4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors

Abstract

There are provided substituted 4-carboxamido-isoindolinone derivatives which selectively inhibit the activity of poly (ADP-ribose) polymerase PARP-I with respect to poly (ADP-ribose) polymerase P ARP-2. The compounds of this invention are therefore useful in treating diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of in-flammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

Claims

1. A process for the preparation of a compound of formula (I): ##STR00055## selected from the group consisting of: 2-(1-cyclohexyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide; and 2-(1-cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide, wherein: R is hydrogen or fluorine; and n, m, R1 and R2 have the following meanings: a) n is 0 and m is 0; R1 is piperidinyl; and R2 cyclohexyl; or a pharmaceutically acceptable salt thereof, which process comprises one of the following sequences of steps: SEQUENCE A: Step h) cyclizing a compound of formula (V): ##STR00056## wherein T is a (C.sub.1-C.sub.6)-alkyl or an aryl-(C.sub.1-C.sub.6)-alkyl, by reaction with a suitable amine of formula (XIII)
X-R1-[CH.sub.2].sub.n—NH.sub.2  (XIII) wherein R1 and n are as defined above, and X is R2-[CH.sub.2].sub.m—, wherein R2 and m are as defined above; Step c′) hydrolyzing the resultant compound of formula (IV): ##STR00057## so as to obtain a compound of formula (I), as defined above.

Description

EXAMPLE 1

(1) Step a

2-Bromo-4-fluoro-6-methyl-phenylamine (X) [Hal=Br]

(2) A solution of N-bromosuccinimide (18.7 g, 0.105 mol) in 70 mL of N,N-dimethylformamide was added dropwise to a solution of 4-fluoro-2-methyl-phenylamine (XI) (12.5 g, 0.1 mol) in 70 mL of the same solvent at 20° C. The reaction mixture was stirred overnight. The dark solution was poured into a mixture of water (1000 mL), brine (50 mL) and ethyl acetate (300 mL). The mixture was transferred into a separatory funnel, shaken and separated. The aqueous phase was extracted with ethyl acetate (4×150 mL). The combined organic layers were washed with water (5×100 mL), brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The product was purified by lash chromatography (eluent ethyl acetate:n-hexane=1:8). The pure fractions were combined and evaporated to give 14.9 g of product. The impure fractions were combined, concentrated, re-dissolved in diethyl ether (30 mL) and extracted with 5% hydrochloric acid (5×10 mL). The acidic phase was basified with aqueous potassium hydroxide and extracted with diethyl ether to provide further 0.8 g of the title compound. Total yield was 15.7 g (77%).

(3) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 2.16 (s, 3H), 4.83 (br. s, 2H), 6.91 (dd, J.sub.H-F=9.3 Hz, J.sub.H-H=2.9 Hz, 1H), 7.16 (dd, J.sub.H-F=8.3 Hz, J.sub.H-H=2.9 Hz, 1H).

(4) Step b

2-Bromo-4-fluoro-6-methyl-benzonitrile (IX) [Hal=Br]

(5) A solution of potassium cyanide (16.25 g, 0.25 mol) in 20 mL of water was added to a suspension of freshly prepared copper(I) chloride (9.5 g, 0.096 mol) in 40 mL of water. Toluene (30 mL) was then added and the mixture was chilled to 0° C. 2-Bromo-4-fluoro-6-methyl-phenylamine (X) (15.7 g, 0.077 mol) was added to a mixture of 16.5 ml of 36% aqueous hydrochloric acid and 40 mL of water. The resultant suspension was heated until a solution was formed. The solution was chilled to 2° C. and the amine hydrochloride precipitated. A solution of sodium nitrite (5.34 g, 0.078 mol) in 15 mL of water was slowly added, keeping the reaction mixture temperature below 5° C. Powdered sodium carbonate decahydrate was added in small portions to adjust the pH of the reaction mixture to about 7. The resultant solution of the diazonium salt was then slowly added to the previously prepared cyanocuprate reagent, again keeping the reaction temperature below 5° C. A bright red-orange precipitate formed. The reaction mixture was allowed to warm to 20° C. and kept at this temperature overnight. Then it was slowly heated to 70° C. for 1 h. The precipitate dissolved almost completely. The reaction mixture was allowed to cool to 20° C. and filtered. The organic phase was separated, and the aqueous phase was extracted with toluene (3×70 mL). The combined organic layers were washed with water (2×100 mL), brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude nitrile (IX) (13.9 g, 84%) was used without further purification.

(6) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 2.52 (s, 3H), 7.44 (dd, J.sub.H-F=9.4 Hz, J.sub.H-H=2.1 Hz, 1H), 7.73 (dd, J.sub.H-F=8.2 Hz, J.sub.H-H=2.1 Hz, 1H).

(7) .sup.13C NMR (75.0 MHz. DMSO-d) S 115.8, 112.7 (d, J.sub.C-F=3 Hz), 117.0 (d, J.sub.C-F=23 Hz), 118.4 (d, J.sub.C-F=27 Hz), 126.1 (d, J.sub.C-F=11 Hz), 147.8 (d, J.sub.C-F=11 Hz), 163.5 (d, J.sub.C-F=257 Hz).

(8) Step c

2-Bromo-4-fluoro-6-methyl-benzamide (VIII) [Hal=Br]

(9) 2-Bromo-4-fluoro-6-methyl-benzonitrile (IX) (0.428 g, 2 mmol) was heated in 70% aqueous sulfuric acid (2 mL) overnight at 150° C. The reaction mixture was poured into ice and extracted with ethyl acetate (4×2 mL). The organic phase was washed with water (4×2 mL), brine (2×2 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 300 mg of crude 2-bromo-4-fluoro-6-methyl-benzamide (VIII). Pure sample was obtained by recrystallization from benzene.

(10) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 3.31 (s, 3H), 7.17 (dd, J.sub.H-F=9.8 Hz, J.sub.H-H=2.2 Hz, 1H), 7.41 (dd, J.sub.H-F=8.6 Hz, J.sub.H-H=2.2 Hz, 1H), 7.89 (br. s, 1H), 7.65 (br. s, 1H).

(11) Step d

2-Bromo-4-fluoro-6-methyl-benzoic acid (VI) [Hal=Br]

(12) 2-Bromo-4-fluoro-6-methyl-benzamide (VIII) (0.9 g, 3.9 mmol) was dissolved in 75% aqueous sulfuric acid (4 mL) at 80° C. Sodium nitrite (0.5 g, 7.2 mmol) was carefully added in small portions during 1 h. The reaction mixture was chilled to 20° C. and cold water (15 ml) was added to the reaction mixture. The product was extracted with ethyl acetate (6×2 mL). The organic phase was washed with water (4×2 mL), brine (2×2 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 0.879 g (97%) of pure acid (VII).

(13) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 2.31 (s, 1H), 7.22 (dd, J.sub.H-F=9.6 Hz, J.sub.H-H=2.2 Hz, 1H), 7.47 (dd, J.sub.H-F=8.5 Hz, J.sub.H-H=2.4 Hz, 1H), 13.7 (br. s, 1H).

(14) .sup.13C NMR (75.0 MHz, DMSO-d.sub.6+CCl.sub.4) δ ppm 19.5, 116.0 (d, J.sub.C-F=22 Hz), 116.8 (d, J.sub.C-F=24 Hz), 118.3 (d, J.sub.C-F=10 Hz), 134.0 (d, c=3 Hz), 138.4 (d, J.sub.C-F=8 Hz), 163.0 (d, J.sub.C-F=250 Hz), 168.0.

(15) Step f

2-Bromo-4-fluoro-6-methyl-benzoic acid methyl ester (VI) [Hal=Br; T=methyl]

(16) A mixture of 2-bromo-4-fluoro-6-methyl-benzoic acid (VII) (1.94 g, 8.33 mmol), anhydrous potassium carbonate (1.72 g, 12.5 mmol), methyl iodide (2.36 g, 17 mmol) in N,N-dimethylformamide (15 mL) was vigorously stirred for 23 h at 20° C. The suspension was poured into 70 mL of water. A dense oil separated out. The product was extracted with ethyl acetate (4×25 mL). The organic phase was washed with water (5×20 mL), brine (2×20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 2.07 g (quantitative yield) of 2-bromo-4-fluoro-6-methyl-benzoic acid methyl ester (VI).

(17) .sup.1H NMR (400.5 MHz, CDCl.sub.3) δ ppm 2.35 (s, 3H), 3.96 (s, 3H), 6.91 (dd, J.sub.H-F=9.0 Hz, J.sub.H-H=2.2 Hz, 1H), 7.18 (dd, J.sub.H-F=8.1 Hz, J.sub.H-H=2.4 Hz, 1H).

(18) Step g

2-Cyano-4-fluoro-6-methyl-benzoic acid methyl ester (V) [T=methyl]

(19) A mixture of 2-bromo-4-fluoro-6-methyl-benzoic acid methyl ester (VI) (275 mg, 1.12 mmol), potassium hexacyanoferrate (II) (206 mg, 0.56 mmol), anhydrous sodium carbonate (237 mg, 2.24 mmol) and palladium(II) acetate (5 mg, 0.0224 mmol) in 3 mL of N-methylpyrrolidone was heated at 120° C. in a sealed tube under argon atmosphere overnight. The reaction mixture was diluted with dichloromethane and filtered through a pad of Celite. The organic phase was washed with water (13×6 mL), brine (2×6 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. Column chromatography (n-hexane/ethyl acetate: 7/3) afforded 2-cyano-4-fluoro-6-methyl-benzoic acid methyl ester (76 mg, 35%).

(20) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 2.42 (s, 3H), 3.93 (s, 3H), 7.65 (dd, J+=9.6, J.sub.HH=2.6 Hz, 1H), 7.85 (dd, J.sub.HF=8.3, 2.6 Hz, 1H).

(21) Step h

6-Fluoro-2-(3-morpholin-4-yl-propyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) [n=3; R1=morpholin-4-yl; X=null, as m=0 and R2=null]

(22) To a solution of 2-cyano-4-fluoro-6-methyl-benzoic acid methyl ester (V) (208 mg, 1.07 mmol) in methyl pivalate (2 mL), N-bromosuccinimide (310 mg, 1.74 mmol) and benzoylperoxide (20 mg, 0.097 mmol) were added. The reaction mixture was stirred at 85° C. under nitrogen atmosphere for 3 h. Crude was filtered on Gooch and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (3 mL). Triethylamine (0.41 mL, 2.9 mmol) and 3-morpholin-4-yl-propylamine (XIII) (140 mg, 0.97 mmol) were added and the reaction mixture was stirred at 90° C. for 3 h. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide. The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated. Column chromatography (gradient from chloroform/methanol: 9614 to chloroform/methanol: 94/6) afforded 6-fluor-2-(3-morpholin-4-yl-propyl)-3-ox-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) (130 mg, 40% yield).

(23) .sup.1H NMR (400.5 MHz, CDCl.sub.3) δ ppm 1.87 (quintet, J=7.1 Hz, 2H), 2.34-2.49 (m, 6H), 3.62-3.74 (m, 6H), 4.45 (s, 2H), 7.42 (dd, J.sub.H-F=7.3 Hz, J.sub.H-H=2.0 Hz, 1H), 7.47 (dd, J.sub.H-F=8.3 Hz, J.sub.H-H=2.0 Hz, 1H).

(24) Step c′

6-Fluoro-2-(3-morpholin-4-yl-propyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (I), cpd 23

(25) [R=F; n=3; R1=morpholin-4-yl; m=0; R2=null]

(26) ##STR00023##

(27) A solution of 6-fluoro-2-(3-morpholin-4-yl-propyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) (100 mg, 0.33 mmol) in 1.5 mL of 36% hydrochloric acid was heated at 50° C. for 10 h. All volatile materials were evaporated and the residue was dissolved in 2 mL of cold water. The solution was neutralized with solid potassium carbonate. The solid precipitated was dissolved in dichloromethane and the organic phase was washed with saturated aqueous sodium carbonate (2×1 mL), brine (2×1 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 73 mg (73%) of 6-fluoro-2-(3-morpholin-4-yl-propyl)-3-ox-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1).

(28) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.79 (quintet, J=7.1 Hz, 2H), 2.28-2.35 (m, 6H), 3.47-3.52 (m, 4H), 3.59 (t, J=7.1 Hz, 2H), 4.58 (s, 2H), 7.68 (dd, J.sub.HF=7.8, J.sub.HH=2.6 Hz, 1H), 7.83 (br. s., 1H), 7.89 (dd, J.sub.HF=10.9, J.sub.HH=2.6 Hz, 1H), 10.81 (br. s., 1H).

(29) HRMS (ESI+): calcd. for C.sub.16H.sub.21FN.sub.3O.sub.3 [M+H].sup.+ 322.1562; found 322.1565.

EXAMPLE 2

(30) Step e

4-Fluoro-2-iodo-6-methyl-benzoic acid (VII) [Hal=I]

(31) A mixture of 4-fluoro-2-methyl-benzoic acid (XII) (20.00 g, 0.130 mol), iodobenzene diacetate (50.15 g, 0.156 mol), iodine (39.52 g, 0.156 mol) and palladium(II) acetate (1.46 g, 0.006 mol) in N,N-dimethylformamide (360 mL) was degassed by cycling vacuum and nitrogen three times and then was heated for 18 h at 100° C. internal temperature, under argon. The resultant dark mixture was cooled to room temperature, diluted with methyl-tert-butylether (200 mL) and treated with a solution of sodium metabisulfite (250 g) in water (500 mL) under efficient stirring. Then, this yellow colored mixture was acidified by slowly adding conc. hydrochloric acid (130 mL). The aqueous layer was separated and extracted twice with methyl-tert-butylether (mL 100×2). The combined organic extracts were treated with a solution of sodium hydroxide pellets (80 g) in water (300 mL) under stirring. The organic layer containing only iodobenzene was discharged, while the aqueous layer was added with sodium chloride, cooled to ice temperature and brought to very low pH with conc. hydrochloric acid (130 mL). From this aqueous medium the product was extracted with methyl-tert-butylether (100 mL×3) and the combined extracts were dried over Na.sub.2SO.sub.4 and finally concentrated under reduced pressure affording 30.5 g (84%) of 4-fluoro-2-iodo-6-methyl-benzoic acid as brown solid. This raw material was used in the next step without purification.

(32) .sup.1H NMR (300.0 MHz, CDCl.sub.3) δ ppm 2.46 (s, 3H), 6.96 (dd, J.sub.HF=9.1, J.sub.HH=2.6 Hz, 1H), 7.45 (dd, J.sub.HF=7.9, 2.3 Hz, 1H).

(33) Step f

4-Fluoro-2-iodo-6-methyl-benzoic acid methyl ester (VI) [Hal=1; T=methyl]

(34) To a solution of 4-fluoro-2-iodo-6-methyl-benzoic acid (VII) (30.05 g, 0.109 mol) in N,N-dimethylformamide (300 mL) was added anhydrous potassium carbonate (22.0 g, 0.16 mol) under efficient magnetic stirring. After 15 min methyl p-toluensulfonate (30.7 g, 0.16 mol) was added. The brown suspension was stirred at room temperature for 2 h. Potassium acetate (12.4 g, 0.13 mol) was then added to destroy the unreacted methyl p-toluensulfonate and the mixture was stirred overnight. The thick reaction mixture was diluted with methyl-tert-butylether (100 mL) and washed with water (600 mL); the aqueous layer was separated and extracted twice with methyl-tert-butylether (70 mL×2). The combined organic extracts were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to a solid residue. This material was purified by chromatography (eluant n-hexane/ethyl acetate 9:1), affording 26.2 g (81%) of product as colorless oil.

(35) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 2.27 (s, 3H), 3.86 (s, 3H), 7.25 (dd, J.sub.HF=9.6, J.sub.HH=2.4 Hz, 1H), 7.63 (dd, J.sub.HF=8.2, J.sub.HH=2.4 Hz, 1H).

(36) Step q

2-Cyano-4-fluoro-6-methyl-benzoic acid methyl ester (V) [T=methyl]

(37) A solution of 4-fluoro-2-iodo-6-methyl-benzoic acid methyl ester (VI) (26.02 g, 88.48 mmol) in 260 mL of N,N-dimethylformamide was treated with copper(I) cyanide (12.18 g; 0.136 mol) and stirred at 110° C. for 5 h. The dark colored mixture was allowed to cool to about 60° C., treated with 105 g of Celite® 560 coarse (Fluka) under efficient stirring and diluted with ethyl acetate (250 mL). After cooling to room temperature, the mixture was slowly poured in 0.25N aqueous sodium hydroxide (500 mL) and then filtered. The reaction flask and the panel were washed with ethyl acetate (100 mL). The aqueous layer was separated and extracted twice with ethyl acetate (250 mL+100 mL). The combined organic extracts were washed with brine (200 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 22.00 g of raw product as yellow solid. This material was crystallized from n-hexane (40 mL): after cooling to room temperature the solid was collected by filtration and the mother liquors were concentrated under reduced pressure. The solid residue so obtained was crystallized from n-hexane (20 mL) yielding, after filtration of the solids, a second crop of product. The combined crops (14.15 g) were finally purified by chromatography eluting in gradient from n-hexane/methyl-tert-butylether 9:1 to n-hexane/ethyl acetate 91. After evaporation of the fractions 12.0 g (70%) of 2-cyano-4-fluoro-6-methyl-benzoic acid methyl ester (V) were obtained.

(38) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 2.42 (s, 3H), 3.93 (s, 3H), 7.65 (dd. J.sub.H-F=9.6, J.sub.HH=2.6 Hz, 1H), 7.85 (dd, J.sub.HF=8.3, 2.6 Hz, 1H).

(39) Step h

2-(1-Cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) [R=F; n=m=0; R1=piperidin-4-yl; R2=1-cyclohexyl]

(40) To a solution of 2-cyano-4-fluoro-6-methyl-benzoic acid methyl ester (V) (208 mg, 1.07 mmol) in methyl pivalate (2 mL), N-bromosuccinimide (310 mg, 1.74 mmol) and benzoylperoxide (20 mg, 0.097 mmol) were added. The reaction mixture was stirred at 85° C. under nitrogen atmosphere for 3 h. Crude was filtered and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (3 mL). Potassium carbonate (670 mg, 4.85 mmol) and 1-cyclohexyl-piperidin-4-ylamine dihydrochloride monohydrate (XIII) (265 mg, 0.97 mmol) were added and the reaction mixture was stirred at 90° C. for 3 h. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide. The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated. Column chromatography (dichloromethane/methanol/ammonia solution, 7N in methanol: 97021) afforded 2-(1-cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) (100 mg, 30%).

(41) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.02-1.13 (m, 1H), 1.16-1.27 (m, 4H), 1.55-1.62 (m, 1H), 1.68-1.80 (br. s., 7H), 2.23-2.39 (m, 3H), 2.87-2.97 (m, 2H), 3.95 (br. s., 1H), 4.52 (s, 2H), 7.86 (dd, J.sub.HF=8.3, J.sub.HH=2.2 Hz, 1H), 7.98 (dd, J.sub.HF=9.3, J.sub.HH=2.2 Hz, 1H).

(42) HRMS (ESI+): calcd. for C.sub.20H.sub.25FN.sub.3O [M+H].sup.− 342.1976; found 342.1988.

(43) Step c′

2-(1-Cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 29

(44) [R=F; n=m=0; R1=piperidin-4-yl; R2=1-cyclohexyl]

(45) ##STR00024##

(46) To a stirred solution of 2-(1-cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) (100 mg, 0.3 mmol) in acetic acid (5 mL), concentrated sulfuric acid (2.7 mL) was added dropwise during 30 min. The reaction was then warmed at 80° C. for 9 h, cooled at room temperature and poured into cold water (10 mL). The aqueous phase was then made basic by adding concentrated aqueous ammonia and extracted with dichloromethane (3×10 mL). The combined organic phases were washed with 2N aqueous sodium hydroxide (2×12 mL) and brine, dried over Na.sub.2SO.sub.4 and evaporated to dryness in vacuo. The title compound was obtained as a white solid (43 mg, 40%) after purification through column chromatography ((dichloromethane/methanol/ammonia solution, 7N in methanol: 97/2/1).

(47) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.00-1.14 (m, 1H), 1.14-1.28 (m, 4H), 1.53-1.61 (m, 1H), 1.67-1.80 (m, 6H), 2.25-2.36 (m, 3H), 2.88-2.95 (m, 2H), 3.94-4.03 (m, 1H), 4.55 (s, 2H), 7.66 (dd, J.sub.HF=7.7, J.sub.HH 2.6 Hz, 1H), 7.85 (br. s., 1H), 7.89 (dd, J.sub.HF=10.9, J.sub.HH=2.6 Hz, 1H), 10.78 (br. s., 1H).

(48) HRMS (ESI+): calcd. for C.sub.20H.sub.27FN.sub.3O.sub.2 [M+H].sup.+ 360.2082; found 360.2098.

EXAMPLE 3

(49) Step m

4-[(Furan-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-buty ester (XVI) [n=0; R1=piperidin-4-yl; X=tert-butoxycarbonyl]

(50) To an equimolar solution of furan-2-carbaldehyde (XV) (250 mg, 2.6 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (XIII) (473 mg, 2.6 mmol) in dichloromethane (14 mL) 1M titanium(IV) chloride in dichloromethane (1.3 mL, 1.3 mmol) and triethylamine (0.32 mL, 2.6 mmol) were added. The reaction mixture was stirred under nitrogen atmosphere for 2 days. Then sodium cyanoborohydride (493 mg, 7.8 mmol) in methanol (7 mL) was added dropwise with stirring and the solution was allowed to stir overnight at room temperature, 35% sodium hydroxide was added and the product was extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to dryness in vacuo. The crude was purified by flash chromatography (dichloromethane/methanol 95:5) to give the title compound as a red oil (406 mg, 56%).

(51) HRMS (ESI+): calcd. for C.sub.15H.sub.25N.sub.2O.sub.3 [M+H].sup.+ 281.1860; found 281.1867.

(52) Operating in an analogous way, but employing suitably substituted starting material (XIII), the following compounds were obtained:

(53) Benzyl-furan-2-ylmethyl-amine (XVI)

(54) HRMS (ESI+): calcd. for CH.sub.14NO [M+H].sup.+ 188.1070; found 188.1075.

(55) Furan-2-ylmethyl-phenethyl-amine (XVI)

(56) HRMS (ESI+): calcd. for C.sub.1NO [M+H].sup.+ 202.1226; found 202.1230.

(57) [2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-furan-2-ylmethyl-amine (XVI)

(58) HRMS (ESI+): calcd. for C.sub.16H.sub.21N.sub.2O [M+H].sup.+ 257.1648; found 257.1642.

(59) Furan-2-ylmethyl-(2-piperidin-1-yl-ethyl)-amine (XVI)

(60) HRMS (ESI+): calcd. for C.sub.12H.sub.21N.sub.2O [M+H].sup.+ 209.1648; found 209.1650.

(61) Furan-2-ylmethyl(2-morpholin-4-yl-ethyl)-amine (XVI)

(62) HRMS (ESI+): calcd. for C.sub.11H.sub.19N.sub.2O.sub.2 [M+H].sup.+ 211.1441; found 211.1446.

(63) Furan-2-ylmethyl-(3-morpholin-4-yl-propyl)-amine (XVI)

(64) HRMS (ESI+): calcd. for C.sub.12H.sub.21N.sub.2O.sub.2 [M+H].sup.+ 225.1598; found 225.1590.

(65) [2-(3,4-Dihydro-2H-quinolin-1-yl)-ethyl]-furan-2-ylmethyl-amine (XVI)

(66) HRMS (ESI+): calcd. for C.sub.15H.sub.21N.sub.2O [M+H].sup.+ 257.1648; found 257.1652.

(67) Furan-2-ylmethyl-3-phenyl-propyl)-amine (XVI)

(68) HRMS (ESI+): calcd. for C.sub.14H.sub.18NO [M+H].sup.+ 216.1383; fund 216.1387

(69) Furan-2-ylmethyl-(2-pyridin-2-yl-ethyl)-amine (XVI)

(70) HRMS (ESI+): calcd. for C.sub.12H.sub.15N.sub.2O [M+H].sup.+ 203.1179; found 203.1181.

(71) [3-(3,4-Dihydro-1H-isoquinolin-2-yl)-propyl]-furan-2-ylmethyl-amine (XVI)

(72) HRMS (ESI+): calcd. for C.sub.17H.sub.23N.sub.2O [M+H].sup.+ 271.1805; found 271.1799.

(73) [3-(3,4-Dihydro-2H-quinolin-1-yl)-propyl]-furan-2-ylmethyl-amine (XVI)

(74) HRMS (ESI+): calcd. for C.sub.17H.sub.23N.sub.2O [M+H].sup.+ 271.1805; found 271.1811.

(75) Furan-2-ylmethyl-(3-(4-methyl-piperazin-1-yl)-propyl-amine (XVI)

(76) HRMS (ESI+): calcd. for C.sub.13H.sub.24N.sub.3O [M+H].sup.+ 238.1914; found 238.1912.

(77) Furan-2-ylmethyl-(3-(4-phenyl-piperazin-1-yl)-propyl-amine (XVI)

(78) HRMS (ESI+): calcd. for C.sub.18H.sub.26N.sub.3O [M+H].sup.+ 300.2070; found 300.2077.

(79) Furan-2-ylmethyl-(3-piperidin-1-yl-propyl)-amine (XVI)

(80) HRMS (ESI+): calcd. for C.sub.13H.sub.23N.sub.2O [M+H].sup.+ 223.1805; found 223.1802.

(81) (3-[1,4′]Bipiperidinyl-1′-yl-propyl)-furan-2-ylmethyl-amine (XVI)

(82) HRMS (ESI+): calcd. for C.sub.18H.sub.32N.sub.3O [M+H].sup.+ 306.2540; found 306.2544.

(83) (3-(2,6-Dimethyl-piperidin-1-yl)-propyl-furan-2-ylmethyl-amine (XVI)

(84) HRMS (ESI+): calcd. for C.sub.15H.sub.25N.sub.2O [M+H].sup.+ 251.2118; found 251.2120.

(85) Furan-2-ylmethyl-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]amine (XVI)

(86) HRMS (ESI+): calcd. for C.sub.15H.sub.25N.sub.2O.sub.2 [M+H].sup.+ 265.1911; found 265.1919.

(87) (1-Benzyl-piperidin-4-yl)-furan-2-ylmethyl-amine (XVI)

(88) HRMS (ESI+): calcd. for C.sub.17H.sub.23N.sub.2O [M+H].sup.+ 271.1805; found 271.1807.

(89) [2-(1-Benzyl-piperidin-4-yl)-ethyl]furan-2-ylmethyl-amine (XVI)

(90) HRMS (ESI+): calcd. for C.sub.18H.sub.27N.sub.2O [M+H].sup.+ 299.2118; found 299.21222.

(91) [3-(4-Benzyl-piperidin-1-yl)-propyl]-furan-2-ylmethyl-amine (XVI)

(92) HRMS (ESI+): calcd. for C.sub.20H.sub.29N.sub.2O [M+H].sup.+ 313.2274; found 313.2280.

(93) (1-Cyclohexyl-piperidin-4-yl)-furan-2-ylmethyl-amine (XVI)

(94) An equimolar solution of furan-2-carbaldehyde (XV) (1.3 g, 13.5 mmol) and 1-cyclohexyl-piperidin-4-ylamine (XIII) (2.46 g, 13.5 mmol) in toluene (140 mL) was heated to reflux for 8 h by employing a Dean-Stark apparatus. The reaction mixture was concentrated under vacuum and rinsed with ethanol (50 mL). Sodium triacetoxyborohydride (3.8 g, 17.93 mmol) was added and the mixture was left overnight at room temperature. Then it was basified with aqueous ammonia (8%) and the aqueous layer was separated and extracted with diethyl ether. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a yellow oil employed in the following step without any further purification.

(95) HRMS (ESI+): calcd. for C.sub.18H.sub.27N.sub.2O [M+H].sup.+ 263.2118; found 263.2120.

(96) Step n

3-(1-Tert-butoxycarbonyl-piperidin-4-yl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII) [n=0; R1=piperidin-4-yl; X=tert-butoxycarbonyl]

(97) To a solution of 4-[(furan-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (XVI) (5.6 g, 21 mmol) in toluene (300 mL) maleic anhydride (2.1 g, 21 mmol) was added. The reaction mixture was refluxed for 6 h and stirred overnight at room temperature. The precipitate solid obtained was filtered, washed with diethyl ether and dried to give the desired compound (6.5 g, 82%) as a white solid.

(98) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.40 (s, 9H), 1.40-1.63 (m, 4H), 2.45 (d, J=9.3 Hz, 1H), 2.75 (br. s., 2H), 2.76 (d, J=9.3 Hz, 1H), 3.59 (d, J 11.6 Hz, 1H), 3.88 (d, J=11.60 Hz, 1H), 3.90 (m, 1H), 3.96-4.06 (m, 2H), 4.95 (d, J=1.6 Hz, 1H), 6.42 (dd, J=5.6, 1.7 Hz, 1H), 6.55 (d, J=5.6 Hz, 1H), 12.03 (br. s., 1H).

(99) HRMS (ESI+): calcd. for C.sub.19H.sub.27N.sub.2O.sub.6 [M+H].sup.+ 379.1864; found 379.1876.

(100) Operating in an analogous way, but employing suitably substituted starting material (XVI) the following compounds were obtained:

(101) 3-Benzyl-4-oxo-1-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylicacid (XVII)

(102) HRMS (ESI+): calcd. for C.sub.16H.sub.16NO.sub.4 [M+H].sup.+ 286.1074; found 286.1078.

(103) 4-Oxo-3-phenethyl-10-oxa-3-aza-tricyclo[52.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(104) HRMS (ESI+): calcd. for C.sub.16H.sub.18NO.sub.4 [M+H].sup.+ 300.1230; found 300.1237.

(105) 3-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(106) HRMS (ESI+): calcd. for C.sub.20H.sub.23N.sub.2O.sub.4 [M+H].sup.+ 355.1652; found 355.1657.

(107) 4-Oxo-3-(2-piperidin-1-yl-ethyl)-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(108) HRMS (ESI+): calcd. for C.sub.16H.sub.23N.sub.2O.sub.4 [M+H].sup.+ 307.1652; found 307.1660.

(109) 3-(2-Morpholin-4-yl-ethyl)-4-oxo-1-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(110) HRMS (ESI+): calcd. for C.sub.15H.sub.21N.sub.2O.sub.5 [M+H].sup.+ 309.1445; found 309.1446.

(111) 3-(3-Morpholin-4-yl-propy)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(112) HRMS (ESI+): calcd. for CH.sub.23N.sub.2O.sub.5 [M+H].sup.+ 323.1601; found 323.1609.

(113) 3-[2-(3,4-Dihydro-2H-quinolin-1-yl)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(114) HRMS (ESI+): calcd. for C.sub.20H.sub.23N.sub.2O.sub.4 [M+H].sup.+ 355.1652; found 355.1660.

(115) 4-Oxo-3-(3-phenyl-propyl)-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylicacid (XVII)

(116) HRMS (ESI+): calcd. for C.sub.18H.sub.20NO.sub.4 [M+H].sup.+ 314.1387; found 314.1392.

(117) 4-Oxo-3-(2-pyridin-2-yl-ethyl)-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(118) HRMS (ESI+): calcd. for C.sub.16H.sub.17N.sub.2O.sub.4 [M+H].sup.+ 301.1183; found 301.1179.

(119) 3-[3-(3,4-Dihydro-1H-isoquindin-2-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(120) HRMS (ESI+): calcd. for C.sub.21H.sub.25N.sub.2O.sub.4 [M+H].sup.+ 369.1809; found 369.1811.

(121) 3-[3-(3,4-Dihydro-2H-quinolin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[52.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(122) HRMS (ESI+): calcd. for C.sub.21H.sub.25N.sub.2O.sub.4 [M+H].sup.+ 369.1809; found 369.1801.

(123) 3-[3-(4-Methyl-piperazin-1-yl)-propyl]4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1.5*]dec-8-ene-6-carboxylic acid (XVII)

(124) HRMS (ESI+): calcd. for CH.sub.2NO.sub.4 [M+H].sup.+ 336.1918; found 336.1920.

(125) 4-Oxo-3-[3-(4-phenyl-piperazin-1-yl)-propyl]-10-oxa-3-aza-tricyclo[5.2.1.0*1,5′]dec-8-ene-6-carboxylic acid (XVII)

(126) HRMS (ESI+): calcd. for C.sub.22H.sub.28N.sub.3O.sub.4 [M+H].sup.+ 398.2074; found 398.2079.

(127) 4-Oxo-3-(3-piperidin-1-yl-propyl)-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(128) HRMS (ESI+): calcd. for C.sub.17H.sub.25N.sub.2O.sub.4 [M+H].sup.+ 321.1809; found 321.1812.

(129) 3-(3-[1,4′]Bipiperidinyl-1′-yl-propyl)-4-oxo-10-oxa-3-aza-tricyclo[52.1.0′1,5*]dec-8-ene-6-carboxylic acid (XVII)

(130) HRMS (ESI+): calcd. for C.sub.22H.sub.34N.sub.3O.sub.4 [M+H].sup.+ 404.2544; found 404.2540.

(131) 3-[3-(2,6-Dimethyl-piperidin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5]dec-8-ene-6-carboxylicacid (XVII)

(132) HRMS (ESI+): calcd. for C.sub.19H.sub.29N.sub.2O.sub.4 [M+H].sup.+ 349.2122; found 349.2119.

(133) 4-Oxo-3-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-10-oxa-3-aza-tricyclo[5.2.1.0*1,5]dec-8-ene-6-carboxylic acid (XVII)

(134) HRMS (ESI+): calcd. for C.sub.19H.sub.27N.sub.2O.sub.5 [M+H].sup.+ 363.1914; found 363.1920.

(135) 3-(1-Benzyl-piperidin-4-yl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylicacid (XVII)

(136) HRMS (ESI+): calcd. for C.sub.21H.sub.25N.sub.2O.sub.4 [M+H].sup.+ 369.1809; found 369.1799.

(137) 3-[2-(1-Benzyl-piperidin-4-yl)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(138) HRMS (ESI+): calcd. for C.sub.23H.sub.29N.sub.2O.sub.4 [M+H].sup.+ 397.2122; found 397.2127.

(139) 3-[3-(4-Benzyl-piperidin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(140) HRMS (ESI+): calcd. for C.sub.24H.sub.31N.sub.2O.sub.4 [M+H].sup.+ 411.2278; found 411.2283.

(141) 3-(1-Cyclohexyl-piperidin-4-yl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII)

(142) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 11.98 (br.s., 1H), 6.58 (d, J=5.6 Hz, 1H), 6.44 (dd, J=5.6, 1.6 Hz, 1H), 4.97 (d, J=1.6 Hz, 1H), 4.00-4.11 (m, 1H), 3.96 (d, J=11.0 Hz, 1H), 3.55 (d, J 11.0 Hz 1H), 3.38-3.48 (m, 2H), 3.04-3.2 (m, 3H), 2.79 (d, J=9.1 Hz, 1H), 2.48 (d, J=9.1 Hz, 1H), 1.55-2.01 (m, 8H), 1.04-1.44 (m, 6H).

(143) HRMS (ESI+): calcd. for C.sub.20H.sub.29N.sub.2O.sub.4 [M+H].sup.+ 361.2122; found 361.2129.

(144) Step o

3-Oxo-2-piperidin-4-yl-23-dihydro-1H-isoindole-4-carboxylic acid hydrochloride (XIX) [n=0; R1=piperidin-4-yl]

(145) 3-(1-Tert-butoxycarbonyl-piperidin-4-yl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (XVII) (6.35 g, 16.8 mmol) was dissolved in 37% hydrochloric acid (80 mL) and the resulted solution was refluxed for 3 h. The solvent was removed under reduced pressure and the residue was diluted with methanol and decanted to obtain the desired product (XIX) as a white solid (4.06 g, 82%).

(146) .sup.1H NMR (400.5 MHz, DMSO-ds) δ ppm 1.95-2.12 (m, 4H), 3.01-3.18 (m, 2H), 3.36-3.45 (m, 2H), 4.36-4.46 (m, 1H), 4.72 (s, 2H), 7.85 (dd, J=7.7, 7.5 Hz, 1H), 7.95 (dd, J=7.5, 0.8 Hz, 1H), 8.17 (dd, J=7.7, 0.8 Hz, 1H), 8.53 (br. s., 1H), 8.79 (br. s., 1H), 15.86 (s, 1H).

(147) HRMS (ESI+): calcd. for C.sub.14H.sub.17N.sub.2O.sub.3 [M+H].sup.+ 261.1234; found 261.1222.

(148) Operating in an analogous way, but employing suitably substituted starting material (XVII) the following compounds were obtained:

(149) 2-Benzyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII)

(150) HRMS (ESI+): calcd. for C.sub.14H.sub.17N.sub.2O.sub.3 [M+H].sup.+ 268.0968; found 268.0972.

(151) 3-Oxo-2-phenethyl-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVII)

(152) HRMS (ESI+): calcd. for C.sub.17H.sub.16NO.sub.3 [M+H].sup.+ 282.1125; found 282.1131.

(153) 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII)

(154) HRMS (ESI+): calcd. for C.sub.20H.sub.21N.sub.2O.sub.3 [M+H].sup.+ 337.1547; found 337.1541.

(155) 3-Oxo-2-(2-piperidin-1-yl-ethyl)-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII)

(156) HRMS (ESI+): calcd. for C.sub.16H.sub.21N.sub.2O.sub.3 [M+H].sup.+ 288.1547; found 288.1552.

(157) 2-(2-Morpholin-4-yl-ethyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVII)

(158) HRMS (ESI+): calcd. for C.sub.15H.sub.19N.sub.2O.sub.4 [M+H].sup.+ 291.1339; found 291.1335.

(159) 2-(3-Morpholin-4-yl-propyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVII)

(160) HRMS (ESI+): calcd. for C.sub.16H.sub.21N.sub.2O.sub.4[M+H].sup.+ 305.1496; found 305.1492.

(161) 2-[2-(3,4-Dihydro-2H-quinolin-1-yl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylicacid (XVIII)

(162) HRMS (ESI+): calcd. for C.sub.20H.sub.21N.sub.2O.sub.3 [M+H].sup.+ 337.1547; found 337.1549.

(163) 3-Oxo-2-(3-phenyl-propyl)-2,3-dihydro-1H-isoindole-4-carboxylicacid (XVIII)

(164) HRMS (ESI+): calcd. for C.sub.18H.sub.18NO.sub.3 [M+H].sup.+ 296.1281; found 296.1290.

(165) 3-Oxo-2-(2-pyridin-2-yl-ethyl)-2,3-dihydro-1H-isoindole-4-carboxylicacid (XVIII)

(166) HRMS (ESI+): calcd. for C.sub.18H.sub.15N.sub.2O [M+H].sup.+ 283.1077; found 283.1080.

(167) 2-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)-propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII)

(168) HRMS (ESI+): calcd. for C.sub.21H.sub.23N.sub.2 [M+H].sup.+ 351.1703; found 351.1706.

(169) 2-[3-(3,4-Dihydro-2H-quinolin-1-yl)-propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylicacid (XVIII)

(170) HRMS (ESI+): calcd. for C.sub.21H.sub.23N.sub.2O.sub.3 [M+H].sup.+ 351.1703; found 351.1699.

(171) 2-[3-(4-Methyl-piperazin-1-yl)-propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVII)

(172) HRMS (ESI+): calcd. for C.sub.17H.sub.24N.sub.3O.sub.3 [M+H].sup.+ 318.1812; found 318.1820.

(173) 3-Oxo-2-[3-(4-phenyl-piperazin-1-yl)-propyl]-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVII)

(174) HRMS (ESI+): calcd. for C.sub.22H.sub.26N.sub.3O.sub.3 [M+H].sup.+ 380.199; found 380.1971.

(175) 3-Oxo-2-(3-piperidin-1-yl-propyl)-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVII) HRMS (ESI+): calcd. for C.sub.17H.sub.23N.sub.2O.sub.3 [M+H].sup.+ 303.1703; found 303.1702.

(176) 2-(3-[1,4′]Bipiperidinyl-1′-yl-propyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII)

(177) HRMS (ESI+): calcd. for C.sub.22H.sub.32N.sub.3O.sub.3 [M+H].sup.+ 386.2438; found 386.2442.

(178) 2-[3-(2,6-Dimethyl-piperidin-1-yl)-propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII)

(179) HRMS (ESI+): calcd. for C.sub.19H.sub.27N.sub.2O.sub.3 [M+H].sup.+ 331.2016; found 331.2011.

(180) 3-Oxo-2-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-2,3-dihydro-1H-isoindole-4-carboxylicacid (XVIII)

(181) HRMS (ESI+): calcd. for C.sub.19H.sub.25N.sub.2O.sub.4 [M+H].sup.+ 345.1809; found 345.1816.

(182) 2-(1-Benzyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVII) HRMS (ESI+): calcd. for C.sub.21H.sub.23N.sub.2O.sub.3 [M+H].sup.+ 351.1703; found 351.1708.

(183) 2-[2-(1-Benzyl-piperidin-4-yl)-ethyl]3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII)

(184) HRMS (ESI+): calcd. for C.sub.23H.sub.27N.sub.2O.sub.3 [M+H].sup.+ 379.2016; found 379.2020.

(185) 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII)

(186) HRMS (ESI+): calcd. for C.sub.24H.sub.29N.sub.2O.sub.3 [M+H].sup.+ 393.2173; found 393.2177.

(187) 2-(1-Cyclohexyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylicacid (XVIII)

(188) HRMS (ESI+): calcd. for C.sub.20H.sub.27N.sub.2O.sub.3 [M+H].sup.+ 343.2016; found 343.2019.

(189) 2-(1-Tert-butoxycarbonyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVII) [n=0; R1=piperidin-4-yl; X=tert-butoxycarbonyl]

(190) To a solution of 3-oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindole-4-carboxylic acid (3.9 g, 13.2 mmol) in pyridine (15 mL) potassium carbonate (3.6 g, 26.5 mmol) and methanol (40 mL) were successively added. Then di-tert-butyl dicarbonate (3.16 g, 14.5 mmol) was added and the reaction mixture was stirred at room temperature for 4 h until HPLC analysis revealed the disappearance of the starting material. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed twice with 5% potassium hydrogen sulfate and the organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The obtained crude wad diluted with diethyl ether and decanted to obtain the title compound (3.7 g, 78%) as a white solid.

(191) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.42 (s, 9H), 1.04-1.74 (m, 2H), 1.80-1.88 (m, 2H), 2.89 (br. s., 2H), 4.04-4.12 (m, 2H), 4.23-4.32 (m, 1H), 4.73 (s, 2H), 7.83 (dd, J=7.5, 0.8 Hz, 1H), 7.91 (dd, J=7.5, 0.8 Hz, 1H), 8.17 (dd, J=7.7, 0.8 Hz, 1H), 16.03 (br. s., 1H).

(192) Step p

(193) 4-(7-Carbamoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (XX) [n=0; R1=piperidin-4-yl; X=tert-butoxycarbonyl]

(194) Method A: to a solution of 2-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII) (3.7 g, 10.3 mmol) in N,N-dimethylformamide (60 mL) hydroxybenzotriazole ammonium salt (3.15 g, 20.7 mmol), 1-ethyl-3-(3′-dimethylamino)carbodiimide hydrochloric acid salt (3.34 g, 20.7 mmol) and diisopropylethylamine (5.3 mL, 30.9 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed twice with saturated sodium carbonate aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (dichloromethane/ethanol 97:3) to afford the title compound (2.74 g, 74%) as a white solid.

(195) Method B: a solution of 2-(1-tert-butoxycarbonyl-piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxylic acid (XVIII) (5.5 g, 15.3 mmol) and carbonyldiimidazole (3.7 g, 22.8 mmol) in dry tetrahydrofuran (80 mL) was stirred at room temperature for 4 h. Then concentrated aqueous ammonia (25 mL) was added and the reaction mixture was left at room temperature until the disappearance of the starting material (3 h). The solvent was evaporated under reduced pressure and the resulting crude primary amide (1.1 g, 20%) was employed without any further purification.

(196) HRMS (ESI+): calcd. for C.sub.19H.sub.25N.sub.3O.sub.4 [M+H].sup.+ 360.1918; found 360.1921.

(197) Operating according to method A, but employing suitably substituted starting material the following compounds were obtained:

(198) 2-benzyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (I), cpd 1

(199) [R=H; n=1; R1=phenyl; m=0; R2=null]

(200) ##STR00025##

(201) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.72-1.88 (m, 4H), 2.04-2.13 (m, 2H), 2.88-2.96 (m, 2H), 3.51 (s, 2H), 4.00-4.11 (m, 1H), 4.56 (s, 2H), 7.20-7.30 (m, 1H), 7.31-7.37 (m, 4H), 7.66 (br. s., 1H), 7.71 (dd, J=7.6, 7.4 Hz, 1H), 7.76 (dd, J=7.6, 1.5 Hz, 1H), 8.20 (dd, J=7.4.1.5 Hz, 1H), 10.72 (br. s., 1H).

(202) HRMS (ESI+): calcd. for C.sub.15H.sub.15N.sub.2O.sub.2 [M+H].sup.+ 267.1128; found 267.1120.

(203) 3-oxo-2-phenethyl-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (I), cpd 2

(204) [R=H; n=2; R1=phenyl; m=0; R2=null]

(205) ##STR00026##

(206) .sup.1H NMR (400.5 MHz, DMSO-4) δ ppm 2.97 (t, J=7.6 Hz, 2H), 3.82 (t, J=7.6 Hz, 2H), 4.49 (s, 2H), 7.17-7.24 (m, 1H), 7.24-7.32 (m, 4H), 7.66 (br. s., 1H), 7.70 (dd, J=7.5, 7.3 Hz, 1H), 7.74 (dd, J=7.5, 1.5 Hz, 1H), 8.19 (dd, J=7.3, 1.5 Hz, 1H), 10.68 (br. s., 1H).

(207) HRMS (ESI+): calcd. for C.sub.17H.sub.15N.sub.2O.sub.2 [M+H].sup.+ 281.1285; found 281.1295.

(208) 2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 3

(209) [R=H; n=2; R1=3,4-dihydro-1H-isoquindin-2-yl; m=0; R2=null]

(210) ##STR00027##

(211) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 2.73-2.84 (m, 6H), 3.65 (s, 2H), 3.81 (t, J=6.2 Hz, 2H), 4.65 (s, 2H), 7.00-7.12 (m, 4H), 7.66 (br. s., 1H), 7.69 (dd, J=7.6, 7.7 Hz, 1H), 7.76 (dd, J=7.6, 1.2 Hz, 1H), 8.19 (dd, J=7.7, 1.2 Hz, 1H), 10.75 (br. s., 1H).

(212) HRMS (ESI+): calcd. for C.sub.20H.sub.23N.sub.3O.sub.2 [M+H].sup.+ 336.1707; found 336.1722.

(213) 3-oxo-2-(2-piperidin-1-yl-ethyl)-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (I), cpd 4

(214) [R=H; n=2; R1=piperidin-1-yl; m=0; R2=null]

(215) ##STR00028##

(216) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.33-1.40 (m, 2H), 1.43-1.50 (m, 4H), 2.35-2.43 (m, 4H), 2.54 (t, J=6.3 Hz, 2H), 3.68 (t, J=6.3 Hz, 2H), 4.63 (s, 2H), 7.66 (br. s., 1H), 7.72 (dd. J=7.7, 7.4 Hz, 1H), 7.78 (dd, J=7.4, 1.2 Hz, 1H), 8.20 (dd, J=7.7, 1.2 Hz, 1H), 10.75 (br. s., 1H).

(217) HRMS (ESI+): calcd. for C.sub.16H.sub.22N.sub.3O.sub.2 [M+H].sup.+ 288.1707; found 288.1712.

(218) 2-(2-morpholin-4-yl-ethyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 5

(219) [R=H; n=2; R1=morpholin-4-yl; m=0; R2=null]

(220) ##STR00029##

(221) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 2.41-2.46 (m, 4H), 2.59 (t, J=6.3 Hz, 2H), 3.52-3.57 (m, 4H), 3.71 (t, J=6.3 Hz, 2H), 4.64 (s, 2H), 7.66 (br. s., 1H), 7.72 (dd. J=7.7, 7.6 Hz, 1H), 7.78 (dd, J=7.6, 1.3 Hz, 1H), 8.20 (dd, J=7.7, 1.3 Hz, 1H), 10.73 (br. s., 1H).

(222) HRMS (ESI+): calcd. for C.sub.15H.sub.20N.sub.3O.sub.3 [M+H].sup.+ 290.1499; found 290.1507.

(223) 2-(3-morpholin-4-yl-propyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 6

(224) [R=H; n=3; R1=morpholin-4-yl; m=0; R2=null]

(225) ##STR00030##

(226) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 1.80 (quintet, J=7.1 Hz, 2H), 2.28-2.38 (m, 6H), 3.47-3.54 (m, 4H), 3.61 (t, J=7.1 Hz, 2H), 4.58 (s, 2H), 7.65 (br. s., 1H), 7.71 (dd, J=7.6, 7.4 Hz, 1H), 7.77 (dd. J=7.4, 1.2 Hz, 1H), 8.20 (dd, J=7.6, 1.2 Hz, 1H), 10.76 (br. s., 1H).

(227) HRMS (ESI+): calcd. for C.sub.16H.sub.22N.sub.3O.sub.3 [M+H].sup.+ 304.1656; found 304.1664.

(228) 2-[2-(3,4-dihydro-2H-quinolin-1-yl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 7

(229) [R=H; n=2; R1=3,4-dihydro-2H-quinolin-1-yl; m=0; R2=null]

(230) ##STR00031##

(231) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.79-1.89 (m, 2H), 2.64-2.70 (m, 2H), 3.27-3.31 (m, 2H), 3.56 (t, J=7.1 Hz, 2H), 3.76 (t, J=7.1 Hz, 2H), 4.65 (s, 2H), 6.44-6.49 (m, 1H), 6.70-6.75 (m, 1H), 6.85-6.89 (m, 1H), 6.92-6.97 (m, 1H), 7.69 (br. s., 1H), 7.72 (dd, J=7.6, 7.6 Hz, 1H), 7.77 (dd, J=7.6, 1.3 Hz 1H), 8.20 (dd, J=7.6, 1.3 Hz, 1H), 10.68 (br. s., 1H).

(232) HRMS (ESI+): calcd. for C.sub.20H.sub.22N.sub.3O.sub.2 [M+H].sup.+ 336.1707; found 336.1692.

(233) 3-ox-2-(3-phenyl-propyl)-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 17

(234) [R=H; n=3; R1=phenyl; m=0; R2=null]

(235) ##STR00032##

(236) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.97 (quintet, J=7.9 Hz, 2H), 2.64 (t, J=7.9 Hz 2H), 3.61 (t, J=7.9 Hz, 2H), 4.59 (s, 2H), 7.15-7.20 (m, 1H), 7.23-7.31 (m, 4H), 7.67 (br. s., 1H), 7.72 (dd, J=7.6, 7.4 Hz, 1H), 7.77 (dd, J=7.6, 1.5 Hz, 1H), 8.21 (dd, J=7.4, 1.5 Hz, 1H), 10.74 (br. s., 1H).

(237) HRMS (ESI+): calcd. for C.sub.18H.sub.19N.sub.2O.sub.2 [M+H].sup.+ 295.1441; found 295.1433.

(238) 3-oxo-2-(2-pyridin-2-yl-ethyl)-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 18

(239) [R=H; n=2; R1=pyrid-2-yl; m=0; R2=null]

(240) ##STR00033##

(241) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 3.12 (t, J=7.3 Hz, 2H), 3.96 (t, J=7.3 Hz, 2H), 4.52 (s, 2H), 7.23 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 7.32 (ddd, J=7.8, 1.2, 0.8 Hz, 1H), 7.65 (br. s., 1H), 7.71 (m, 1H), 7.70 (dd, J=7.6, 7.4 Hz, 1H), 7.75 (dd, J=7.6, 1.3 Hz, 1H), 8.19 (dd, J=7.4, 1.3 Hz, 1H), 8.48 (ddd, J=4.9, 1.8, 0.8 Hz, 1H), 10.66 (br. s., 1H).

(242) HRMS (ESI+): calcd. for C.sub.16H.sub.16N.sub.3O.sub.2 [M+H].sup.+ 282.1237; found 282.1243.

(243) 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 19

(244) [R=H; n=3; R1=3,4-dihydro-1H-isoquinolin-2-yl; m=0; R2=null]

(245) ##STR00034##

(246) .sup.1H NMR (400.5 MHz, DMSO-ds) δ ppm 1.92 (quintet, J=7.3 Hz, 2H), 2.52 (t, J=7.3 Hz, 2H), 2.64-2.70 (m, 2H), 2.76-2.82 (m, 2H), 3.57 (s, 2H), 3.64 (t, J=7.3 Hz, 2H), 4.60 (s, 2H), 7.00-7.70 (m, 4H), 7.66 (br. s., 1H), 7.70 (dd, J=7.6, 7.4 Hz, 1H), 7.75 (dd, J=7.4, 1.3 Hz, 1H), 8.19 (dd, J=7.6, 1.3 Hz, 1H), 10.76 (br. s., 1H).

(247) HRMS (ESI+): calcd. for C.sub.21H.sub.24N.sub.3O.sub.2 [M+H].sup.+ 350.1863; found 350.1866.

(248) 2-[3-(3,4-dihydro-2H-quinolin-1-yl)propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 20

(249) [R=H; n=3; R1=3,4-dihydro-2H-quinolin-1-yl; m=0; R2=null]

(250) ##STR00035##

(251) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.80-1.87 (m, 2H), 1.90 (quintet, J=7.2 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 3.22-3.26 (m, 2H), 3.27-3.30 (m overlapped by water signal, 2H), 3.64 (t, J=7.2 Hz, 2H), 4.59 (s, 2H), 6.42-6.47 (m, 1H), 6.54-6.58 (m, 1H), 6.83-6.87 (m, 1H), 6.89-6.94 (m, 1H), 7.67 (br. s., 1H), 7.72 (dd, J=7.6, 7.6 Hz, 1H), 7.77 (dd, J=7.6, 1.3 Hz, 1H), 8.20 (dd. J=7.6.1.3 Hz, 1H), 10.72 (br. s., 1H).

(252) HRMS (ESI+): calcd. for C.sub.21H.sub.24N.sub.3O.sub.2 [M+H].sup.+ 350.1863; fund 350.1868

(253) 2-[3-(4-methyl-piperazin-1-yl)-propyl]3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 21

(254) [R=H; n=3; R1=4-methyl-piperazin-1-yl; m=0 R2=null]

(255) ##STR00036##

(256) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.80 (quintet, J=7.2 Hz, 2H), 2.11 (s, 3H), 2.15-2.43 (br. s., 8H), 2.33 (t, J=7.2 Hz, 2H), 3.60 (t, J=7.2 Hz, 2H), 4.58 (s, 2H), 7.66 (br. s., 1H), 7.72 (dd, J=7.6, 7.4 Hz, 1H), 7.77 (dd, J=7.6, 1.3 Hz, 1H), 8.21 (dd, J=7.4, 1.3 Hz, 1H), 10.79 (br. s., 1H).

(257) HRMS (ESI+): calcd. for C.sub.17H.sub.25N.sub.4O.sub.2 [M+H].sup.+ 317.1972; found 317.1975.

(258) 3-oxo-2-[3-(4-phenyl-piperazin-1-yl-propyl]-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 22

(259) [R=H; n=3; R1=piperazin-1-yl; m=0; R2=4-phenyl]

(260) ##STR00037##

(261) .sup.1H NMR (400.5 MHz, DMSO-dc) δ ppm 1.85 (quintet, J=7.1 Hz, 2H), 2.39 (t, J=7.1 Hz, 2H), 3.02-3.10 (m, 4H), 3.63 (t, J=7.1 Hz, 2H), 4.60 (s, 2H), 6.75 (t, J=7.3 Hz, 1H), 6.89 (d, J=7.9 Hz, 2H), 7.19 (dd, J=7.9, 7.3 Hz, 2H), 7.66 (br. s., 1H), 7.70 (dd, J=7.7, 7.4 Hz, 1H), 7.76 (dd, J=7.4, 1.2 Hz, 1H), 8.20 (dd, J=7.7, 1.2 Hz, 1H), 10.78 (br. s., 1H).

(262) HRMS (ESI+): calcd. for C.sub.22H.sub.27N.sub.4O.sub.2 [M+H].sup.+ 379.2129; found 379.2145.

(263) 3-oxo-2-(3-piperidin-1-yl-propyl)-2,3-dihydro-1H-isoindole-4-carboxylic acid amide hydrochloride (I), cpd 25

(264) [R=H; n=3; R1=piperidin-1-yl; m=0; R2=null]

(265) ##STR00038##

(266) .sup.1H NMR (400.5 MHz, DMSO-4) δ ppm 1.29 (m, 1H), 1.50-1.73 (m, 3H), 1.75-1.85 (m, 2H), 2.00-2.09 (m, 2H), 2.79-2.92 (m, 2H), 3.03-3.14 (m, 2H), 3.40-3.50 (m, 2H), 3.66 (t, J=6.6 Hz, 2H), 4.59 (s, 2H), 7.71 (br. s., 1H), 7.74 (dd, J=7.6, 7.4 Hz, 1H), 7.80 (dd, J=7.4, 1.1 Hz, 1H), 8.21 (dd, J=7.6, 1.1 Hz, 1H), 8.93 (br. s., 1H), 10.58 (br. s., 1H).

(267) HRMS (ESI+): calcd. for CH.sub.24NO.sub.2 [M+H].sup.+ 302.1863; found 302.1865.

(268) 2-(3-[1,4′]bipiperidinyl-1′-yl-propyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide dihydrochloride (1), cpd 26

(269) [R=H; n=3; R1=piperidin-1-yl; m=0; R2=4-piperidin-1-yl]

(270) ##STR00039##

(271) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 1.33-1.49 (m, 1H), 1.57-1.74 (m, 3H), 1.74-1.94 (m, 4H), 1.95-2.13 (m, 2H), 2.16-2.30 (m, 2H), 2.87-3.72 (m, 11H), 3.66 (t, J=6.5 Hz, 2H), 4.59 (s, 2H), 7.72 (br. s., 1H), 7.75 (dd, J=7.6, 6.7 Hz, 1H), 7.80 (d, J=6.7 Hz, 1H), 8.21 (dd, J=7.6, 1.2 Hz, 1H), 9.38 (br. s., 2H), 10.58 (br. s., 1H).

(272) HRMS (ESI+): calcd. for C.sub.22H.sub.33N.sub.4O.sub.2 [M+H].sup.+ 385.2598; found 385.2611.

(273) 2-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide hydrochloride (1), cpd 27

(274) [R=H; n=3; R1=2,6-dimethyl-piperidin-1-yl; m=0; R2=null]

(275) ##STR00040##

(276) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.25 (d, J=6.3 Hz, 6H), 1.40-1.55 (m, 3H), 1.80-1.91 (m, 2H), 1.95-2.05 (m, 2H), 3.02-3.46 (m, 4H), 3.68 (m, 2H), 4.63 (s, 2H), 7.70 (br. s., 1H), 7.74 (dd, J=7.6, 7.6 Hz, 1H), 7.80 (dd, J=7.6, 1.2 Hz, 1H), 8.21 (dd, J=7.6, 1.2 Hz, 1H), 8.72 (br. s., 1H), 10.58 (br. s., 1H).

(277) HRMS (ESI+): calcd. for C.sub.19H.sub.28N.sub.3O.sub.2 [M+H].sup.+ 330.2176; found 330.2176.

(278) 3-oxo-2-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-2,3-dihydro-1H-isoindole-4-carboxylicacid amide (1), cpd 28

(279) [R=H; n=m=0; R1=piperidin-4-yl; R2=1-(tetrahydro-pyran-4-yl)]

(280) ##STR00041##

(281) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.38-1.50 (m, 2H), 1.65-1.72 (m, 2H), 1.73-1.81 (m, 4H), 2.18-2.28 (m, 2H), 2.43-2.47 (m, 1H), 2.97-3.04 (m, 2H), 3.30 (m overlapped by water signal, 2H), 3.89 (dd, J=11.1, 3.9 Hz, 2H), 4.02 (m, 1H), 4.55 (a, 2H), 7.66 (br. s., 1H), 7.71 (dd, J=7.6, 7.4 Hz, 1H), 7.76 (dd, J=7.4, 1.5 Hz, 1H), 8.20 (dd, J=7.6, 1.5 Hz, 1H), 10.74 (br. s., 1H).

(282) HRMS (ESI+): calcd. for C.sub.19H.sub.26N.sub.3O.sub.3 [M+H].sup.+ 344.1969; found 344.1962.

(283) 2-(1-benzyl-piperidin-4-yl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (I), cpd 30

(284) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=phenyl]

(285) ##STR00042##

(286) .sup.1H NMR (400.5 MHz, DMSO-4) δ ppm 1.70-1.88 (m, 4H), 1.99-2.13 (m, 2H), 2.89-2.96 (m, 2H), 3.51 (s, 2H), 4.00-4.11 (m, 1H), 4.56 (s, 2H), 7.20-7.30 (m, 1H), 7.30-7.36 (m, 4H), 7.66 (br. s., 1H), 7.71 (dd, J=7.6, 7.4 Hz, 1H), 7.76 (dd, J=7.6, 1.5 Hz, 1H), 8.20 (dd, J=7.4, 1.5 Hz, 1H), 10.72 (br. s., 1H).

(287) HRMS (ESI+): calcd. for C.sub.2H.sub.24N.sub.3O.sub.2 [M+H].sup.+ 350.1863; found 350.1874.

(288) 2-[2-(1-benzyl-piperidin-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide hydrochloride (I), cpd 31

(289) [R=H; n=2; R1=piperidin-4-yl; m=1; R2=phenyl]

(290) ##STR00043##

(291) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 1.29-1.41 (m, 2H), 1.43-1.54 (m, 1H), 1.56-1.64 (m, 2H), 1.92-2.00 (m, 2H), 2.83-2.96 (m, 2H), 3.30 (m overlapped by water signal, 2H), 3.61 (t, J=6.8 Hz, 2H), 4.25 (d, J=5.1 Hz, 2H), 4.57 (s, 2H), 7.47 (s, 5H), 7.69 (br. s., 1H), 7.72 (dd, J=7.6, 7.4 Hz, 1H), 7.77 (dd, J=7.4, 1.3 Hz, 1H), 8.20 (dd, J=7.6, 1.3 Hz, 1H), 9.22 (br. s., 1H), 10.68 (br. s., 1H).

(292) HRMS (ESI+): calcd. for C.sub.23H.sub.28N.sub.3O.sub.2 [M+H].sup.+ 378.2176; found 378.2178.

(293) 2-[3-(4-benzyl-piperidin-1-yl)-propyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 32

(294) [R=H; n=3; R1=piperidin-1-yl; m=1 R2=phenyl]

(295) ##STR00044##

(296) .sup.1H NMR (400.5 MHz, DMSO-4) δ ppm 0.93-1.12 (m, 2H), 1.34-1.53 (m, 3H), 1.68-1.82 (m, 4H), 2.22-2.33 (m, 2H), 2.41 (d, J=6.8 Hz, 2H), 2.75-2.85 (m, 2H), 3.59 (t, J=6.9 Hz, 2H), 4.56 (s, 2H), 7.09-7.14 (m, 2H), 7.14-7.19 (m, 1H), 7.23-7.29 (m, 2H), 7.65 (br. s., 1H), 7.72 (dd, J=7.4, 7.4 Hz, 1H), 7.77 (dd, J=7.4, 1.3 Hz, 1H), 8.21 (dd, J=7.4, 1.3 Hz, 1H), 10.78 (br. s., 1H).

(297) HRMS (ESI+): calcd. for C.sub.24H.sub.30N.sub.3O.sub.2 [M+H].sup.+ 392.2333; found 392.2346.

(298) Step i′

(299) 3-Oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindole-4-carboxylic acid amide hydrochloride (XXI)

(300) [n=0; R1=piperidin-4-yl]

(301) A solution of 4-(7-carbamoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (XX) (2.7 g, 7.5 mmol) in 4M hydrochloric acid in dioxane (18 mL, 75 mmol) was stirred at 50° C. for 2 h until HPLC analysis revealed the disappearance of the starting material. The solvent was removed under reduced pressure and the product was dissolved in diethyl ether and filtered to obtain the title compound (2.09 g, 95%) as its hydrochloride.

(302) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.93-2.09 (m, 4H), 3.03-3.17 (m, 2H), 3.35-3.48 (m overlapped by water signal, 2H), 4.32-4.45 (m, 1H), 4.56 (s, 2H), 7.71 (br. s., 1H), 7.75 (dd, J=7.5, 7.5 Hz, 1H), 7.82 (dd, J=7.5, 1.1 Hz 1H), 8.21 (dd, J=7.5, 1.1 Hz, 1H), 8.59 (br. s., 1H), 8.82 (br. s., 1H), 10.58 (br. s., 1H).

(303) HRMS (ESI+): calcd. for C.sub.14H.sub.18N.sub.3O.sub.2 [M+H].sup.+ 260.1394; found 260.1398.

(304) Step I′

(305) 2-(1-cyclohexyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 11

(306) [R=H; n=m=0; R1=piperidin-4-yl; R2=1-cyclohexyl]

(307) ##STR00045##

(308) Method A: to a suspension of 3-oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindole-4-carboxylic acid amide hydrochloride (56 mg, 0.19 mmol) in dichloromethane (2 mL), cyclohexanone (XIV) (27.5 mg, 0.28 mmol), sodium acetate (32 mg, 0.38 mmol) and methanol (0.3 mL) were added. The resultant solution was stirred at room temperature for 5 h. Then sodium cyanoborohydride (13 mg, 0.21 mmol) was added and the mixture was stirred overnight. Solvents were removed under reduced pressure and the residue was dissolved in dichloromethane and washed twice with water. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo and the residue was purified by flash chromatography (dichloromethane/methanol 95:5) to give 27 mg (40%) of 2-(1-cyclohexyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide.

(309) Method B: to a solution of 2-piperidin-4-yl-2,3-dihydro-1H-isoindole-4-carboxylic acid amide hydrochloride (4.4 g, 14.8 mmol) and cyclohexanone (2.2 g, 22.45 mmol) in N,N-dimethylformamide (100 mL), glacial acetic acid (4.5 ml) and tetramethylammonium triacetoxyborohydride (11.8 g, 44.85 mmol) were added. The resulting solution was allowed to stir overnight at room temperature.

(310) The solvent was then evaporated under reduced pressure and the resultant residue was diluted with aqueous 8% ammonia solution and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated. The crude was purified by flash chromatography (dichloromethane/methanol 95:5) and subsequently dissolved in a small amount of methanol and precipitated with diethyl ether. The precipitate was filtered and washed with diethyl ether to give 1.77 g of the desired product as a white solid (35%).

(311) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 1.00-1.14 (m, 1H), 1.14-1.32 (m, 4H), 1.55-1.62 (m, 1H), 1.70-1.80 (m, 8H), 2.25-2.37 (m, 3H), 2.88-2.98 (m, 2H), 3.95-4.06 (m, 1H), 4.55 (s, 2H), 7.66 (br. s., 1H), 7.71 (dd, J=7.6, 7.6 Hz, 1H), 7.76 (dd, J=7.6, 1.5 Hz, 1H), 8.20 (dd, J=7.6, 1.5 Hz, 1H), 10.74 (br. s., 1H).

(312) HRMS (ESI+): calcd. for C.sub.20H.sub.28N.sub.3O.sub.2 [M+H].sup.+ 342.2176; found 342.2175.

(313) Operating according to method A, but employing suitably substituted starting material (XIV), the following compounds were obtained:

(314) 3-oxo-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 8

(315) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=pyrid-4-yl]

(316) ##STR00046##

(317) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 1.75-1.92 (m, 4H), 2.11-2.22 (m, 2H), 2.88-2.95 (m, 2H), 3.56 (s, 2H), 4.02-4.14 (m, 1H), 4.58 (s, 2H), 7.33-7.38 (m, 2H), 7.68 (br. s., 1H), 7.73 (dd, J=7.6, 7.6 Hz, 1H), 7.78 (dd, J=7.6, 1.51H), 8.21 (dd, J=7.6, 1.4 Hz, 1H), 8.51-8.55 (m, 2H), 10.72 (br. s., 1H).

(318) HRMS (ESI+): calcd. for C.sub.20H.sub.23N.sub.4O.sub.2 [M+H].sup.+ 351.1816; found 351.1817.

(319) 3-oxo-2-(1-thiophen-2-ylmethyl-piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 9

(320) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=thiophen-2-yl]

(321) ##STR00047##

(322) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.73-1.88 (m, 4H), 2.06-2.20 (m, 2H), 2.94-3.03 (m, 2H), 3.73 (s, 2H), 4.01-4.11 (m, 1H), 4.58 (s, 2H), 6.96-7.00 (m, 2H), 7.42-7.46 (m, 1H), 7.67 (br. s., 1H), 7.72 (dd, J=7.6, 7.4 Hz, 1H), 7.77 (dd, J=7.6, 1.5 Hz, 1H), 8.21 (dd, J=7.4, 1.5 Hz, 1H), 10.72 (br. s., 1H).

(323) HRMS (ESI+): calcd. for C.sub.19H.sub.22N.sub.3O.sub.2S [M+H].sup.+ 356.1427; found 356.1430.

(324) 3-oxo-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxylicacid amide (1), cpd 10

(325) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=pyrid-3-yl]

(326) ##STR00048##

(327) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 1.70-1.80 (m, 4H), 2.08-2.18 (m, 2H), 2.87-2.96 (m, 2H), 3.55 (s, 2H), 4.01-4.12 (m, 1H), 4.56 (s, 2H), 7.37 (dd. J=7.7, 4.8 Hz 1H), 7.66 (br. s., 1H), 7.71 (t, J=7.7, 7.4 Hz, 1H), 7.73 (signal overlapped by others, 1H), 7.76 (dd, J=7.7, 1.3 Hz, 1H), 8.20 (dd, J=7.4, 1.3 Hz, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.52 (s, 1H), 10.71 (br. s., 1H).

(328) HRMS (ESI+): calcd. for C.sub.20H.sub.23N.sub.4O.sub.2 [M+H].sup.+ 351.1816; found 351.1822.

(329) 2-(1-furan-2-ylmethyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylicacid amide (1), cpd 12

(330) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=fur-2-yl]

(331) ##STR00049##

(332) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.70-1.87 (m, 4H), 2.07-2.16 (m, 2H), 2.90-2.97 (m, 1H), 3.53 (s, 2H), 3.98-4.06 (m, 1H), 4.55 (s, 2H), 6.30 (d, J=2.4 Hz, 1H), 6.41 (dd, J=2.4, 1.8 Hz, 1H), 7.59 (br. s., 1H), 7.66 (br. s., 1H), 7.71 (dd, J=7.6, 7.4 Hz, 1H), 7.76 (dd, J=7.4, 1.3 Hz, 1H), 8.19 (dd, J=7.6, 1.3 Hz, 1H), 10.71 (br. s., 1H).

(333) HRMS (ESI+): calcd. for C.sub.19H.sub.22N.sub.3O.sub.3 [M+H].sup.+ 340.1656; found 340.1651.

(334) 3-oxo-2-(1-thiophen-3-ylmethyl-piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxylicacid amide (1), cpd 13

(335) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=thiophen-3-yl]

(336) ##STR00050##

(337) .sup.1H NMR (400.5 MHz, DMSO-4) δ ppm 1.72-1.90 (m, 4H), 2.00-2.12 (m, 2H), 2.90-2.99 (m, 2H), 3.53 (s, 2H), 4.00-4.09 (m, 1H), 4.57 (s, 2H) 7.08 (d, J=4.6 Hz, 1H), 7.33 (br. s., 1H), 7.49 (dd, J=4.6, 2.8 Hz, 1H), 7.67 (br. s., 1H), 7.72 (dd, J=7.6, 7.4 Hz, 1H), 7.75 (dd, J=7.6, 1.3, 1H), 8.21 (dd, J=7.4, 1.3 Hz, 1H), 10.73 (br. s., 1H).

(338) HRMS (ESI+): calcd. for C.sub.19H.sub.22N.sub.3O.sub.2S [M+H].sup.+ 356.1427; found 356.1432.

(339) 2-(1-furan-3-ylmethyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylicacid amide (1), cpd 14

(340) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=fur-3-yl]

(341) ##STR00051##

(342) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.72-1.89 (m, 4H), 2.02-2.12 (m, 2H), 2.90-3.02 (m, 2H), 3.37 (s, 2H), 4.00-4.10 (m, 1H), 4.56 (s, 2H), 6.45 (s, 1H), 7.58 (s, 1H), 7.62 (s, 1H), 7.67 (br. s., 1H), 7.72 (dd, J=7.6, 7.4 Hz, 1H), 7.76 (dd, J=7.4, 1.5 Hz, 1H), 8.21 (dd, J=7.6, 1.5 Hz, 1H), 10.73 (br. s., 1H).

(343) HRMS (ESI+): calcd. for C.sub.19H.sub.22N.sub.3O.sub.3 [M+H].sup.+ 340.1656; found 340.1649.

(344) 3-oxo-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxylicacid amide (1), cpd 15

(345) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=pyrid-2-yl]

(346) ##STR00052##

(347) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 1.74-1.93 (m, 4H), 2.12-2.28 (m, 2H), 2.91-3.00 (m, 2H), 3.65 (s, 2H), 4.02-4.13 (m, 1H), 4.58 (s, 2H), 7.28 (dd, J=6.8, 4.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.67 (br. s., 1H), 7.73 (dd, J=7.4, 7.4 Hz, 1H), 7.76-7.83 (m, 2H), 8.21 (dd, J=7.4, 1.3 Hz, 1H), 8.51 (d, J=4.8 Hz, 1H), 10.73 (br. s., 1H).

(348) HRMS (ESI+): calcd. for C.sub.20H.sub.23N.sub.4O.sub.2 [M+H].sup.+ 351.1816; fund 351.1815

(349) 3-oxo-2-[1-(1H-pyrrol-2-ylmethyl-piperidin-4-yl]-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 16

(350) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=1H-pyrrol-2-yl]

(351) ##STR00053##

(352) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 1.70-1.88 (m, 4H), 1.96-2.09 (m, 2H), 2.88-2.99 (m, 2H), 3.44 (s, 2H), 3.94-4.09 (m, 1H), 4.55 (s, 2H), 5.89 (br. s., 1H), 5.94 (br. s., 1H), 6.65 (br. s., 1H), 7.67 (br. s., 1H), 7.72 (dd, J=7.6, 7.4 Hz, 1H), 7.77 (dd, J=7.6, 1.3 Hz, 1H), 8.20 (dd, J=7.4, 1.3 Hz, 1H), 10.65 (br. s., 1H), 10.73 (br. s., 1H).

(353) HRMS (ESI+): calcd. for C.sub.19H.sub.23N.sub.4O.sub.2 [M+H].sup.+ 339.1816; found 339.1812.

(354) 2-(1-cyclopropylmethyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (1), cpd 24

(355) [R=H; n=0; R1=piperidin-4-yl; m=1; R2=cyclopropyl]

(356) ##STR00054##

(357) .sup.1H NMR (400.5 MHz, DMSO-d) δ ppm 0.06-0.12 (m, 2H), 0.44-0.50 (m, 2H), 0.80-0.89 (m, 1H), 1.72-1.88 (m, 4H), 2.00-2.11 (m, 2H), 2.21 (d, J=6.3 Hz, 2H), 3.04-3.13 (m, 2H), 3.98-4.09 (m, 1H), 4.56 (s, 2H), 7.66 (br. s., 1H), 7.72 (dd, J=7.6, 7.6 Hz, 1H), 7.77 (dd. J=7.6, 1.2 Hz, 1H), 8.20 (dd, J=7.6, 1.2 Hz, 1H), 10.73 (br. s., 1H).

(358) HRMS (ESI+): calcd. for C.sub.18H.sub.24N.sub.3O.sub.2 [M+H].sup.+ 314.1863; found 314.1860.