Disubstituted piperidines as butyrylcholinesterase inhibitors

Abstract

This invention relates to new inhibitors of butyrylcholinesterase with general formulas I and II, where substituents are described in patent description. Compounds can be in the form of pure enantiomers or as racemic mixtures, or in the form of pharmaceutically acceptable salts. The present invention relates to the use of these inhibitors for the treatment of Alzheimer's disease and other forms of dementia. ##STR00001##

Claims

1. A compound having formula (II): ##STR00143## or a pharmaceutically acceptable salt thereof, wherein: the piperidine ring is 1,3-disubstituted; W is ##STR00144## V is H, CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, (CH.sub.2).sub.2OCH.sub.3 or (CH.sub.2).sub.3OCH.sub.3; and Q is ##STR00145##

2. The compound of claim 1, wherein V is (CH.sub.2).sub.2OCH.sub.3 or (CH.sub.2).sub.3OCH.sub.3.

3. The compound of claim 1, wherein V is (CH.sub.2).sub.2OCH.sub.3.

4. The compound of claim 1, wherein V is (CH.sub.2).sub.3OCH.sub.3.

5. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one compound having formula (II): ##STR00146## or a pharmaceutically acceptable salt thereof, wherein: the piperidine ring is 1,3-disubstituted or 1,4-disubstituted; W is ##STR00147## V is H, CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, (CH.sub.2).sub.2OCH.sub.3 or (CH.sub.2).sub.3OCH.sub.3; and Q is ##STR00148##

6. The pharmaceutical composition of claim 5, wherein: the piperidine ring is 1,3-disubstituted; W is ##STR00149## and Q is ##STR00150##

7. The pharmaceutical composition of claim 6, wherein V is CH.sub.3, (CH.sub.2).sub.2OCH.sub.3 or (CH.sub.2).sub.3OCH.sub.3.

8. The pharmaceutical composition of claim 5, wherein: the piperidine ring is 1,4-disubstituted; W is ##STR00151## V is (CH.sub.2).sub.2OCH.sub.3; and Q is ##STR00152##

9. The pharmaceutical composition of claim 5, wherein: the piperidine ring is 1,4-disubstituted; W is ##STR00153## V is (CH.sub.2).sub.3OCH.sub.3; and Q is ##STR00154##

10. A method for modulating butyrylcholinesterase activity in a human or mammal, the method comprising administering to the human or mammal a therapeutically effective amount of a compound having formula (II): ##STR00155## or a pharmaceutically acceptable salt thereof, wherein: the piperidine ring is 1,3-disubstituted or 1,4-disubstituted; W is ##STR00156## V is H, CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, (CH.sub.2).sub.2OCH.sub.3 or (CH.sub.2).sub.3OCH.sub.3; and Q is ##STR00157##

11. The method of claim 10, wherein: the piperidine ring is 1,3-disubstituted; W is ##STR00158## and Q is ##STR00159##

12. The method of claim 11, wherein V is CH.sub.3, (CH.sub.2).sub.2OCH.sub.3 or (CH.sub.2).sub.3OCH.sub.3.

13. The method of claim 11, wherein V is CH.sub.3.

14. The method of claim 11, wherein V is (CH.sub.2).sub.2OCH.sub.3.

15. The method of claim 11, wherein V is (CH.sub.2).sub.3OCH.sub.3.

16. The method of claim 10, wherein: the piperidine ring is 1,4-disubstituted; W is ##STR00160## V is (CH.sub.2).sub.2OCH.sub.3; and Q is ##STR00161##

17. The method of claim 10, wherein: the piperidine ring is 1,4-disubstituted; W is ##STR00162## V is (CH.sub.2).sub.3OCH.sub.3; and Q is ##STR00163##

18. The method of claim 1, wherein the human or mammal has a disease or disorder selected from the group consisting of Alzheimer's disease, multiple sclerosis and dementia.

19. The method of claim 1, wherein the human or mammal has a disease or disorder selected from the group consisting of Alzheimer's disease and dementia.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The invention describes the compounds having general formula (I),

(2) ##STR00003##

(3) wherein the substituents are the following:

(4) X: CH.sub.2-Ph,

(5) ##STR00004##

(6) Y: CH.sub.2CH.sub.2NMe.sub.2, CH.sub.2CH.sub.2CH.sub.2NMe.sub.2

(7) Z:

(8) ##STR00005##

(9) and compounds having general formula (II)

(10) ##STR00006##

(11) where the piperidine scaffold is 1,3- and 1,4-disubstituted, wherein the substituents are the following:

(12) W:

(13) ##STR00007##

(14) V: H, Me, Et, n-Pr, n-Bu, CH.sub.2CH.sub.2OMe, CH.sub.2CH.sub.2CH.sub.2OMe,

(15) Q:

(16) ##STR00008##

(17) Some compounds from this invention possess stereogenic center with an absolute configuration of R or S. The compounds can appear in a racemic form, in a form of pure enantiomers or in the form of conglomerates.

(18) The invention further relates to the pharmaceutically acceptable salts with a general formula I or II.

(19) The invention further relates to the use of the compounds with general formula I or II as active ingredients for the preparation of medicaments.

(20) Compounds with the general formula I or II are the inhibitors of the enzyme butyrylcholinesterase and are used for the treatment of symptoms of Alzheimer's disease, multiple sclerosis, all forms of dementias and cognitive disorders related to decreased cholinergic neurotransmission.

(21) The invention is related to parenteral, per oral or other pharmaceutically acceptable forms containing the compounds with the general formula I or II.

(22) Beside active pharmaceutical ingredient, the pharmaceutical composition can contain excipients suitable for the intended route of administration.

(23) Pharmaceutical compositions are prepared using standard procedures.

(24) Pharmaceutical compositions can be prepared in the way that ensures the sustained release of the active pharmaceutical ingredient.

(25) The dose, frequency and way of use are dependent from several factors, which are further dependent also from the active pharmaceutical ingredient used, its pharmacokinetic properties and patient's condition.

(26) Compounds with general formula I can be prepared using modified synthetic procedures described in the literature (Koak U. et al. Tetrahedron Lett. 2014, 55, 2037-2039; Brus B. et al. J. Med Chem. 2014, 57, 8167-8179). Compounds with the general formula II can be prepared using procedures described in the chapter Synthesis of the compounds with the general formula II.

(27) The invention is clarified, though not limited by the following examples.

EXAMPLES

(28) Biological Evaluation

(29) I. Enzyme Assay for the Determination of BChE Inhibitors Potency

(30) 1. Principle

(31) Ellman's method was used to evaluate the inhibitory activities of the synthesized compounds against the cholinesterases. (Ellman G. L. et al. Biochem. Pharmacol. 1961, 7, 88-95) Employing this reaction the concentration of thiol groups are determined using Ellman's reagent (5,5-dithiobis (2-nitrobenzoic acid), DTNB). As a substrate butyrylthiocholine (BTC) and acetylthiocholine (ATC) iodides were used for BChE and AChE, respectively. Enzyme cleaves the corresponding substrate to thiocholine, which further reacts with DTNB and forms the yellow colored product, 5-thio-2-nitrobenzoate anion. The reaction was monitored using a 96-well microtiter plate and a 96-well microplate reader (Synergy H4, BioTek Instruments, Inc., USA) as change in absorbance at 412 nm. For the reference sample, 1% dimethylsulfoxide (DMSO) replaced the inhibitor's solution.

(32) ##STR00009##

(33) Potency of the inhibitor is expressed as a residual activity (RA) of the enzyme at the employed inhibitor's concentration, half maximal inhibitory concentration (IC.sub.50 value) and as an inhibition constant (K.sub.i).

(34) 2. Reagents

(35) Ezymes:

(36) The enzyme reactions were carried out using murine acetylcholinesterase (mAChE) and human recombinant butyrylcholinesterase (huBChE). From the lyophilised powders of both enzymes, the solutions were obtained by dissolution of the powders in 10 mM MES buffer (pH 6.5) to reach the concentration of 4 mg/mL. The concentrated enzyme solution was diluted prior use in 100 mM phosphate buffer (pH 8.0) to reach the activity of the enzyme in the assay of approximately 500 mAu per minute.

(37) Substrates, ATCI and BTCI:

(38) ATCI in BTCI solutions were prepared in 100 mM phosphate buffer (pH 8.0) to reach the final concentration in the assay of 500 M.

(39) Ellman's Reagent, DTNB:

(40) DTNB solution was prepared in 100 mM phosphate buffer (pH 8.0) to reach the final concentration in the assay of 333 M.

(41) Investigated Compounds:

(42) Stock solutions of compounds were prepared in DMSO in a concentration of 10 mM. For the IC.sub.50 determination, the stock solutions were further diluted in DMSO to reach the range of inhibition from 5-95% in the final assay.

(43) 3. Procedure

(44) Enzyme solutions were prepared by dilution of the concentrated stocks in the 100 mM phosphate buffer (pH 8.0). The reactions were carried out in microtiter plates in a final volume of 300 L containing phosphate buffer, 333 M DTNB, 510.sup.4 M BTCI/ATCI and 110.sup.9 M or 510.sup.11 M of huBChE or mAChE, respectively. Enzyme reaction was started with the addition of the substrate. The DMSO concentration in the test solution was always 1%. The formation of yellow colored product of the reaction of DTNB with thiocholines was monitored for 1 minute as a change in absorbance at 412 nm using the microtiter plate reader (Synergy H4, BioTek Instruments, Inc., USA). For the determination of blank (b) the phosphate buffer replaced the enzyme solution. Initial velocity of the enzyme reaction (v.sub.0) was determined from the linear curve of the enzyme reaction product formation, where each measurement was performed in triplicate. For the initial screening of inhibition ability, 1 mM concentration of the investigated compounds was used. Compounds were pipetted in the corresponding wells to reach the final concentration of 10 M. Tested compound and the enzyme solution were first preincubated for 300s, followed by the substrate addition, which triggered the enzyme reaction. The initial velocity in presence of the inhibitor was further calculated (v.sub.i). The inhibition capability was expressed as residual activity (RA=(v.sub.ib)/(v.sub.ob)).

(45) For the IC.sub.50 value determination, 8 different concentrations of the investigated compounds were used, which resulted in the decrease of the enzyme reaction from 5% do 90%. IC.sub.50 values were determined by plotting the RA versus the concentration of the investigated compound. Experimental data were fitted using the following equation (1):
Y=Min+(MaxMin)/(1+10^((Log IC.sub.50X)Hill Slope))(1),

(46) Where X is a common logarithm of the concentration of the inhibitor and Y is the residual activity. For solving the equation Gnuplot software and an in-house python script were used. For the determination of the inhibition constant full progress curves of the product formation in presence and absence of investigated compounds were monitored. The curves were submitted in the ENZO web-application, which allows solving of numerical equations. (Bevc et al., PLoS One 2011, 6, e22265)

(47) Results of Biological Evaluation

(48) TABLE-US-00001 TABLE 1 Inhibitory activity of compounds with general formula (I). (I) 0 % inhibition STD at IC.sub.50 STD 10 M (nM) inhibitor X Y Z huBChE mAChE CH.sub.2CH.sub.2NMe.sub.2 1.03 0.04 17.4 3.7 CH.sub.2CH.sub.2NMe.sub.2 9.5 0.001 n.d. CH.sub.2CH.sub.2NMe.sub.2 13.18 0.61 n.d. STD = standard deviation n.d. = not done huBChE = human butyrycholinesterase mAChE = murine acetylcholinesterase

(49) TABLE-US-00002 TABLE 2 Inhibitory activity of compounds with general formula (I). (II) IC.sub.50 STD (M) or IC.sub.50 STD % (M) or inhibition Disub- % inhibition at at stitucijana 10 M 10 M piperidinu W V Q huBChE mAChE 1,3- CH.sub.2CH.sub.2OMe 0.053 0.004 M 72 0.86% 1,3- 0 CH.sub.2CH.sub.2OMe 0.343 0.005 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.279 0.008 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.887 0.08 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.482 0.066 M n.i. 1,3- CH.sub.2CH.sub.2OMe 3.466 0.052 M n.i. 1,3- 0 CH.sub.2CH.sub.2OMe 0.314 0.036 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.321 0.035 M n.i. 1,3- CH.sub.2CH.sub.2OMe 3.611 0.528 M 68 4.42% 1,3- CH.sub.2CH.sub.2OMe 0.197 0.008 M n.i. 1,3- CH.sub.2CH.sub.2OMe 8.207 0.601 M n.i. 1,3- 0 CH.sub.2CH.sub.2OMe 0.359 0.018 M n.i. 1,3- CH.sub.2CH.sub.2OMe 3.225 0.492 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.0049 0.0003 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.231 0.006 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.0491 0.0012 M n.i. 1,3- 0 CH.sub.2CH.sub.2OMe 1.464 0.115 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.338 0.008 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.311 0.022 M n.i. 1,3- H 0.0569 0.0098 M n.i. 1,3- Me 0.0250 0.0038 M n.i. 1,3- 0 Et 0.0380 0.0026 M n.i. 1,3- n-Pr 0.0428 0.0064 M n.i. 1,3- n-Bu 0.0355 0.0044 M n.i. 1,3- CH.sub.2CH.sub.2CH.sub.2OMe 0.0144 0.0008 M n.i. 1,4- CH.sub.2CH.sub.2OMe 0.0394 0.0028 M n.i. 1,4- 0 CH.sub.2CH.sub.2CH.sub.2OMe 0.0193 0.0037 M n.i. 1,4- H 0.195 0.017 M 1.78 0.085 M 1,4- CH.sub.2CH.sub.2OMe 0.0525 0.0020 M n.i. 1,4- CH.sub.2CH.sub.2CH.sub.2OMe 0.0712 0.0019 M n.i. 1,3 H 0.287 0.022 M 57 3.55% 1,3- 0 H 0.583 0.043 M 75 4.19% 1,3- H 0.366 0.031 M 71 3.68% 1,3- H 0.347 0.060 M 73 3.60% 1,3- H 1.673 0.256 M n.i. 1,3- H 2.093 0.328 M n.i. 1,3- 0 H 51% n.i. 1,3- Me 0.427 0.044 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.059 0.0054 M n.i. 1,3- CH.sub.2CH.sub.2OMe 0.156 0.033 M n.i. 1,3- CH.sub.2CH.sub.2CH.sub.2OMe 0.113 0.008 M n.i. STD = standard deviation n.i. = no inhibiton huBChE = human butyrycholinesterase mAChE = murine acetylcholinesterase

Synthesis of Compounds with General Formula (I)

Example 1: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide

(50) ##STR00100##

Step 1: Synthesis of ()-1-benzoylpiperidine-3-carboxylic acid

(51) ##STR00101##

(52) To a 250-mL round-bottomed flask equipped with a stirring bar, nipecotic acid (9.946 g, 77.007 mmol, 1.0 equiv) was added. THF (80 mL), H.sub.2O (80 mL) and K.sub.2CO.sub.3 (53.214 g, 385.023 mmol, 5.0 equiv) were added, and the mixture was cooled to 0 C. A solution of benzoyl chloride (8.931 mL, 77.007 mmol, 1.0 equiv) in THF (35 mL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with EtOAc (3150 mL). The aqueous phase was cooled to 0 C. and adjusted to pH 1-2 with 6 M aq HCl. The white precipitate was collected in a Bchner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P.sub.2O.sub.5 and silica gel to constant mass to produce 17.028 g of ()-1-benzoylpiperidine-3-carboxylic acid. This product was used in the next step without further purification.

(53) Product appearance: white solid

(54) Yield: 95%

(55) Melting point: 171-175 C.

(56) TLC: 0.53 (MeCN-MeOHH.sub.2O=3/1/1, v/v/v)

(57) IR (ATR): 2865, 2563, 1709, 1584, 1564, 1464, 1277, 1212, 929, 861, 791, 729, 632, 572 cm.sup.1.

(58) .sup.1H NMR (400 MHz, DMSO-d6): =1.45-1.69 (3H, m), 1.96-2.00 (1H, m), 2.42-2.46 (1H, m), 3.00-3.17 (2H, m), 3.45-3.63 (1H, m), 4.13-4.43 (1H, m), 7.37-7.52 (5H, m), 12.44 (1H, bs).

(59) .sup.13C NMR (100 MHz, DMSO-d6): =23.63, 24.40, 26.79, 40.63, 41.54, 43.41, 47.29, 48.72, 48.72, 126.64, 128.33, 129.32, 136.24, 169.14, 174.24.

(60) HRMS (ESI.sup.+): m/z calculated for C.sub.13H.sub.16NO.sub.3: 234.1130; found: 231.1129.

(61) CHN analysis: calculated for C.sub.13H.sub.15NO.sub.3: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.15; H, 6.74; 6.16.

Step 2: Synthesis of ()-1-benzoyl-N-(2-(dimethylamino)ethyl)piperidine-3-carboxamide

(62) ##STR00102##

(63) To a 500-mL round-bottomed flask equipped with a stirring bar, ()-1-benzoylpiperidine-3-carboxylic acid (17.000 g, 72.876 mmol) and CH.sub.2Cl.sub.2 (350 mL) were added. Et.sub.3N (20.205 mL, 145.754 mmol) was added drop-wise, followed by TBTU (23.400 g, 72.876 mmol). After 30 min, N,N-dimethylethylenediamine (15.900 mL, 145.754 mmol) was added dropwise, and the reaction mixture was stirred for 18 h. The reaction mixture was transferred into a 1000-mL separating funnel and washed with sat. aq NaHCO.sub.3 (2150 mL), H.sub.2O (2150 mL) followed by sat. brine solution (150 mL), and dried over anhyd Na.sub.2SO.sub.4 and evaporated, to produce 27,190 g of crude ()-1-benzoyl-N-(2-(dimethylamino)ethyl)piperidine-3-carboxamide. This product was used in the next step without further purification.

(64) Product appearance: golden-yellow oil

(65) TLC: R.sub.f=0.19 (CH.sub.2Cl.sub.2-MeOH=9:1, v/v)

(66) HRMS (ESI+): m/z calculated for C.sub.17H.sub.26N.sub.3O.sub.2: 304.2025; found: 304.2018.

Step 3: Synthesis of ()-N1-((1-benzylpiperidin-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine

(67) ##STR00103##

(68) To a 500-mL tree-neck round-bottomed flask equipped with a stirring bar and a reflux condenser, LiAlH.sub.4 (4.378 g, 115.359 mmol) was added under an argon atmosphere. Anhydrous THF (ca. 120 mL) was added with a double-tipped needle. A solution of crude ()-1-benzoyl-N-(2-(dimethylamino)ethyl)piperidine-3-carboxamide (7.000 g, 23.072 mmol) in anhydrous THF (ca. 60 mL) was added with a double-tipped needle, and the reaction mixture was refluxed for 3 h. The mixture was then cooled to 0 C. and the excess hydride was decomposed by drop-wise addition of H.sub.2O (4.378 mL) followed by 15% aq NaOH (4.378 mL) and then H.sub.2O (13.134 mL). After vigorous stirring for 1 h at r.t., the mixture was filtered under suction and the white precipitate was washed thoroughly with THF (560 mL). The combined filtrates were evaporated to produce 4.239 g of ()-N.sup.1-((1-benzylpiperidin-3-yl)methyl)-N.sup.2,N.sup.2-dimethylethane-1,2-diamine. This product was used in the next step without further purification.

(69) Product appearance: colorless oil

(70) TLC: R.sub.f=0.04 (CH.sub.2Cl.sub.2-MeOH=9:1, v/v+0.3% Et.sub.3N)

(71) HRMS (ESI+): m/z calculated for C.sub.17H.sub.30N.sub.3: 276.2440; found: 276.2439.

Step 4: Synthesis of ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-(dimethylamino)ethyl)carbamate

(72) ##STR00104##

(73) CH.sub.2Cl.sub.2 (150 mL) and a stirring bar were added to crude ()-N.sup.1-((1-benzylpiperidin-3-yl)methyl)-N.sup.2,N.sup.2-dimethyletane-1,2-diamine (4.239 g, 15.390 mmol) in a 250-mL round-bottomed flask. Et.sub.3N (2.133 mL, 15.390 mmol) was added drop-wise, and the reaction mixture was cooled to 0 C. A solution of Boc.sub.2O (3.359 g, 15.390 mmol) in CH.sub.2Cl.sub.2 (20 mL) was added drop-wise, and the reaction mixture was allowed to warm to r.t. and then stirred for 18 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with H.sub.2O (150 mL), sat. aq NaHCO.sub.3 (150 mL), dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (9:1, v/v) as the eluent to produce 3.190 g of ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-(dimethylamino)ethyl)carbamate.

(74) Product appearance: slightly golden-yellow oil

(75) Yield: 37% (from ()-1-benzoylpiperidine-3-carboxylic acid)

(76) TLC: R.sub.f=0.42 (CH.sub.2Cl.sub.2-MeOH=9:1, v/v)

(77) IR (ATR): 2972, 2933, 2766, 1690, 1455, 1416, 1365, 1247, 1156, 1096, 1068, 1025, 886, 863, 773, 739, 698 cm.sup.1

(78) .sup.1H NMR (400 MHz, CDCl.sub.3): =0.85-0.97 (1H, m), 1.38 (9H, s), 1.47-1.54 (1H, m), 1.59-1.66 (3H, m), 1.81-1.94 (2H, m), 2.20 (3H, s), 2.21 (3H, s), 2.31 (1H, t, J=7.4 Hz), 2.38 (1H, t, J=7.0 Hz), 2.72 (2H, bs), 3.02-3.06 (2H, m), 3.11-3.27 (2H, m), 3.45 (2H, s), 7.17-7.26 (5H, m).

(79) .sup.13C NMR (100 MHz, CDCl.sub.3): =24.81, 28.32, 28.52, 35.61, 36.03, 45.43, 45.57, 45.67, 50.84, 51.25, 53.93, 54.13, 56.81, 57.51, 57.70, 58.06, 63.50, 79.20, 79.28, 126.82, 126.86, 128.06, 129.06, 129.13, 138.09, 138.20, 155.55.

(80) HRMS (ESI+): m/z calculated for C.sub.22H.sub.38N.sub.3O.sub.2: 376.2964; found: 376.2972.

Step 5: Synthesis of ()-tert-butyl (2-(dimethylamino)ethyl)(piperidin-3-ylmethyl)carbamate

(81) ##STR00105##

(82) To a 250-mL round-bottomed flask with a stirring bar, ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-(dimethylamino)ethyl)carbamate (3.190 g, 8.494 mmol) and MeOH (70 mL) were added at room temperature. The resulting solution was stirred and agitated with a stream of argon for 15 min. Pd(OH).sub.2 on carbon (20 wt. %) (0.320 g, 10% mass of ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-(dimethylamino)ethyl)carbamate) was added, followed by cyclohexene (8.150 mL, 84.942 mmol). The resulting suspension was refluxed under an atmosphere of argon for 15 h, then filtered through a pad of Celite, and evaporated, to produce 2.410 g of crude ()-tert-butyl (2-(dimethylamino)ethyl)(piperidin-3-ylmethyl)carbamate. This product was used in the next step without further purification.

(83) Product appearance: slightly yellow oil

(84) Yield: 97%

(85) TLC: R.sub.f=0.09 (CH.sub.2Cl.sub.2-MeOH=9:1, v/v+0.3% Et.sub.3N)

(86) IR (ATR): 3368, 2978, 1671, 1560, 1477, 1405, 1368, 1313, 1251, 1159, 1042, 1015, 649 cm.sup.1

(87) .sup.1H NMR (400 MHz, CDCl.sub.3): =0.80-0.94 (1H, m), 1.02-1.14 (1H, m), 1.44 (9H, s), 1.49-1.75 (3H, m), 1.81-1.91 (1H, m), 2.23 (6H, s), 2.36-2.44 (2H, m), 2.53-2.62 (0.5H, m), 2.72-2.76 (0.5H, m), 2.84-3.10 (4H, m), 3.16-3.31 (2H, m)

(88) HRMS (ESI+): m/z calculated for C.sub.15H.sub.32N.sub.3O.sub.2: 286.2495; found: 286.2487.

Step 6: Synthesis of ()-tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)(2-(dimethylamino)ethyl)carbamate

(89) ##STR00106##

(90) To a 100-mL round-bottomed flask with a stirring bar, ()-tert-butyl (2-(dimethylamino)ethyl)(piperidin-3-ylmethyl)carbamate (1.920 g, 6.727 mmol) and 1,2-dichloroethane (50 mL) were added at room temperature. The resulting solution was stirred and agitated with a stream of argon for 15 min. NaBH(OAc).sub.3 (4.277 g, 20.181 mmol), 1H-inden-2(3H)-one (0.889 g, 6.727 mmol) and AcOH (0.577 mL, 10.091 mmol) were added, and the resulting suspension was stirred under an atmosphere of argon for 18 h. The reaction mixture was opened to the air and quenched with saturated aqueous NaHCO.sub.3 solution (50 mL). The mixture was transferred into a 250-mL separating funnel, and CH.sub.2Cl.sub.2 (50 mL) was added. The separating funnel was shaken vigorously and the organic phase was separated, dried over anhydrous Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2/MeOH (9:1, v/v) as the eluent, to produce 1.870 g ()-tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)(2-(dimethylamino)ethyl)carbamate.

(91) Product appearance: slightly golden-yellow oil

(92) Yield: 69% (from ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-(dimethylamino)ethyl)carbamate)

(93) TLC: R.sub.f=0.11 (CH.sub.2Cl.sub.2-MeOH=9:1, v/v)

(94) IR (ATR): 2934, 2766, 1690, 1461, 1416, 1390, 1365, 1249, 1156, 1099, 1023, 937, 888, 863, 771, 742 cm.sup.1

(95) .sup.1H NMR (400 MHz, CDCl.sub.3): =0.87-1.01 (1H, m), 1.44 (9H, s), 1.60-1.83 (4H, m), 1.92-1.97 (2H, m), 2.24 (6H, s), 2.38-2.46 (2H, m), 2.86-2.96 (4H, m), 3.01-3.15 (5H, m), 3.24 (1H, t, J=7.2 Hz), 3.30 (1H, t, J=7.4 Hz), 7.08-7.14 (4H, m)

(96) .sup.13C NMR (100 MHz, CDCl.sub.3): =24.80, 24.89, 28.33, 28.68, 35.69, 36.02, 36.81, 37.02, 45.43, 45.55, 45.64, 50.88, 51.45, 52.11, 56.16, 56.43, 56.82, 57.52, 67.19, 79.33, 124.25, 126.27, 141.35, 141.39, 155.51, 155.62.

(97) HRMS (ESI+): m/z calculated for C.sub.14H.sub.40N.sub.3O.sub.2: 402.3121; found: 402.3115.

Step 7: Synthesis of ()-N1-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine tri(2,2,2-trifluoroacetate)

(98) ##STR00107##

(99) To a 50-mL round-bottomed flask equipped with a stirring bar, ()-tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)(2-(dimethylamino)ethyl)carbamate (1,870 g, 4,656 mmol) and CH.sub.2Cl.sub.2 (20 mL) were added at room temperature. The resulting solution was stirred and TFA (16.045 mL, 209.542 mmol) was added drop-wise. After 2 h, the reaction mixture was evaporated. The residue was co-evaporated with CH.sub.2Cl.sub.2 (230 mL), followed by n-hexane (230 mL). Et.sub.2O (30 mL) was added to the oily residue, and the flask was placed in an ultrasonic bath for 15 min. During this time, the oily residue transformed into a white solid. The flask was removed from the ultrasonic bath and the precipitate was allowed to settle to the bottom of the flask. The supernatant was removed, Et.sub.2O (30 mL) was added, and the flask was placed back in the ultrasonic bath for 1 min. The flask was removed from the ultrasonic bath and the precipitate was allowed to settle to the bottom of the flask. The supernatant was removed, Et.sub.2O (30 mL) was added again, and this procedure was repeated two more times. After the final supernatant was removed, the solid residue was dried at reduced pressure to produce 3.020 g of crude ()-N.sup.1-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N.sup.2,N.sup.2-dimethylethane-1,2-diamine tri(2,2,2-trifluoroacetate). This product was used in the next step without further purification.

(100) Product appearance: white solid

(101) Yield: 99%

(102) TLC: R.sub.f=0.08 (CH.sub.2Cl.sub.2-MeOH=9:1, v/v)

(103) IR (ATR): 2674, 1664, 1476, 1418, 1174, 1118, 1001, 973, 830, 798, 776, 748, 719 cm.sup.1

(104) .sup.1H NMR (400 MHz, MeOD): =1.36-1.50 (1H, m), 1.84-1.94 (1H, m), 2.03-2.11 (2H, m), 2.39-2.49 (1H, m), 2.87-3.03 (8H, m), 3.15 (2H, bd, J=6.4 Hz), 3.27 (2H, dd, J=16.0, 8.0 Hz), 3.41-3.49 (2H, m), 3.56-3.65 (5H, m), 3.87 (1H, bd, J=11.6 Hz), 4.10 (1H, p, J=8.2 Hz), 7.22-7.29 (4H, m), NH exchanged

(105) HRMS (ESI+): m/z calculated for C.sub.19H.sub.32N.sub.3: 302.2596; found: 302.2591.

Step 8: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide

(106) ##STR00108##

(107) To a 250-mL round-bottomed flask with a stirring bar, ()-N.sup.1-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N.sup.2,N.sup.2-dimethylethane-1,2-diamine tri(2,2,2-trifluoroacetate) (2.418 g, 3.757 mmol) and CH.sub.2Cl.sub.2 (150 mL) were added. The resulting suspension reaction mixture was stirred and cooled to 0 C. Et.sub.3N (2.095 mL, 15.028 mmol) was added drop-wise, followed by 2-naphtoyl chloride (0.716 g, 3.757 mmol) and the reaction mixture was allowed to warm to r.t. and then stirred for 94 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with H.sub.2O (150 mL), sat. aq NaHCO.sub.3 (150 mL), dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH-Et.sub.3N (120:10:1, v/v/v) as the eluent to produce 1.172 g of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide.

(108) Product appearance: golden-brown oil

(109) Yield: 68%

(110) TLC: R.sub.f=0.14 (CH.sub.2Cl.sub.2-MeOH-Et.sub.3N=150:10:1, v/v/v)

(111) .sup.1H NMR (400 MHz, DMSO-d6, 80 C.): =0.95 (1H, bs), 1.43-1.51 (1H, m), 1.59-1.67 (2H, m), 1.81 (1H, bs), 1.98-2.09 (7H, m), 2.70-2.83 (4H, m), 2.96-3.21 (6H, m), 3.35-3.45 (4H, m), 7.09-7.20 (4H, m), 7.41-7.43 (1H, m), 7.55-7.59 (2H, m), 7.87 (1H, s), 7.94-7.98 (3H, m).

(112) HRMS (ESI+): m/z calculated for C.sub.31H.sub.40N.sub.3O 470.3171; found: 470.3180.

Example 2: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-oxo-2H-chromene-3-carboxamide

(113) ##STR00109##

Step 1: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-oxo-2H-chromene-3-carboxamide

(114) ##STR00110##

(115) To a 50-mL round-bottomed flask with a stirring bar, 2-oxo-2H-chromene-3-carboxylic acid (0.323 g, 1.699 mmol) was added. Thionyl chloride (8 mL) was added at room temperature and the resulting solution was stirred under an atmosphere of argon at 80 C. for 4 h. The reaction mixture was evaporated and the residue was dried in vacuo. Anhydrous pyridine (10 mL) was added, followed by a solution of ()-N.sup.1-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N.sup.2,N.sup.2-dimethylethane-1,2-diamine tri(2,2,2-trifluoroacetate) (0.323 g, 0.502 mmol) in anhydrous pyridine (5 mL). After 18 h the reaction mixture was evaporated and the residue was dried in vacuo. CH.sub.2Cl.sub.2 (100 mL) was added the resulting solution was transferred into a 250-mL separating funnel and washed with sat. aq NaHCO.sub.3 (270 mL), followed by sat. brine solution (150 mL), and dried over anhyd Na.sub.2SO.sub.4 and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOHNH.sub.3 (25% aqueous solution) (9:1:0.003, v/v/v) to produce 0.044 g of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-oxo-2H-chromene-3-carboxamide.

(116) Product appearance: light orange oil

(117) Yield: 19%

(118) TLC: R.sub.f=0.22 (CH.sub.2Cl.sub.2-MeOHNH.sub.3(25% aqueous solution)=9:1:0.003, v/v/v)

(119) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.78-0.89 (0.5H, m), 1.09-1.20 (0.5H, m), 1.56-2.04 (5H, m), 2.06-2.14 (4H, m), 2.20-3.31 (1H, m), 2.34 (2H, s), 2.40-2.47 (1.5H, m), 2.62-2.66 (0.5H, m), 2.81-2.89 (1.5H, m), 2.97-3.45 (8.5H, m), 3.57-3.66 (1H, m), 7.11-7.21 (4H, m), 7.29-7.34 (1H, m), 7.36-7.38 (1H, m), 7.47-7.53 (1H, m), 7.56-7.61 (1H, m), 7.75-7.82 (1H, m).

(120) .sup.13C-NMR (100 MHz, CDCl.sub.3): =24.62, 28.24, 28.44, 34.44, 35.34, 36.59, 36.80, 36.94, 43.59, 45.64, 45.71, 46.58, 47.81, 51.87, 52.03, 53.13, 55.68, 56.14, 57.60, 66.97, 67.35, 116.84, 118.20, 118.27, 124.29, 124.32, 124.38, 124.49, 125.81, 125.99, 126.38, 126.45, 128.32, 128.46, 132.57, 132.63, 141.34, 141.89, 142.10, 153.94, 157.94, 158.06, 165.32, 165.72.

(121) HRMS (ESI+): m/z calculated for C.sub.29H.sub.36N.sub.3O.sub.3 474.2757; found: 474.2750.

Example 3: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-8-hydroxyquinoline-7-carboxamide

(122) ##STR00111##

Step 1: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-8-hydroxyquinoline-7-carboxamide

(123) ##STR00112##

(124) To a 50-mL round-bottomed flask with a stirring bar, 8-hydroxyquinoline-7-carboxylic acid (0.230 g, 1.216 mmol) and 1,1-carbonyldiimidazole (CDI) (0.198 g, 1.221 mmol) was added. Anhydrous THF (15 mL) was added at room temperature and the resulting solution was stirred under an atmosphere of argon at 65 C. for 1.5 h. A solution of ()-N.sup.1-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N.sup.2,N.sup.2-dimethylethane-1,2-diamine tri(2,2,2-trifluoroacetate) (0.589 g, 0.915 mmola) and Et.sub.3N (0.675 mL, 4.870 mmol) in anhydrous THF (5 mL) was added and the reaction mixture was stirred at 65 C. for 72 h. The reaction mixture was evaporated and CH.sub.2Cl.sub.2 (50 mL) was added to residue. The resulting solution transferred into a 100-mL separating funnel and washed with sat. aq NaHCO.sub.3 (350 mL), H.sub.2O (250 mL), followed by sat. brine solution (50 mL), and dried over anhyd Na.sub.2SO.sub.4 and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOHNH.sub.3(25% aqueous solution) (20:1:0.003, v/v/v; then 15:1:0.003, v/v/v) then crystallized from aceton to produce 0.024 g of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-8-hydroxyquinoline-7-carboxamide.

(125) Product appearance: white solid

(126) Yield: 6%

(127) TLC: R.sub.f=0.15 (CH.sub.2Cl.sub.2-MeOHNH.sub.3(25% aqueous solution)=9:1:0.003, v/v/v)

(128) .sup.1H-NMR (400 MHz, DMSO-d6): =0.53-0.61 (0.4H, m), 1.00-1.08 (0.6H, m), 1.23-1.53 (2.5H, m), 1.67-1.89 (6H, m), 2.00-2.08 (1.5H, m), 2.20-3.27 (3.5H, m), 2.62-2.67 (1.5H, m), 2.76-3.13 (7H, m), 3.22-3.27 (2H, m), 3.54-3.58 (1H, m), 7.09-7.23 (4.5 H, m), 7.31-7.33 (0.5H, m), 7.41-7.47 (1H, m), 7.60-7.63 (1H, m), 8.34-8.38 (1H, m), 8.88-8.91 (1H, m).

(129) .sup.13C-NMR (100 MHz, DMSO-d6): =34.28, 34.69, 36.06, 36.38, 36.54, 44.93, 45.39, 45.79, 47.60, 51.34, 51.68, 52.06, 55.04, 55.43, 56.15, 57.38, 66.23, 66.82, 117.67, 117.77, 120.30, 120.71, 122.35, 124.07, 124.17, 124.30, 126.10, 126.35, 126.51, 128.43, 128.51, 136.17, 138.14, 141.46, 141.54, 141.66, 148.39, 148.63, 148.72, 168.36, 168.50.

(130) HRMS (ESI+): m/z calculated for C.sub.29H.sub.37N.sub.4O.sub.2 473.2917; found: 473.2927.

Synthesis of Compounds with General Formula (II)

Example 1: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide

(131) ##STR00113##

Step 1: Synthesis of ()-1-benzoylpiperidine-3-carboxylic acid

(132) ##STR00114##

(133) To a 250-mL round-bottomed flask equipped with a stirring bar, nipecotic acid (9.946 g, 77.007 mmol) was added. THF (80 mL), H.sub.2O (80 mL) and K.sub.2CO.sub.3 (53.214 g, 385.023 mmol) were added, and the mixture was cooled to 0 C. A solution of benzoyl chloride (8.931 mL, 77.007 mmol, 1.0 equiv) in THF (35 mL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with EtOAc (3150 mL). The aqueous phase was cooled to 0 C. and adjusted to pH 1-2 with 6 M aq HCl. The white precipitate was collected in a Bchner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P.sub.2O.sub.5 and silica gel to constant mass to produce 17.028 g of ()-1-benzoylpiperidine-3-carboxylic acid. This product was used in the next step without further purification.

(134) Product appearance: white solid

(135) Yield: 95%

(136) Melting point: 171-175 C.

(137) TLC: 0.53 (MeCN-MeOHH.sub.2O=3/1/1, v/v/v)

(138) IR (ATR): 2865, 2563, 1709, 1584, 1564, 1464, 1277, 1212, 929, 861, 791, 729, 632, 572 cm.sup.1.

(139) .sup.1H NMR (400 MHz, DMSO-d6): =1.45-1.69 (3H, m), 1.96-2.00 (1H, m), 2.42-2.46 (1H, m), 3.00-3.17 (2H, m), 3.45-3.63 (1H, m), 4.13-4.43 (1H, m), 7.37-7.52 (5H, m), 12.44 (1H, bs).

(140) .sup.13C NMR (100 MHz, DMSO-d6): =23.63, 24.40, 26.79, 40.63, 41.54, 43.41, 47.29, 48.72, 48.72, 126.64, 128.33, 129.32, 136.24, 169.14, 174.24.

(141) HRMS (ESI.sup.+): m/z calculated for C.sub.13H.sub.16NO.sub.3: 234.1130; found: 231.1129.

(142) CHN analysis: calculated for C.sub.13H.sub.15NO.sub.3: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.15; H, 6.74; 6.16.

Step 2: Synthesis of ()-1-benzoyl-N-(2-methoxyethyl)piperidine-3-carboxamide

(143) ##STR00115##

(144) To a 250-mL round-bottomed flask equipped with a stirring bar, ()-1-benzoylpiperidine-3-carboxylic acid (2.883 g, 12.359 mmol) and CH.sub.2Cl.sub.2 (160 mL) were added. Et.sub.3N (3.446 mL, 24.719 mmol, 2.0 equiv) was added drop-wise, followed by TBTU (3.969 g, 12.359 mmol). After 30 min, 2-methoxyethylamine (2.125 mL, 24.719 mmol) was added drop-wise, and the reaction mixture was stirred for 22 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with H.sub.2O (2200 mL), 0.5 M aq HCl (2200 mL), sat. aq NaHCO.sub.3 solution (2200 mL) followed by sat. brine solution (200 mL), and dried over anhyd Na.sub.2SO.sub.4 and evaporated, to produce 3.756 g of crude ()-1-benzoyl-N-(2-methoxyethyl)piperidine-3-carboxamide. This product was used in the next step without further purification.

(145) Product appearance: colorless oil

(146) HRMS (ESI.sup.+): m/z calculated for C.sub.16H.sub.23N.sub.2O.sub.3: 291.1709; found: 291.1707.

Step 3: Synthesis of ()-N-((1-benzylpiperidin-3-yl)methyl)-2-methoxyethan-1-amine

(147) ##STR00116##

(148) To a 250-mL tree-neck round-bottomed flask equipped with a stirring bar and a reflux condenser, LiAlH.sub.4 (2.455 g, 64.679 mmol) was added under an argon atmosphere. Anhydrous THF (ca. 120 mL) was added with a double-tipped needle. A solution of crude ()-1-benzoyl-N-(2-methoxyethyl)piperidine-3-carboxamide (3.756 g, 12.936 mmol) in anhydrous THF (ca. 40 mL) was added with a double-tipped needle, and the reaction mixture was refluxed for 3 h under an argon atmosphere. The mixture was then cooled to 0 C. and the excess hydride was decomposed by drop-wise addition of H.sub.2O (2.455 mL) followed by 15% aq NaOH (2.455 mL) and then H.sub.2O (7.365 mL). After vigorous stirring for 1 h at r.t., the mixture was filtered under suction and the white precipitate was washed thoroughly with THF (560 mL). The combined filtrates were evaporated to produce 2.794 g of crude ()-N-((1-benzylpiperidin-3-yl)methyl)-2-methoxyethan-1-amine. This product was used in the next step without further purification.

(149) Product appearance: slightly golden liquid

(150) HRMS (ESI.sup.+): m/z calculated for C.sub.16H.sub.27N.sub.2O: 263.2123; found: 263.2128.

Step 4: Synthesis of ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-methoxyethyl)carbamate

(151) ##STR00117##

(152) CH.sub.2Cl.sub.2 (50 mL) and a stirring bar were added to crude ()-N-((1-benzylpiperidin-3-yl)methyl)-2-methoxyethan-1-amine (2.794 g, 10.648 mmol) in a 100-mL round-bottomed flask equipped with a stirring bar. Et.sub.3N (1.484 mL, 10.648 mmol) was added drop-wise, and the reaction mixture was cooled to 0 C. A solution of Boc.sub.2O (2.324 g, 10.648 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added drop-wise, and the reaction mixture was allowed to warm to r.t. and then stirred for 20 h. The reaction mixture was transferred into a 100-mL separating funnel and washed with H.sub.2O (30 mL), dried over anhyd. Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (30:1) then CH.sub.2Cl.sub.2-MeOH (10:1) as the eluent to produce 3.484 g of ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-methoxyethyl)carbamate.

(153) Product appearance: slightly golden oil

(154) Yield: 78% (from ()-1-benzoylpiperidine-3-carboxylic acid)

(155) TLC: R.sub.f.sup.=0.53 (CH.sub.2Cl.sub.2-MeOH=10:1, v/v)

(156) IR (ATR): 2973, 2929, 1690, 1412, 1364, 1244, 1158, 1116, 867, 738, 698, 560 cm.sup.1

(157) .sup.1H NMR (400 MHz, CDCl.sub.3): =0.88-1.01 (1H, m), 1.43 (9H, s), 1.51-1.58 (1H, m), 1.62-1.72 (3H, m), 1.88-1.96 (2H, m), 2.74-2.79 (2H, m), 3.11-3.15 (2H, m), 3.24-3.36 (5H, m), 3.39-3.49 (4H, m), 7.21-7.38 (5H, m).

(158) .sup.13C NMR (100 MHz, CDCl.sub.3): =24.85, 28.32, 28.51, 35.54, 36.02, 47.03, 51.31, 51.89, 53.94, 54.15, 57.72, 58.05, 58.73, 63.54, 70.83, 71.03, 79.21, 79.32, 126.76, 126.80, 126.85, 128.03, 129.05, 129.10, 138.15, 138.35, 155.59.

(159) HRMS (ESI.sup.+): m/z calculated for C.sub.21H.sub.35N.sub.2O.sub.3: 363.2648; found: 363.2638.

(160) CHN analysis: calculated for C.sub.21H.sub.34N.sub.2O.sub.3: C, 69.58; H, 9.45; N, 7.73. Found: C, 69.75; H, 9.67; N, 7.86.

Step 5: Synthesis of ()-tert-butyl (2-methoxyethyl)(piperidin-3-ylmethyl)carbamate

(161) ##STR00118##

(162) To a 250-mL round-bottomed flask with a stirring bar, ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-methoxyethyl)carbamate (4.137 g, 11.412 mmol) and MeOH (160 mL) were added at room temperature. The resulting solution was stirred and agitated with a stream of argon for 30 min. Pd(OH).sub.2 on carbon (20 wt. %) (0.828 g, 20% mass of ()-tert-butyl ((1-benzylpiperidin-3-yl)methyl)(2-methoxyethyl)carbamate) was added, followed by cyclohexene (11.571 mL, 114.122 mmol). The resulting suspension was refluxed under an atmosphere of argon for 17 h, then filtered through a pad of Celite, and evaporated, to produce 3.015 g of crude amine ()-tert-butyl (2-methoxyethyl)(piperidin-3-ylmethyl)carbamate. This product was used in the next step without further purification.

(163) Product appearance: colorless oil

(164) Yield: 97%

(165) TLC: R.sub.f=0.44 (CH.sub.2Cl.sub.2-MeOH-Et.sub.3N=20:2:1, v/v/v)

(166) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.00-1.14 (1H, m), 1.37-1.49 (10H, m), 1.60-1.80 (5H, m), 2.25-2.37 (1H, m), 2.51-2.58 (1H, m), 2.95-3.00 (2H, m), 3.13-3.25 (1H, m), 3.28-3.38 (5H, m), 3.44-3.52 (2H, m).

(167) HRMS (ESI.sup.+): m/z calculated for C.sub.14H.sub.29N.sub.2O.sub.3 273.2178; found 273.2174.

Step 6: Synthesis of ()-tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)(2-methoxyethyl)carbamate

(168) ##STR00119##

(169) To a 100-mL round-bottomed flask with a stirring bar, ()-tert-butyl (2-methoxyethyl)(piperidin-3-ylmethyl)carbamate (1.094 g, 4.016 mmol) and 1,2-dichloroethane (50 mL) were added at room temperature. The resulting solution was stirred and agitated with a stream of argon for 15 min. NaBH(OAc).sub.3 (1.596 g, 7.530 mmol), 1H-inden-2(3H)-one (0.531 g, 4.018 mmol) and AcOH (0.230 mL, 4.018 mmol) were added, and the resulting suspension was stirred under an atmosphere of argon for 72 h. The reaction mixture was opened to the air and quenched with saturated aqueous NaHCO.sub.3 solution (50 mL). The mixture was transferred into a 250-mL separating funnel, and CH.sub.2Cl.sub.2 (20 mL) was added. The separating funnel was shaken vigorously and the organic phase was separated, dried over anhydrous Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2/MeOH (30:1, v/v) as the eluent, to produce 1.292 g of ()-tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)(2-methoxyethyl)carbamate.

(170) Product appearance: slightly golden oil

(171) Yield: 83%

(172) TLC: R.sub.f=0.50 (CH.sub.2Cl.sub.2/MeOH, 10:1, v/v)

(173) IR (ATR): 2930, 2359, 1692, 1463, 1414, 1365, 1170, 1117, 1010, 867, 743, 526 cm.sup.1

(174) .sup.1H-NMR (400 MHz, DMSO-d6, 60 C.): =0.90-0.99 (1H, m), 1.40 (9H, s), 1.56-1.67 (2H, m), 1.77-1.88 (2H, m), 2.01-2.07 (1H, m), 2.73-2.81 (4H, m), 2.95-3.02 (2H, m), 3.10 (2H, d, J=6.90 Hz), 3.14-3.15 (3H, m), 3.25 (3H, s), 3.28-3.31 (1H, m), 3.41-3.44 (2H, m), 7.07-7.12 (2H, m), 7.15-7.19 (2H, m).

(175) .sup.13C-NMR (100 MHz, DMSO-d6, 60 C.): =24.08, 27.70, 27.85, 35.92, 36.02, 46.29, 51.18, 54.95, 57.67, 66.13, 78.09, 123.76, 125.78, 141.04, 141.10, 154.52.

(176) HRMS (ESI+): m/z calculated for C.sub.23H.sub.37N.sub.2O.sub.3 389.2804; found 389.2798.

Step 7: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-2-methoxyethan-1-amine di(2,2,2-trifluoroacetate)

(177) ##STR00120##

(178) To a 100-mL round-bottomed flask equipped with a stirring bar, (f)-tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)(2-methoxyethyl)carbamate (1.203 g, 3.096 mmol) and CH.sub.2Cl.sub.2 (50 mL) were added at room temperature. The resulting solution was stirred and TFA (2.371 mL, 30.960 mmol) was added drop-wise. After 22 h, the reaction mixture was evaporated. The residue was co-evaporated with CH.sub.2Cl.sub.2 (240 mL), followed by n-hexane (250 mL). Et.sub.2O (50 mL) was added to the oily residue, and the flask was placed in an ultrasonic bath for 15 min. During this time, the oily residue transformed into a white solid. The flask was removed from the ultrasonic bath and the precipitate was allowed to settle to the bottom of the flask. The supernatant was removed, Et.sub.2O (30 mL) was added, and the flask was placed back in the ultrasonic bath for 1 min. The flask was removed from the ultrasonic bath and the precipitate was allowed to settle to the bottom of the flask. The supernatant was removed, Et.sub.2O (30 mL) was added again, and this procedure was repeated two more times. After the final supernatant was removed, the solid residue was dried at reduced pressure. This product was used in the next step without further purification.

(179) Product appearance: white solid

(180) HRMS (ESI+): m/z calculated for C.sub.18H.sub.29N.sub.2O 289.2280; found 289.2274.

Step 8: Synthesis of ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide

(181) ##STR00121##

(182) To a 25-mL round-bottomed flask equipped with a stirring bar, ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-2-methoxyethan-1-amine di(2,2,2-trifluoroacetate) (0.256 g, 0.496 mmol) and CH.sub.2Cl.sub.2 (10 mL) were added at room temperature. The resulting suspension was stirred and Et.sub.3N (0.207 mL, 1.487 mmol) was added drop-wise, followed by naphthalene-2-sulfonyl chloride (0.113 g, 0.496 mmol) and the reaction mixture was allowed to warm to r.t. and then stirred for 20 h. The reaction mixture was transferred into a 50-mL separating funnel, CH.sub.2Cl.sub.2 (15 mL) was added and washed with H.sub.2O (20 mL), followed by saturated aqueous NaHCO.sub.3 solution (20 mL). The organic phase was dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (20:1, v/v) as the eluent to produce 0.220 g ()-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide.

(183) Product appearance: slightly golden oil

(184) Yield: 93%

(185) TLC: R.sub.f=0.51 (CH.sub.2Cl.sub.2/MeOH, 10:1, v/v)

(186) IR (ATR): 2928, 1687, 1589, 1456, 1334, 1154, 1115, 1072, 991, 858, 816, 743, 649, 614 cm.sup.1

(187) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.92-1.03 (1H, m), 1.58-1.77 (4H, m), 1.97-2.06 (2H, m), 2.82-3.06 (6H, m), 3.09-3.21 (3H, m), 3.24 (3H, s), 3.34-3.41 (2H, m), 3.49-3.55 (2H, m), 7.11-7.17 (4H, m), 7.59-7.66 (2H, m), 7.80 (1H, dd, J.sub.1=8.7 Hz, J.sub.2=1.9 Hz), 7.88-7.98 (3H, m), 8.40 (1H, d, J=1.4 Hz).

(188) .sup.13C-NMR (100 MHz, CDCl.sub.3): =24.70, 28.41, 34.73, 36.72, 36.95, 47.81, 52.06, 53.20, 55.92, 58.58, 67.07, 70.96, 122.42, 124.16, 124.21, 126.16, 127.34, 127.69, 128.24, 128.50, 128.99, 129.08, 131.97, 134.49, 136.39, 141.38.

(189) HRMS (ESI+): m/z calculated for C.sub.28H.sub.35N.sub.2O.sub.3S 479.2368; found 479.2354.

Example 2: Synthesis of ()-N-((1-benzylpiperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide

(190) ##STR00122##

Step 1: Synthesis of ()-N-((1-benzylpiperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide

(191) ##STR00123##

(192) To a 50-mL round-bottomed flask equipped with a stirring bar, ()-N-((1-benzylpiperidin-3-yl)methyl)-2-methoxyethan-1-amine (1.062 g, 4.047 mmol) and CH.sub.2Cl.sub.2 (25 mL) were added at room temperature. The resulting solution was stirred and cooled to 0 C. Et.sub.3N (0.564 mL, 4.047 mmol) was added drop-wise, followed by naphthalene-2-sulfonyl chloride (0.918 g, 4.047 mmol) and the reaction mixture was allowed to warm to r.t. and then stirred for 20 h. The reaction mixture was transferred into a 100-mL separating funnel, CH.sub.2Cl.sub.2 (25 mL) was added and washed with H.sub.2O (40 mL), followed by saturated aqueous NaHCO.sub.3 solution (40 mL). The organic phase was dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (30:1, v/v) as the eluent to produce 1.654 g ()-N-((1-benzylpiperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide.

(193) Product appearance: colorless oil

(194) Yield: 90%

(195) TLC: R.sub.f=0.57 (CH.sub.2Cl.sub.2/MeOH, 10:1, v/v)

(196) IR (ATR): 2928, 2803, 1452, 1333, 1154, 1115, 1072, 983, 883, 859, 817, 732, 699, 650, 615 cm.sup.1

(197) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.95-1.04 (1H, m), 1.54 (1H, bs), 1.66-1.74 (3H, m), 1.98 (2H, bs), 2.76 (2H, d, J=30.4 Hz), 3.06-3.16 (2H, m), 3.21 (3H, s), 3.30 (2H, t, J=6.3 Hz), 3.45-3.48 (4H, m), 7.23-7.30 (5H, m), 7.59-7.66 (2H, m), 7.76 (1H, dd, =8.6 Hz, J.sub.2=1.8 Hz), 7.89-7.97 (3H, m), 8.38 (1H, d, J=1.4 Hz).

(198) .sup.13C-NMR (100 MHz, CDCl.sub.3): =24.54, 28.21, 34.82, 48.04, 53.21, 53.89, 57.60, 58.66, 63.44, 71.10, 122.52, 126.85, 127.39, 127.78, 128.05, 128.36, 128.56, 129.07, 129.11, 129.14, 132.07, 134.59, 136.40, 138.25.

(199) HRMS (ESI+): m/z calculated for C.sub.26H.sub.33N.sub.2O.sub.3S 453.2212; found 453.2209.

Example 3: Synthesis of N-((1-benzylpiperidin-3-yl)methyl)naphthalene-2-sulfonamide

(200) ##STR00124##

Step 1: Synthesis of ()-1-benzoylpiperidine-3-carboxamide

(201) ##STR00125##

(202) To a 500-mL round-bottomed flask equipped with a stirring bar, nipecotamide (10.000 g, 78.020 mmol) and THF (260 mL) were added. The suspension was cooled to 0 C. and Et.sub.3N (10.875 mL, 78.020 mmol) was added drop-wise. A solution of benzoyl chloride (9.049 mL, 78.020 mmol) in THF (30 mL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The solvent was evaporated, the residue dissolved in H.sub.2O (200 mL) and transferred into a 500 mL separating funnel, and washed with CH.sub.2Cl.sub.2 (3300 mL). The combined organic phases were dried over anhyd Na.sub.2SO.sub.4, and evaporated, to produce 17.809 g of ()-1-benzoylpiperidine-3-carboxamide. This product was used in the next step without further purification.

(203) Product appearance: slightly yellow solid

(204) Yield: 98%

(205) Melting point: 171-173 C.

(206) TLC: R.sub.f.sup.=0.58 (CH.sub.2Cl.sub.2-MeOH=5:1, v/v)

(207) IR (ATR): 3339, 3139, 2938, 2360, 1670, 1617, 1442, 1271, 1102, 936, 855, 670, 577 cm.sup.1

(208) .sup.1H NMR (400 MHz, DMSO-d6): =1.38 (1H, bs), 1.53-1.75 (2H, m), 1.91 (1H, bs), 2.30 (1H, bs), 2.78-3.08 (2H, m), 3.49-3.56 (1H, m), 4.35-4.46 (1H, m), 6.85-6.90 (1H, m), 7.29-7.52 (6H, m).

(209) .sup.13C NMR (100 MHz, DMSO-d6): =23.98, 24.80, 27.54, 27.79, 41.59, 41.60, 42.23, 43.99, 47.33, 49.35, 126.61, 128.36, 129.32, 136.20, 169.01, 174.52, 174.64.

(210) HRMS (ESI.sup.+): m/z calculated for C.sub.13H.sub.17N.sub.2O.sub.2: 233.1290; found: 233.1296.

(211) CHN analysis: Calculated for C.sub.13H.sub.16N.sub.2O.sub.2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.58; H, 7.01; N, 12.11.

Step 2: Synthesis of ()-(1-benzylpiperidin-3-yl)methanamine

(212) ##STR00126##

(213) To a 250-mL tree-neck round-bottomed flask equipped with a stirring bar and a reflux condenser, LiAlH.sub.4 (2.879 g, 75.863 mmol) was added under an argon atmosphere. Anhydrous THF (ca. 150 mL) was added with a double-tipped needle. Then ()-1-benzoylpiperidine-3-carboxamide (3.524 g, 15.171 mmol) was added in small portions over 1 h, and the reaction mixture was refluxed for 3 h under an argon atmosphere. The mixture was then cooled to 0 C. and the excess hydride was decomposed by drop-wise addition of H.sub.2O (2.879 mL) followed by 15% aq NaOH (2.879 mL) and then H.sub.2O (8.637 mL). After vigorous stirring for 1 h at r.t., the mixture was filtered under suction and the white precipitate was washed thoroughly with THF (560 mL). The combined filtrates were evaporated, to produce 3.085 g of crude ()-(1-benzylpiperidin-3-yl)methanamine. This product was used in the next step without further purification.

(214) Product appearance: slightly golden liquid

(215) HRMS (ESI.sup.+): m/z calculated for C.sub.13H.sub.21N.sub.2: 205.1705; found: 205.1710.

Step 3: Synthesis of ()-N-((1-benzylpiperidin-3-yl)methyl)naphthalene-2-sulfonamide

(216) ##STR00127##

(217) To a 50-mL round-bottomed flask equipped with a stirring bar, ()-(1-benzylpiperidin-3-yl)methanamine (1.553 g, 7.503 mmol) and CH.sub.2Cl.sub.2 (50 mL) were added at room temperature. The resulting solution was stirred and cooled to 0 C. Et.sub.3N (1.046 mL, 7.503 mmol) was added drop-wise, followed by naphthalene-2-sulfonyl chloride (1.723 g, 7.503 mmol) and the reaction mixture was allowed to warm to r.t. and then stirred for 20 h. The reaction mixture was transferred into a 100-mL separating funnel and washed with H.sub.2O (40 mL), followed by saturated aqueous NaHCO.sub.3 solution (40 mL). The organic phase was dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (20:1, v/v) as the eluent to produce 1.288 g of ()-N-((1-benzylpiperidin-3-yl)methyl)naphthalene-2-sulfonamide.

(218) Product appearance: white solid

(219) Yield: 43%

(220) TLC: R.sub.f=0.43 (CH.sub.2Cl.sub.2-MeOH=10:1, v/v)

(221) IR (ATR): 3062, 2938, 2816, 2769, 1467, 1452, 1328, 1159, 1068, 972, 817, 759, 701, 658, 640, 614 cm.sup.1

(222) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.02-1.11 (1H, m), 1.45-1.55 (1H, m), 1.60-1.71 (2H, m), 1.76-1.90 (2H, m), 2.09-2.15 (1H, m), 2.52-2.67 (2H, m), 2.85-2.97 (2H, m), 3.38-3.46 (2H, m), 5.20 (1H, bs), 7.22-7.31 (5H, m), 7.59-7.67 (2H, m), 7.78 (1H, dd, J.sub.1=8.7 Hz, J.sub.2=1.9 Hz), 7.90-7.97 (3H, m), 8.41 (1H, t, J=0.9 Hz)

(223) .sup.13C-NMR (100 MHz, CDCl.sub.3): =24.07, 28.06, 35.36, 47.02, 53.78, 57.14, 63.23, 122.23, 126.95, 127.41, 127.80, 128.11, 128.26, 128.60, 129.05, 129.12, 129.38, 132.03, 134.62, 136.64, 137.77.

(224) HRMS (ESI+): m/z calculated for C.sub.23H.sub.27N.sub.2O.sub.2S: 395.1793; found: 395.1784.

Example 4: Synthesis of N-((1-benzylpiperidin-3-yl)methyl)-N-methylnaphthalene-2-sulfonamide

(225) ##STR00128##

Step 1: Synthesis of ()-N-((1-benzylpiperidin-3-yl)methyl)-N-methylnaphthalene-2-sulfonamide

(226) ##STR00129##

(227) To a 25-mL round-bottomed flask equipped with a stirring bar, ()-N-((1-benzylpiperidin-3-yl)methyl)naphthalene-2-sulfonamide (0.104 g, 0.264 mmol) and MeCN (10 mL) were added at room temperature. The resulting solution was stirred and agitated with a stream of argon for 15 min. Cs.sub.2CO.sub.3 (0,258 g, 0,792 mmol), MeI (0.050 mL, 0,792 mmol) and NaI (catalytic amount) were added and the resulting suspension was stirred for 70 min at 60 C. under an argon atmosphere. The reaction mixture was evaporated, and CH.sub.2Cl.sub.2 (20 mL) was added to the residue. The mixture was transferred to a 50-mL separating funnel and washed with H.sub.2O (20 mL), followed by saturated aqueous NaHCO.sub.3 solution (20 mL). The organic phase was dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (24:1, v/v) as the eluent to produce 0.076 g of ()-N-((1-benzylpiperidin-3-yl)methyl)-N-methylnaphthalene-2-sulfonamide.

(228) Product appearance: white solid

(229) Yield: 70%

(230) TLC: R.sub.f=0.29 (CH.sub.2Cl.sub.2-MeOH=20:1, v/v)

(231) IR (ATR): 2937, 2809, 1453, 1334, 1155, 1132, 1070, 960, 889, 740, 653 cm.sup.1

(232) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.00-1.10 (1H, m), 1.66-1.77 (3H, m), 1.82-2.04 (3H, m), 2.74 (4H, s), 2.84-2.97 (3H, m), 3.43-3.60 (2H, m), 7.21-7.25 (1H, m), 7.30 (4H, d, J=4.4 Hz), 7.60-7.67 (2H, m), 7.74 (1H, dd, J.sub.1=8.6, J.sub.2=1.8 Hz), 7.90-7.99 (3H, m), 8.34-8.35 (1H, s).

(233) .sup.13C-NMR (100 MHz, CDCl.sub.3): =24.48, 28.12, 34.20, 35.23, 53.78, 57.68, 63.38, 122.63, 126.88, 127.43, 127.81, 128.08, 128.53, 128.60, 120.09, 129.17, 132.11, 134.33, 134.63, 138.13.

(234) HRMS (ESI+): m/z calculated for C.sub.24H.sub.29N.sub.2O.sub.2S: 409.1950; found: 409.1939.

Example 5: Synthesis of ()-N-((1-(3-fluorobenzyl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide

(235) ##STR00130##

Step 1: Synthesis of ()-tert-butyl ((1-(3-fluorobenzyl)piperidin-3-yl)methyl)(2-methoxyethyl)carbamate

(236) ##STR00131##

(237) To a 50-mL round-bottomed flask equipped with a stirring bar, ()-tert-butyl (2-methoxyethyl)(piperidin-3-ylmethyl)carbamate (0.208 g, 0.764 mmol) and 1,2-dichloroethane (15 mL) were added at room temperature. The resulting solution was stirred and agitated with a stream of argon for 15 min. NaBH(OAc).sub.3 (0,283 g, 1,335 mmol), 3-fluorobenzaldehid (0.083 mL, 0.764 mmol) and AcOH (0.044 mL, 0,764 mmol) were added, and the resulting suspension was stirred under an atmosphere of argon for 72 h. The reaction mixture was opened to the air and quenched with saturated aqueous NaHCO.sub.3 solution (30 mL). The mixture was transferred into a 100-mL separating funnel, and CH.sub.2Cl.sub.2 (20 mL) was added. The separating funnel was shaken vigorously and the organic phase was separated, dried over anhydrous Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2/MeOH (28:1, v/v) as the eluent, to produce 0.184 g of ()-tert-butyl ((1-(3-fluorobenzyl)piperidin-3-yl)methyl)(2-methoxyethyl)carbamate.

(238) Product appearance: slightly golden oil

(239) Yield: 63%

(240) TLC: R.sub.f=0.46 (CH.sub.2Cl.sub.2-MeOH=10:1, v/v)

(241) IR (ATR): 2974, 2931, 1689, 1590, 1484, 1451, 1412, 1391, 1365, 1250, 1161, 1117, 777 cm.sup.1

(242) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.89-1.00 (1H, m), 1.42-1.46 (10H, m), 1.63-1.77 (3H, m), 1.87-1.98 (2H, m), 2.72-2.75 (2H, m), 3.11-3.16 (2H, m), 3.24-3.37 (5H, m), 3.39-3.49 (4H, m), 6.89-6.94 (1H, m), 7.03-7.06 (2H, m), 7.21-7.25 (1H, m).

(243) .sup.13C-NMR (100 MHz, CDCl.sub.3): =24.88, 28.37, 28.49, 35.63, 36.11, 47.16, 51.37, 51.93, 54.07, 54.23, 57.76, 58.12, 58.81, 62.96, 70.95, 71.13, 79.33, 79.43, 113.77 (d, .sup.2J=21.3 Hz), 115.64 (d, .sup.2J=21.3 Hz), 124.47 (d, .sup.4J=2.9 Hz), 129.49 (d, .sup.3J=8.1 Hz), 141.26 (d, .sup.3J=8.1 Hz), 155.66, 162.86 (d, .sup.1J=245.76 Hz).

(244) HRMS (ESI+): m/z calculated for C.sub.21H.sub.34N.sub.2O.sub.3F: 381.2553; found: 381.2558.

Step 2: Synthesis of ()-N-((1-(3-fluorobenzyl)piperidin-3-yl)methyl)-2-methoxyethanamine di(2,2,2-trifluoroacetate)

(245) ##STR00132##

(246) To a 25-mL round-bottomed flask with a stirring bar, ()-tert-butyl ((1-(3-fluorobenzyl)piperidin-3-yl)methyl)(2-methoxyethyl)carbamate (0.133 g, 0.350 mmol) and CH.sub.2Cl.sub.2 (10 mL) were added at room temperature. The solution was stirred and TFA (0.270 mL, 3,500 mmol) was added drop-wise. After 22 h the reaction mixture was evaporated and the residue was coevaporated with CH.sub.2Cl.sub.2 (215 mL), followed by n-hexane (215 mL) to produce 0.163 g of ()-N-((1-(3-fluorobenzyl)piperidin-3-yl)methyl)-2-methoxyethanamine di(2,2,2-trifluoroacetate). This product was used in the next step without further purification.

(247) Product appearance: slightly golden oil

(248) Yield: 92%

(249) HRMS (ESI+): m/z calculated for C.sub.16H.sub.25N.sub.2OF 281.2029; found 281.2034.

Step 3: Synthesis of ()-N-((1-(3-fluorobenzyl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide

(250) ##STR00133##

(251) To a 50-mL round-bottomed flask equipped with a stirring bar, ()-N-((1-(3-fluorobenzyl)piperidin-3-yl)methyl)-2-methoxyethanamine di(2,2,2-trifluoroacetate) (0.150 g, 0.295 mmol) and CH.sub.2Cl.sub.2 (20 mL) were added at room temperature. The resulting solution was stirred and cooled to 0 C. Et.sub.3N (0.123 mL, 0.885 mmol) was added drop-wise, followed by naphthalene-2-sulfonyl chloride (0.067 g, 0.295 mmol) and the reaction mixture was allowed to warm to r.t. and then stirred for 20 h. The reaction mixture was transferred into a 50-mL separating funnel and washed with H.sub.2O (20 mL), followed by saturated aqueous NaHCO.sub.3 solution (20 mL). The organic phase was dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (28:1, v/v) as the eluent to produce 0.121 g of ()-N-((1-(3-fluorobenzyl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide.

(252) Product appearance: slightly golden oil

(253) Yield: 87%

(254) TLC: R.sub.f=0.46 (CH.sub.2Cl.sub.2-MeOH=15:1, v/v)

(255) IR (ATR): 2932, 1589, 1449, 1335, 1252, 1155, 1129, 1116, 1072, 748, 728, 651, 615 cm.sup.1 1H-NMR (400 MHz, CDCl.sub.3): =0.96-1.06 (1H, m), 1.49-1.55 (1H, m), 1.66-1.78 (3H, m), 1.95-2.01 (2H, m), 2.66-2.79 (2H, m), 3.11-3.13 (2H, m), 3.22 (3H, s), 3.28-3.33 (2H, m), 3.42-3.51 (4H, m), 6.90-6.95 (1H, m), 7.02-7.06 (2H, m), 7.21-7.25 (1H, m), 7.59-7.66 (2H, m), 7.76 (1H, dd, J.sub.1=8.7 Hz, J.sub.2=1.9 Hz), 7.89-7.97 (3H, m), 8.37-8.38 (1H, m).

(256) .sup.13C-NMR (100 MHz, CDCl.sub.3): =24.54, 28.17, 34.85, 48.18, 53.25, 53.99, 57.65, 58.71, 62.73, 71.23, 113.74 (d, .sup.2J=21.3 Hz), 115.57 (d, .sup.2J=21.3 Hz), 122.54, 124.44 (d, .sup.4J=2.9 Hz), 127.45, 127.83, 128.42, 128.62, 129.16, 129.21, 129.50 (d, .sup.3J=8.1 Hz), 132.12, 134.65, 136.39, 141.36 (d, .sup.3J=8.1 Hz), 162.86 (d, .sup.1J=245.0 Hz).

(257) HRMS (ESI+): m/z calculated for C.sub.26H.sub.32N.sub.2O.sub.3SF: 471.2118; found: 471.2110.

Example 6: Synthesis of N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide

(258) ##STR00134##

Step 1: Synthesis of 1-benzoylpiperidine-4-carboxylic acid

(259) ##STR00135##

(260) To a 250-mL round-bottomed flask equipped with a stirring bar, isonipecotic acid (10.000 g, 77.425 mmol) was added. THF (80 mL), H.sub.2O (80 mL) and K.sub.2CO.sub.3 (53.504 g, 387.121 mmol) were added, and the mixture was cooled to 0 C. A solution of benzoyl chloride (8.980 mL, 77.425 mmol) in THF (35 mL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with EtOAc (3150 mL). The aqueous phase was cooled to 0 C. and adjusted to pH 1-2 with 6 M aq HCl. The white precipitate was collected in a Bchner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P.sub.2O.sub.5 and silica gel to constant mass to produce 15.369 g of 1-benzoylpiperidine-4-carboxylic acid. This product was used in the next step without further purification.

(261) Product appearance: white solid

(262) Yield: 85%

(263) Melting point: 118-122 C.

(264) TLC: R.sub.f.sup.=0.55 (MeCNH.sub.2O-MeOH=3:1:1)

(265) IR (ATR): 2857, 2359, 1730, 1612, 1447, 1207, 1169, 1014, 791, 731, 707, 628, 577. cm.sup.1

(266) .sup.1H NMR (400 MHz, DMSO-d6): =1.49 (2H, bs), 1.83 (2H, bd, J=45.68 Hz), 2.52-2.57 (1H, m), 3.01 (2H, bd, J=52.08 Hz), 3.52 (1H, bs), 4.31 (1H, bs), 7.34-7.46 (5H, m), 12.32 (1H, bs).

(267) .sup.13C NMR (100 MHz, DMSO-d6): =27.62, 28.24, 40.06, 40.74, 46.38, 126.61, 128.38, 129.31, 136.23, 168.96, 175.48.

(268) HRMS (ESI.sup.+): m/z calculated for C.sub.13H.sub.16NO.sub.3: 234.1130; found 231.1125.

(269) CHN analysis: Calculated for C.sub.13H.sub.15NO.sub.3: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.22; H, 6.78; N, 6.22.

Step 2: Synthesis of 1-benzoyl-N-(2-methoxyethyl)piperidine-4-carboxamide

(270) ##STR00136##

(271) To a 250-mL round-bottomed flask equipped with a stirring bar, 12 (3.201 g, 13.723 mmol) and CH.sub.2Cl.sub.2 (180 mL) were added. Et.sub.3N (3.824 mL, 27.446 mmol) was added drop-wise, followed by TBTU (4.406 g, 13.723 mmol). After 30 min, 2-methoxyethylamine (2.355 mL, 27.446 mmol) was added drop-wise, and the reaction mixture was stirred for 23 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with H.sub.2O (2200 mL), 0.5 M aq HCl (2200 mL), sat. aq NaHCO.sub.3 solution (2200 mL) followed by sat. brine solution (200 mL), dried over anhyd Na.sub.2SO.sub.4, and evaporated to produce 3.711 g of crude 1-benzoyl-N-(2-methoxyethyl)piperidine-4-carboxamide. This product was used in the next step without further purification.

(272) Product appearance: white solid

(273) HRMS (ESI.sup.+): m/z calculated for C.sub.16H.sub.23N.sub.2O.sub.3: 291.1709; found: 291.1703.

Step 3: Sinteza N-((1-benzylpiperidin-4-yl)methyl)-2-methoxyethan-1-amine

(274) ##STR00137##

(275) To a 250-mL tree-neck round-bottomed flask equipped with a stirring bar and a reflux condenser, LiAlH.sub.4 (2.425 g, 63.904 mmol) was added under an argon atmosphere. Anhydrous THF (ca. 120 mL) was added with a double-tipped needle. A solution of crude 1-benzoyl-N-(2-methoxyethyl)piperidine-4-carboxamide (3.711 g, 12.781 mmol) in anhydrous THF (ca. 40 mL) was added with a double-tipped needle, and the reaction mixture was refluxed for 2 h. The mixture was then cooled to 0 C., and the excess hydride was decomposed by drop-wise addition of H.sub.2O (2.425 mL) followed by 15% aq NaOH (2.425 mL) and then H.sub.2O (7.275 mL). After vigorous stirring for 1 h at r.t., the mixture was filtered under suction and the white precipitate was washed thoroughly with THF (560 mL). The combined filtrates were evaporated to produce 2.833 g of crude N-((1-benzylpiperidin-4-yl)methyl)-2-methoxyethan-1-amine as a slightly golden liquid.

(276) Product appearance: slightly golden liquid

(277) HRMS (ESI.sup.+): m/z calculated for C.sub.16H.sub.27N.sub.2O: 263.2123; found: 263.2120.

Step 4: Synthesis of tert-butyl (1-benzylpiperidin-4-yl)methyl(2-methoxyethyl)carbamate

(278) ##STR00138##

(279) CH.sub.2Cl.sub.2 (50 mL) and a stirring bar were added to crude N-((1-benzylpiperidin-4-yl)methyl)-2-methoxyethan-1-amine (2,833 g, 10.797 mmol) in a 100-mL round-bottomed flask equipped with a stirring bar. Et.sub.3N (1.505 mL, 10.797 mmol) was added drop-wise, and the reaction mixture was cooled to 0 C. A solution of Boc.sub.2O (2.357 g, 10.797 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added drop-wise, and the reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 100-mL separating funnel and washed with H.sub.2O (30 mL), dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (30:1) then CH.sub.2Cl.sub.2-MeOH (10:1) as the eluent to produce 3.254 g of tert-butyl (1-benzylpiperidin-4-yl)methyl(2-methoxyethyl)carbamate.

(280) Product appearance: slightly golden oil

(281) Yield: 65% (from 1-benzoylpiperidine-4-carboxylic acid)

(282) TLC: R.sub.f.sup.=0.52 (CH.sub.2Cl.sub.2-MeOH=10:1)

(283) IR (ATR): 2923, 2801, 1689, 1411, 1364, 1147, 1117, 973, 872, 773, 737, 698, 568 cm.sup.1

(284) .sup.1H NMR (400 MHz, CDCl.sub.3): =1.26-1.31 (2H, m), 1.44 (9H, s), 1.58-1.61 (3H, m), 1.89-1.95 (2H, m), 2.88-2.91 (2H, m), 3.14 (2H, d, J=6.90 Hz), 3.28-3.38 (5H, m), 3.43-3.50 (4H, m), 7.24-7.32 (5H, m).

(285) .sup.13C NMR (100 MHz, CDCl.sub.3): =28.35, 29.93, 35.07, 35.49, 46.96, 47.66, 53.31, 53.49, 53.57, 58.72, 63.19, 63.39, 70.90, 71.09, 79.22, 79.31, 126.83, 128.03, 129.04, 129.16, 138.25, 138.43, 155.53, 155.69.

(286) HRMS (ESI.sup.+): m/z calculated for C.sub.21H.sub.35N.sub.2O.sub.3: 363.2648; found: 363.2648.

(287) CHN analysis: calculated for C.sub.21H.sub.34N.sub.2O.sub.3: C, 69.58; H, 9.45; N, 7.73. Found: C, 69.66; H, 9.57; N, 7.69.

Step 5: Synthesis of tert-butyl (2-methoxyethyl)(piperidin-4-ylmethyl)carbamate

(288) ##STR00139##

(289) To a 250-mL round-bottomed flask with a stirring bar, tert-butyl (1-benzylpiperidin-4-yl)methyl(2-methoxyethyl)carbamate (2,351 g, 6,486 mmol) and MeOH (100 mL) were added at room temperature. The resulting solution was stirred and agitated with a stream of argon for 30 min. Pd(OH).sub.2 on carbon (20 wt. %) (0.828 g, 20% mass of -butyl (1-benzylpiperidin-4-yl)methyl(2-methoxyethyl)carbamate) was added, followed by cyclohexene (6.576 mL, 64,860 mmol). The resulting suspension was refluxed under an atmosphere of argon for 18 h, then filtered through a pad of Celite, and evaporated, to produce 1.696 g of crude tert-butyl (2-methoxyethyl)(piperidin-4-ylmethyl)carbamate. This product was used in the next step without further purification.

(290) Product appearance: slightly golden oil

(291) Yield: 96%

(292) TLC: R.sub.f=0.57 (CH.sub.2Cl.sub.2-MeOH-Et.sub.3N=20:2:1, v/v/v)

(293) HRMS (ESI.sup.+): m/z calculated for C.sub.14H.sub.29N.sub.2O.sub.3: 273.2178; found: 273.2172.

Step 6: Synthesis of tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)(2-methoxyethyl)carbamate

(294) ##STR00140##

(295) To a 100-mL round-bottomed flask with a stirring bar, tert-butyl (2-methoxyethyl)(piperidin-4-ylmethyl)carbamate (1.050 g, 3.854 mmol) and 1,2-dichloroethane (50 mL) were added at room temperature. The resulting solution was stirred and agitated with a stream of argon for 15 min. NaBH(OAc).sub.3 (1.532 g, 7.226 mmol), 1H-inden-2(3H)-one (0.509 g, 3.854 mmol) and AcOH (0.221 mL, 3.854 mmol) were added, and the resulting suspension was stirred under an atmosphere of argon for 72 h. The reaction mixture was opened to the air and quenched with saturated aqueous NaHCO.sub.3 solution (50 mL). The mixture was transferred into a 250-mL separating funnel, and CH.sub.2Cl.sub.2 (20 mL) was added. The separating funnel was shaken vigorously and the organic phase was separated, dried over anhydrous Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2/MeOH (30:1, v/v) as the eluent, to produce 1.198 g of tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)(2-methoxyethyl)carbamate.

(296) Product appearance: slightly yellow solid

(297) Yield: 80%

(298) TLC: R.sub.f=0.47 (CH.sub.2Cl.sub.2-MeOH=10:1, v/v)

(299) IR (KBe): 2930, 2808, 1688, 1475, 1407, 1282, 1149, 1113, 1012, 979, 871, 745, 664 cm.sup.1

(300) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.25-1.45 (11H, m), 1.68 (3H, d, J=12.3 Hz), 1.95-2.06 (2H, m), 2.88-2.93 (2H, m), 3.05-3.17 (7H, m), 3.34-3.39 (5H, m), 3.44-3.53 (2H, m), 7.11-7.18 (4H, m).

(301) .sup.13C-NMR (100 MHz, CDCl.sub.3): =28.35, 29.82, 35.08, 35.39, 37.12, 46.92, 47.93, 51.48, 51.73, 53.54, 58.73, 67.11, 70.91, 71.08, 79.27, 79.37, 124.24, 126.24, 141.49, 155.53, 155.69 HRMS (ESI+): m/z calculated for C.sub.23H.sub.37N.sub.2O.sub.3: 389.2804; found: 389.2810.

Step 7: Synthesis of N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)-2-methoxyethanamine di(2,2,2-trifluoroacetate)

(302) ##STR00141##

(303) To a 100-mL round-bottomed flask equipped with a stirring bar, tert-butyl ((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)(2-methoxyethyl)carbamate (1,100 g, 2.831 mmol) and CH.sub.2Cl.sub.2 (50 mL) were added at room temperature. The resulting solution was stirred and TFA (2.168 mL, 28,310 mmol) was added drop-wise. After 24 h, the reaction mixture was evaporated. The residue was co-evaporated with CH.sub.2Cl.sub.2 (240 mL), followed by n-hexane (250 mL). Et.sub.2O (50 mL) was added to the oily residue, and the flask was placed in an ultrasonic bath for 15 min. During this time, the oily residue transformed into a white solid. The flask was removed from the ultrasonic bath and the precipitate was allowed to settle to the bottom of the flask. The supernatant was removed, Et.sub.2O (30 mL) was added, and the flask was placed back in the ultrasonic bath for 1 min. The flask was removed from the ultrasonic bath and the precipitate was allowed to settle to the bottom of the flask. The supernatant was removed, Et.sub.2O (30 mL) was added again, and this procedure was repeated two more times. After the final supernatant was removed, the solid residue was dried at reduced pressure to produce 1,272 g of crude N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)-2-methoxyethanamine di(2,2,2-trifluoroacetate). This product was used in the next step without further purification.

(304) Product appearance: white solid

(305) Yield: 87%

(306) HRMS (ESI+): m/z calculated for C.sub.18H.sub.29N.sub.2O 289.2280; found 289.2286.

Step 8: Synthesis of N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide

(307) ##STR00142##

(308) To a 25-mL round-bottomed flask equipped with a stirring bar, N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)-2-methoxyethanamine di(2,2,2-trifluoroacetate) (0.250 g, 0.484 mmol) and CH.sub.2Cl.sub.2 (10 mL) were added at room temperature. The resulting suspension was stirred and Et.sub.3N (0.202 mL, 1.452 mmol) was added drop-wise, followed by naphthalene-2-sulfonyl chloride (0,110 g, 0,484 mmol) and the reaction mixture was allowed to warm to r.t. and then stirred for 20 h. The reaction mixture was transferred into a 50-mL separating funnel, CH.sub.2Cl.sub.2 (15 mL) was added and washed with H.sub.2O (20 mL), followed by saturated aqueous NaHCO.sub.3 solution (20 mL). The organic phase was dried over anhyd Na.sub.2SO.sub.4, and evaporated. The residue was purified by flash column chromatography using CH.sub.2Cl.sub.2-MeOH (20:1, v/v) as the eluent to produce 0.208 g of N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)methyl)-N-(2-methoxyethyl)naphthalene-2-sulfonamide.

(309) Product appearance: white solid

(310) Yield: 90%

(311) TLC: R.sub.f=0.48 (CH.sub.2Cl.sub.2/MeOH, 10:1, v/v)

(312) IR (ATR)=2937, 1672, 1329, 1153, 1129, 1073, 999, 820, 743, 652, 617 cm.sup.1

(313) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.57 (2H, bs), 1.89-1.92 (3H, m), 2.36 (2H, bs), 3.09-3.34 (13H, m), 3.48 (3H, t, J=5.5 Hz), 7.14-7.20 (4H, m), 7.60-7.67 (2H, m), 7.75-7.79 (1H, m), 7.89-7.98 (3H, m), 8.37 (1H, s).

(314) .sup.13C-NMR (400 MHz, CDCl.sub.3): =28.35, 34.30, 36.06, 49.00, 50.98, 54.79, 58.68, 66.63, 71.31, 122.48, 124.31, 126.78, 127.53, 127.82, 128.49, 128.71, 129.14, 129.29, 132.08, 134.67, 135.97, 140.33.

(315) HRMS (ESI+): m/z calculated for C.sub.28H.sub.35N.sub.2O.sub.3S: 479.2368; found: 479.2358.