = 0.8 Hz, IH), 8.21 (d, J = 8.5 Hz, IH), 7.85 (d, J = 9.0 Hz,, IH), 7.79 (d, J = 0.0 Hz, IH).79 (d, J = 0.9 Hz, IH), 7.62 (d, J = 8.5 Hz, IH), 7.34 (dd, J = 9.0, 2.8 Hz, IH), 7.32 (d, J = 2.7 Hz, IH), 4.15 (q, J = 6.9 Hz, 2H), 3.97 (s, 2H), 3.92 (s, 2H), 3.03 (t, J = 11.2 Hz, IH), 2.36 (td, J = 14.0, 5.7Hz, 2H).0, 5.7 Hz, 2H), 2.21 (d, J = 14.4 Hz, 2H), 2.06 (bs, 2H), 1.92 - 1.79 (m, 2H), 1.40 (t, J = 6.9 Hz, 3H).

[1167] 4-(((6-Ethoxyquinolin-2-yl)methyl)(thiazol-5-methyl)amino)cyclohexan-1-ol (compound 15.3, scheme 15)

[1170]

[1172] The compound was synthesized according to the Q procedure, starting from 4-(((6-Ethoxyquinolin-2-yl)methyl)(thiazol-5-ylmethyl)amino)cyclohexan-1-one 15.2 (1 eq, 0.096 mmol, 38 mg), sodium borohydride (2 eq, 0.192 mmol, 7 mg) in dry methanol (2 mL), with stirring for 1 h. Purification by silica gel column chromatography (100:0 to 80:20 dichloromethane/methanol) afforded the pure product in 63% yield (24 mg). Characterization: Rt 1.92 min, generic method, MS (ESI) m/z = 398.2 [M+H]<+>. Exact mass: 397.1824. H NMR (400 MHz, DMSO) ? 9.00 (d, J = 0.8 Hz, IH), 8.24 (d, J = 8.5 Hz, IH) 7.89 (d, J = 9.1 Hz, IH), 7.80 (d, J = 0.1 Hz. IH).80 (d, J = 0.9 Hz, IH), 7.64 (d, J = 8.5 Hz, IH), 7.39 (dd, J = 9.1, 2.8 Hz, IH), 7.35 (d, J = 2.8 Hz, IH), 4. (d, J = 4.5 Hz, IH).54 (d, J = 4.5 Hz, IH), 4.20 (q, J = 7.0 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 2H), 3.42 - 3.36 (signal superimposed on D20, IH), 2.54 - 2.43 (m, IH), 1.94 - 1.77 (m, 4H), 1.51-1.28 (m, 5H), 1.16 - 1.01 (m, 2H).

[1173] N-cyclohexyl-N-((6-fluoroquinolin-2-yl)methyl)-1,2,3-thiadiazole-4-carboxamide (compound 16.1, scheme 16)

[1176]

[1178] The titrated compound was synthesized according to the W procedure, starting from N-((6-fluoroquinolin-2-yl)methyl)cyclohexanamine 1.15 (0.33 mmol, 1.0 eq, 78 mg), 1,2,3-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). Purification by silica gel column chromatography (hexane/i-PrOH 100:0 to 80:20) afforded the pure titrated product as a light brown oil in 66% yield (80 mg). Characterization: MS (ESI) m/z 371.2 [M+H]<+ >. Exact mass: 370.1264. ? NMR (400 MHz DMSO) ? 9.67 (s, IH), 8.34 (d, J = 8.6 Hz, IH), 8.04 (dd, J = 9.2, 5.4 Hz, IH), 7.82 - 7.76 (m, IH), 7.67 (td, J = 9.5, 3.8 Hz, IH), 7.60 (d, J = 8.5 Hz, IH), 4.99 (d, J = 9.5 Hz, IH).99 (d, J = 9.9 Hz, 2H), 3.76 (t, J = 11.8 Hz, IH), 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, IH), 1.05 (d, J = 12.7 Hz, 3H).

[1179] N-Clclohexyl-N-((6-fluoroquinolin-2-yl)methyl)thiazole-5-carboxamide (compound 16.2, scheme 16)

[1182]

[1184] The titrated compound was synthesized according to the W procedure, starting from A/-((6-fluoroquinolin-2-yl)methyl)cyclohexanamine 1.15 (0.33 mmol, 1.0 eq, 78 mg), thiazole-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 µL). Purification by silica gel column chromatography (hexane(s) -PrOH 100:0 to 80:20) afforded the pure titrated compound as a light brown oil in 45% yield (55 mg). Characterization: MS (ESI) m/z = 370.2 [M+H]<+>. Exact mass: 369.1311. H NMR (400 MHz, DMSO) ? 9.18 (bs, IH), 8.32 (d, J = 8.6 Hz, IH), 8.20 (s, IH), 8.02 (dd, J = 9.2, 5.4 Hz, IH), 7.77 (dd, J = 9.4, 2.9 Hz, IH), 7.65 (td, J = 8.9, 2.9 Hz, IH), 7.52 (d, J = 8.9, 2.9 Hz, IH).52 (d, J = 8.6 Hz, IH), 4.92 (s, 2H), 3.30 (signal superimposed on D<2 >O, IH), 1.83 - 1.62 (m, 4H), 1.52 (d, J = 13.0 Hz, 2H), 1.22 (d, J = 11.8 Hz, 2H), 1.11 - 0.96 (m, IH).

[1185] N-((6-fluoroquinolin-2-yl)methyl)-N-(thiazol-5-methyl)cyclohexanamine (compound 16.3, scheme 16)

[1188]

[1190] The titrated compound was synthesized according to the N procedure, starting from N-((6-fluoroquinolin-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/i-propanol 100:0 to 90:10) afforded the pure titrated compound as a white crystalline powder in 60% yield (70 mg). Characterization: MS (ESI) m/z = 356.2 [M+H]+. Exact mass: 355.1518. ? NMR (400 MHz, DMSO) ? 8.93 (d, J = 0.8 Hz, IH), 8.31 (d, J = 8.7 Hz, IH), 8.00 (dd, J = 9.3, 5.4 Hz, IH), 7.77 - 7.67 (m, 3H), 7.62 (td, J = 8.9, 2.9 Hz, IH), 3.91 (d, J = 7.9, 2.9 Hz, IH).91 (d, J = 7.7 Hz, 4H), 2.43-2.50 (m, IH, superimposed on the 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).

[1191] N-((2-chlorothiazol-5-yl)methyl)-N-((6-fluoroquinolin-2-yl)methyl)cyclohexanamine (compound 16.4, scheme 16)

[1194]

[1196] The titrated compound was synthesized according to the N procedure, starting from 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) afforded 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) ? 8.33 (d, J = 8.6 Hz, IH), 8.00 (dd, J = 9.3, 5.4 Hz, IH), 7.74 (dd, J = 9.4, 2.9 Hz, IH), 7.67 (d, J = 8.8 Hz, IH), 7.65 - 7.59 (m, IH), 7.50 (s, IH), 3.92 (s, 2H), 3.50 (s, IH).92 (s, 2H), 3.87 (s, 2H), 2.53 (IH, signal superimposed on the solvent signal), 1.83 (d, J = 12.1 Hz, 2H), 1.76 - 1.69 (m, 2H), 1.54 (s, IH), 1.33 (q, J = 11.7 Hz, 2H), 1.11 (d, J = 17.6 Hz, 3H).

[1197] N-((2-((diphenylmethylene)animino)thiazol-5-yl)methyl)-N-((6-fluoroquinolin-2-yl)methyl)cyclohexanamine (compound 17.2, scheme 17)

[1200]

[1202] To the mixture of N- ((2-chlorothiazol-5-yl)methyl)-N-((6-fluoroquinolin-2-yl ) methyl)cyclohexanamine 16.4 (250 mg, 0.64 mmol, 1.0 eq), diphenylmethanimine 17.1 (1.05 eq, 0.672 mmol, 122 mg) and CS<2>CO<3 >(1.5 eq, 0.96 mmol, 313 mg) in dry 1.4-dioxane (0.1 M, 6.4 mL) at room temperature in an inert atmosphere, Pd<2>dba<3 >(0.12 eq, 0.076 mmol, 70 mg) and XantPhos (0.2 eq, 0.12 mmol, 70 mg) and the reaction mixture ? The reaction mixture was stirred at 95°C overnight. The reaction mixture was evaporated and quenched with saturated aqueous Na<2>CO<3>. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered, and evaporated. The crude was purified on silica gel using 100:0 to 60:40 hexane/acetone as the eluent to afford the compound as an off-white solid in 37% yield (125 mg). Characterization: LMCS only, MS (ESI) m/z = 535.1 [M+H]+. Exact mass: 534.2253.

[1203] 2-((((2-ammoniothiazol-5-yl)methyl)(cyclohexyl)ammonium)methyl)-6-fluoroquinolin-1-ium chloride (compound 17.4, Scheme 17)

[1206]

[1208] To a solution of N-((2-((diphenylmethylene)amino)thiazol-5-yl)methyl)-N-((6-fluoroquinolin-2-yl)methyl)cyclohexanamine (145 mg, 0.27 mmol, 1.0 eq) in 1,4-dioxane (0.06 M, 5 mL) was added concentrated aq. HCl (1 mL) 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 afford the pure titrated compound as a white solid in 70% yield (90 mg). Characterization: MS (ESI) m/z = 371.2 [M+H]<+ >. Exact mass: 370.1627. H NMR (400 MHz, CD<3 >OD) ? 8.39 (d, J = 8.5 Hz, IH), 8.25 (dd, J = 10.2, 5.2 Hz, IH), 7.69 (dd, J = 10.6, 5.0 Hz, 2H), 7.50 (t, J = 4.3 Hz, 2H), 4.86 (s, 2H), 4.73 (s, 2H), 3.67 (t, J = 12.1 Hz, IH), 3.67 (t, J = 12.1 Hz, IH), 3.5 (s, 2H).1 Hz, IH), 3.49 (q, J = 7.0 Hz, IH), 2.28 (d, J = 11.5 Hz, 2H), 1.98 (d, J = 13.2 Hz, 2H), 1.75 - 1.64 (m, 3H), 1.49 (q, J = 13.2 Hz, 2H), 1.31 (t, J = 13.3 Hz, IH), 1.18 (t, J = 7.1 Hz, IH). N-((6-fluoroquinolin-2-yl)methyl)-N-((2-methoxythiazol-5-yl)methyl)cyclohexanamine (compound 17.3, scheme 17)

[1209]

[1211] To a solution of N-((2-chlorothiazol-5-yl)methyl)-N-((6-fluoroquinolin-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 carefully quenched with water. The mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na<2>SO<4 >, filtered and evaporated. The crude was was purified on silica gel using hexane/acetone from 90:10 to 60:40 to afford the compound as a white solid in 37% yield (60 mg). Characterization: MS (ESI) m/z = 386.2 [M+H]<+>. Exact mass: 385.1624. H NMR (400 MHz, dmso) ? 8.31 (d, J = 8.6 Hz, IH), 8.00 (dd, J = 9.2, 5.4 Hz, IH), 7.73 (dd, J = 9.4, 2.9 Hz, IH).4, 2.9 Hz, IH), 7.67 (d, J = 8.5 Hz, IH), 7.62 (td, J = 8.9, 2.9 Hz, IH), 7.00 (s, IH), 3.92 (d, J = 0.8 Hz, 3H), 3.00 (s, 3H).8 Hz, 3H), 3.88 (s, 2H), 3.72 (s, 2H), 2.48 (IH, superimposed on the solvent signal), 1.80 (d, J = 12.2 Hz, 2H), 1.72 (d, J = 10.4 Hz, 2H), 1.53 (s, IH), 1.28 (dd, J = 26.4, 15.1 Hz, 2H), 1.08 (t, J = 11.2 Hz, 3H).

[1212] 2-((cyclohexyl ((2-hydroxythiazol-5-yl)methyl)ammonium)methyl)-6 fluoroquinolin-1-ium chloride (compound 17.5, scheme 17)

[1215]

[1217] To a 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 HCl (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 afford the compound as a yellow solid in 64% yield (22 mg). Characterization: MS (ESI) m/z = 372.1 [M+H]<+>. Exact mass: 371.1468. <1>H NMR (400 MHz, DMSO) ? 11.24 (s, IH), 8.42 (d, J = 8.5 Hz, IH), 8.13 (dd, J = 9.3, 5.4 Hz, IH), 7.85 (dd, J = 9.3, 2.9 Hz, IH), 7.76 (td, J = 8.8, 2.9 Hz, IH), 7.54 (d, J = 8.5 Hz, IH), 7.14 - 7.10 (m, IH), 4.69 (s, 2H), 4.41 (s, 2H), 2.50 (IH superimposed on the solvent signal) 2.16 -2.05 (m, 2H), 1.83 (d, J = 12.9 Hz, 2H), 1.57 (d, J = 16.9Hz, 2H), 1.37-1.21 (m, 2H), 1.19 (t, J = 12.2 Hz, IH).

[1218] Biological data

[1219] Fluorescent Cl<- >influx assay in HEK cells.

[1220] Culture and transfection of HEK cells. HEK293T cells were cultured and transfected as described in

[1221] Chem 2020. Briefly, 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 ?g/ml streptomycin, at 37 ?C in a humidified atmosphere of 5% CO<2>. 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 μg mbYFPQS plasmid (Addgene #80742), 8 μg PRK-NKCC1 plasmid or empty PRK plasmid as a mock control, and 32 μl Lipofectamin 2000. After 4 h, cells were harvested and plated in black-walled, clear-bottom 96-well plates at a density of 2.5 × 10<4>. After 48 h, cells were used for the assay. All reagents were purchased from , unless otherwise specified.

[1222] Assay for the measurement of Cl<- >influx in HEK cells. The assay was performed as described in protocols present in the literature (

[1223] J. Med. Chem 2021). Briefly, transfected cells were treated with DMSO (as a negative control) or with different concentrations (10 or 50 pM) of the target compound in 200 μL/well of a hypotonic Cl<- >free solution (67.

[1224] 5 mM Na<+ >Gluconate, 2.5 mM K<+ >Gluconate, 15 mM HEPES pH 7.4, 5 mM Glucose, 1 mM Na<2>HPO<4>, 1 mM NaH<2>PO<4>, 1 mM MgSO<4>, 1 mM CaSO<4>) and incubated for 30 minutes. Then, the plates were loaded into a Tecan Spark multiplate reader equipped with an automatic liquid injection system and the fluorescence of Cl-sensitive mbYFPQS was measured (excitation 485 nm and emission 535 nm). For each well, the fluorescence was Fluorescence was recorded for 20 s of baseline and then for 60 s after the application of a NaCl solution (final concentration of 74 mM in the assay well). mbYFPQS fluorescence is inversely related to the intracellular Cl- concentration, therefore chloride influx into cells causes a decrease in mbYFPQS fluorescence. For data analysis, the fluorescence value was normalized for each time point to the mean of the fluorescence value of the first 20 s of baseline (AF/FO), and the decrease in fluorescence upon application of NaCl was expressed as the mean of the last 10 s of the normalized fluorescence values. Additionally, for each plate, to isolate the contribution of NKCC1 alone to Cl- changes, the value of the last 10 s of the normalized AF/FO values obtained from mock cells (both control and treated) was expressed as the mean of the last 10 s of the normalized fluorescence values. was subtracted from the respective AF/F0 values obtained from the transfected NKCCl cells. The percentage decrease in fluorescence normalized to the DMSO control was then calculated, and consequently the percentage of inhibition (100 - % of the fluorescence decrease).

[1225] The results are reported in Table 1.

[1226] Table 1

[1227]

[1228]

[1229]

[1230]

[1231]

[1232]

[1233]

[1234]

[1235]

Claims (11)

1. CLAIMS 1.- Compound of formula (I or its pharmaceutically acceptable salts, zwitterions, enantiomers, diastereomers, geometric isomers, solvates and tautomers wherein: R1? selected from the group consisting of H, C<1>-C<6 >alkyl, C<1>-C6 haloalkyl, halogen, -O-C1-C6alkyl, -O-C<4>-C<10 >cycloalkyl optionally substituted with a C<1>-C<6 >alkyl, -O-C1-C6 haloalkyl, -NH<2>, -NH-C1-C6 alkyl, -NH-C4-C10 heterocycloalkyl, -N-di-C1-C6 alkyl, -NHSO<2>-C<1>-C6 alkyl, -NHC(=O)C<3>-C<6 >cycloalkyl; R<2 >? chosen from the group consisting of H, OH, halogen, -O-C<1>-C<6 >alkyl optionally substituted with a Re substituent, R3 ? selected from the group consisting of H, C<1>-C<4 >alkyl optionally substituted with an R<7> substituent, phenyl optionally substituted with an R<8> substituent, C<6>-C<10 >monocyclic or bicyclic aromatic heterocycle having 1 or 2 heteroatoms, C(=O) C<5>-C<10 >monocyclic aromatic heterocycle having 1 or 2 heteroatoms; R<4 >? chosen from the group consisting of H, - C1-C<6 >linear or branched alkyl optionally substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl, OH, -O-C<1>-C6 alkyl, halogen, COOH; - C<3>-C<6 >cycloalkyl optionally substituted with a substituent chosen from the group consisting of OH, NH<2>, -NHC(=0)C1-C6 alkyl; - C<3>-C<10 >monocyclic or bicyclic heterocycloalkyl comprising 1 or 2 heteroatoms optionally substituted with a substituent selected from the group consisting of C<1>-C6 linear or branched alkyl - C<6>-C<10 >spiro-linked heterobicycloalkyl comprising one or two heteroatoms; or R<3 >and FU taken together with the nitrogen to which they are bonded form a ring having the formula where R<a>, Rb, Rc, Rd, Re and R<f >are independently selected from the group consisting of H, halogen, C<1>-C<3 >haloalkyl, OH, -C(=O)NH-Rg where Rg is selected from the group consisting of phenyl optionally substituted with a substituent chosen from the group consisting of halogen, -O-C1 Cealkyl, -SO<2>NH<2>, -SO<2>NH-C1-C<6>alkyl, -SO<2>N (C1-C<6>alkyl ) <2>, CN, C (=O) NH<2 >; - Monocyclic or bicyclic aromatic Ci-Cioheterocycle; R<6 >? selected from the group consisting of phenyl, fluorophenyl, pyrazine; R<7 >? selected from the group consisting of C<3>-C<6 >cycloalkyl, C<4>-C<6 >heterocycloalkyl comprising one heteroatom selected from N to O, phenyl optionally substituted with at least one R9 substituent, C<5>-C<10 >monocyclic or bicyclic aromatic heterocycle having from 1 to 4 heteroatoms optionally substituted with at least one R9 substituent; Re? chosen from the group consisting of CONH<2>, CN, halogen, OH, methoxy, CF3, C<1>-C<4 >alkyl, NH<2>; Rg? chosen from the group consisting of straight or branched C<1>-C<6>alkyl, halogen, NH<2>, OH, -O-C1-C<4>alkyl, phenyl. 2.- Compound according to claim 1, characterised in that: R1 ? chosen from the group consisting of C<1>-C<4 >alkyl, Ci-C<4 >fluoroalkyl, halogen, -O-C<1>-C3 alkyl, -O-C<1>-C3 haloalkyl, -NH<2>, -NH-C<1>-C3 alkyl, -N-di-C1-C3 alkyl, -NHSO<2>-C<1>-C<4 >alkyl, -NHC(=O)C<1>-C3 alkyl, -NHC(=O)C<3>-C<6 >cycloalkyl; R<2 >? chosen from the group consisting of H, halogen, -O-C1-C<4 >alkyl optionally substituted with an R<6> substituent,? R3 ? selected from the group consisting of H, C<1>-C<4 >alkyl optionally substituted with an R<7> substituent, phenyl optionally substituted with an R8 substituent, C<6>-C<10 >monocyclic or bicyclic aromatic heterocycle having 1 or 2 heteroatoms, C(=O)C<5>-C<6 >monocyclic aromatic heterocycle having 1 or 2 heteroatoms, R<4 >? chosen from the group consisting of H, - C<1>-C<4 >linear or branched alkyl optionally substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl, OH, -O-C<1>-C3 alkyl, halogen, COOH; - C<4>-C<6 >cycloalkyl optionally substituted with a substituent chosen from the group consisting of OH, N?, -NHC(=0)C<1>-C<3 >alkyl; - C<4>-C<10 >monocyclic or bicyclic heterocycloalkyl comprising one heteroatom and optionally substituted with a straight or branched C<1>-C<4 >alkyl; - C<6>-C<10 >spiro-linked heterobicycloalkyl comprising one or two heteroatoms; R<6 >? chosen from the group consisting of phenyl, fluorophenyl, pyrazine; R7 ? selected from the group consisting of C5-C<10 >monocyclic or bicyclic aromatic heterocycles having 1 to 3 heteroatoms optionally substituted with at least one R9 substituent; R8? chosen from the group consisting of CONH<2>, CN; R9 ? chosen from the group consisting of halogen, N?, OH, -O-C<1>-C<4>alkyl, phenyl. 3.- Compound according to claim 1, characterised in that: R1 ? chosen from the group consisting of C<1>-C<4 >alkyl, C<1>-C<3 >haloalkyl, halogen, -NHSO<2>-C<1>-C<4 >alkyl, -NHC(=O)C<1>-C3 alkyl, -NHC(=0)C3-C6 cycloalkyl; R<2 >? chosen from the group consisting of H, -O-C<1>-C<4 >alkyl optionally substituted with an R<6> substituent,? R<3 >and R<4 >taken together with the nitrogen to which they are bonded form a ring having the formula where R<a>, Rb, Rc, Rd, Re and R<f >are independently selected from the group consisting of H, halogen, 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 halogen, -0-C1-C6alkyl, -SO<2>NH<2>, C<6>alkyl)<2>, CN, -C(=O)NH<2>; - -C<3>-C<10 >monocyclic or bicyclic aromatic heterocycle; R<6 >? selected from the group consisting of phenyl, fluorophenyl, pyrazine. 4.- Compound according to any of the claims 1 or 2, characterized by the fact that: R<7 >? selected from the group consisting of oxazole optionally substituted with at least one R9 substituent; oxadiazole optionally substituted with at least one R9 substituent; quinoline optionally substituted with at least one R9 substituent; thiazole optionally substituted with at least one R9 substituent; isoxazole optionally substituted with at least one R9 substituent. 5.- Compound according to any of claims 1 or 2, characterised in that: R<4 >? chosen from the group consisting of: - C<1>-C<4 >linear alkyl optionally substituted with at least one substituent selected from the group consisting of C3-C6 cycloalkyl, OH, -O-C<1>-C3 alkyl, halogen, COOH; - C<4>-C<6 >cycloalkyl optionally substituted with a substituent chosen from the group consisting of OH, NH<2>, -NHC(=O)C<1>-C<3 >alkyl; - C<4>-C<10 >monocyclic or bicyclic heterocycloalkyl comprising a heteroatom selected from N and O optionally substituted with a straight or branched C<1>-C<4 >alkyl; - C10 spiro-linked heterobicycloalkyl comprising a nitrogen atom. 6.- Compound according to any of the claims previous, characterized by the fact that: R1 ? chosen from the group consisting of butyl, trifluoromethyl, fluorine, methoxyl, ethoxyl, -O-CF<3>, NHC(=O)CH<3>, -NHC (=O)ethyl, -NHC(=0)cyclohexyl, -NHSO<2>-butyl, N (CH3)<2>; R<2 >? selected from the group consisting of H, chloro, ethoxy, methoxy optionally substituted with a substituent selected from the group consisting of phenyl, fluorophenyl, pyrazine; R<3 >? selected from the group consisting of H, methyl optionally substituted with an R<7> substituent, phenyl optionally substituted with an R8 substituent, benzothiazole, benzoimidazole, benzoxazole, pyridine, pyrimidine, thiazole, thiophene, quinoxaline, quinazoline, 2-benzoxazolinone, 3,4-dihydro-1,4-benzoxazin-2-one, R<4 >? selected from the group consisting of methyl substituted with cyclopropyl; ethyl substituted with a substituent selected from the group consisting of OH, COOH, OCH<3 >and CF<3>; butyl optionally substituted with a substituent selected from the group consisting of OH, and OCH<3>; cyclohexyl optionally substituted with a substituent selected from the group consisting of OH, NH<2 >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 R<3 >and R<4 >taken together with the nitrogen to which they are bonded form a ring having the formula where R<a>, Rb, Rc, Rd, Re and R<f >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, OCH<3>, SO<2>N(CH<3>)<2>, CN, -C(=O)NH<2>; - pyridine; - benzothiazole; - benzoimidazole; - benzoxazole; - pyrimidine; - thiazole; - oxazole; thiophene; quinoxaline; - quinazoline; R.<6 >? chosen from the group consisting of phenyl, fluorophenyl, pyrazine; R<7 >? selected from the group consisting of oxazole optionally substituted with at least one Rg substituent; 1,3,4-oxadiazole optionally substituted with at least one Rg substituent; 1,2,4-oxadiazole optionally substituted with at least one Rg substituent; quinoline optionally substituted with at least one Rg substituent; thiazole optionally substituted with at least one Rg substituent; Re is chosen from the group consisting of C(=O)NH<2 >and CN; Rg is chosen from the group consisting of phenyl, fluorine, chlorine, NH<2>, OH, OCH<3>. 7.- Compound according to any of the preceding claims selected from the group consisting of: 8.- Compound according to any of claims 1 to 6 for use as a medicament. 9.- Compound according to any of claims 1 to 6 for use in the prevention or treatment of a disorder associated with depolarizing GABAergic transmission. 10.- Compound for use according to claim 8, characterized in that said disorder associated with depolarizing GABAergic transmission is selected from the group consisting of idiopathic autism, Rett syndrome, Fragile X syndrome, Asperger syndrome, DiGeorge syndrome, Angelman syndrome, 15qll.2 duplication, Tuberous sclerosis complex, Down syndrome, obsessive compulsive disorder, Prader-Willi syndrome, Schizophrenia, depressive-like behaviors, 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, posttraumatic stress disorder, and fetal alcohol spectrum disorder (FASD). 11.- Pharmaceutical composition comprising a compound of formula (I) according to any of claims 1 to 7 and at least one pharmaceutically acceptable excipient.