FURANE DERIVATIVES AS INHIBITORS OF ATAD2

Abstract

The invention relates to furane derivatives of formula (I) as inhibitors of ATAD2, a process for their preparation and use thereof.

Claims

1. A compound of general formula I ##STR00306## formula (I)] in which R.sup.1 represents a benzyl group wherein the -position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group, a halogen atom, a 4-trifluoromethyl group, R.sup.2 represents a C.sub.1-6-alkyl group, a C.sub.1-6-hydroxyalkyl group, a C.sub.1-3-alkylen-O(C.sub.1-6-alkyl) group, a C.sub.1-6-aminoalkyl group, a C.sub.1-3-alkylen-N(C.sub.1-6-alkyl).sub.2 group, a C.sub.1-3-alkylen-NH(C.sub.1-6-alkyl) group, a C.sub.1-3-alkylen-NH(C.sub.1-4-alkyl)-OH group, a C.sub.1-3-alkylen-NH(C.sub.3-7-cycloalkyl)-NH.sub.2 group, a C.sub.1-3-alkylen-NHC.sub.1-4-alkylen-heterocycloalkyl group which is optionally substituted with C.sub.1-3-alkyl, a C.sub.1-3-alkylen-NH-heterocycloalkyl group which is optionally substituted independently from each occurrence one or more times with C.sub.1-4-alkyl, halogen, benzyl, C(O)R.sup.7, a C.sub.1-3-alkylen-NH(C.sub.1-3-alkylen)-phenyl group, a C.sub.1-3-alkylen-NHC(O)(C.sub.1-4-alkyl) group, a C.sub.1-3-alkylen-NHC(O)C.sub.1-4-alkylen-heterocycloalkyl group, a C.sub.1-3-alkylen-NHC.sub.1-3-alkylen-C(O)-heterocycloalkyl group, a C.sub.1-3-alkylen-NHC(O)-heterocycloalkyl group, a C.sub.1-3-alkylen-NHS(O).sub.2(C.sub.1-4-alkyl) group, a C.sub.1-3-alkylen-(4-cyano-phenyl) group, a C.sub.1-3-alkylen-C(O)NH(C.sub.1-6-alkyl) group, a C.sub.1-3-alkylen-C(O)NH(C.sub.1-4-alkyl)-OH group, a C.sub.1-3-alkylen-C(O)NR.sup.8R.sup.9 group, a C.sub.1-3-alkylen-C(O)R.sup.7 group, a C.sub.1-3-alkylen-C(O)-heterocycloalkyl group which is optionally substituted with C.sub.1-3-alkyl, a C.sub.1-3-alkylen-heterocycloalkyl group which is optionally one or more times substituted with C.sub.1-3-alkyl, a C(O)R.sup.7 group, a C(O)NR.sup.8R.sup.9 group, a C(O)NH(C.sub.3-7-cycloalkyl)-NH.sub.2 group, a C(O)NH-heterocycloalkyl group which is optionally substituted with C.sub.1-3-alkyl, a heteroaryl group, R.sup.3 a C.sub.1-3-alkylen-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C.sub.1-3-alkyl, C.sub.1-3-alkoxy, amino, C(O)R.sup.7, C(O)NR.sup.8R.sup.9, a C.sub.1-4-alkylen-heteroaryl group, or R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom of absolute configuration R ##STR00307## R.sup.4 represents a hydrogen atom, a methyl group, a chlorine atom, R.sup.5 represents a hydrogen atom or a halogen atom, R.sup.6 represents a hydrogen atom, a halogen atom, a hydroxy group, a C.sub.1-3 alkoxy group, or a cyano group, R.sup.7 represents a OC.sub.1-4-alkyl group, R.sup.8, R.sup.9, represents, independently for each occurrence, a hydrogen atom or a C.sub.1-4-alkyl group, or the salts thereof, the solvates thereof or the solvates of the salts thereof, with the proviso that the following compounds 2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide 2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamide are excluded.

2. The compound according to claim 1, in which in which R.sup.1 represents a benzyl group wherein the -position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group, a halogen atom, a 4-trifluoromethyl group, R.sup.2 represents a C.sub.1-3-alkyl group, a C.sub.1-3-hydroxyalkyl group, a C.sub.1-3-alkylen-O(C.sub.1-3-alkyl) group, a C.sub.1-3-aminoalkyl group, a C.sub.1-3-alkylen-N(C.sub.1-3-alkyl).sub.2 group, a C.sub.1-3-alkylen-NH(C.sub.1-3-alkyl) group, a C.sub.1-3-alkylen-NH(C.sub.1-3-alkyl)-OH group, a C.sub.1-3-alkylen-NH(C.sub.5-6-cycloalkyl)-NH.sub.2 group, a C.sub.1-3-alkylen-NHC.sub.1-3-alkylen-heterocycloalkyl group which is optionally substituted with C.sub.1-3-alkyl, a C.sub.1-3-alkylen-NH-heterocycloalkyl group which is optionally substituted independently from each occurrence one or more times with C.sub.1-4-alkyl, halogen, benzyl, C(O)R.sup.7, a C.sub.1-3-alkylen-NH(C.sub.1-3-alkylen)-phenyl group, a C.sub.1-3-alkylen-NHC(O)(C.sub.1-3-alkyl) group, a C.sub.1-3-alkylen-NHC(O)C.sub.1-3-alkylen-heterocycloalkyl group, a C.sub.1-3-alkylen-NHC.sub.1-3-alkylen-C(O)-heterocycloalkyl group, a C.sub.1-3-alkylen-NHC(O)-heterocycloalkyl group, a C.sub.1-3-alkylen-NHS(O).sub.2(C.sub.1-3-alkyl) group, a C.sub.1-3-alkylen-(4-cyano-phenyl) group, a C.sub.1-3-alkylen-C(O)NH(C.sub.1-3-alkyl) group, a C.sub.1-3-alkylen-C(O)NH(C.sub.1-3-alkyl)-OH group, a C.sub.1-3-alkylen-C(O)NR.sup.8R.sup.9 group, a C.sub.1-3-alkylen-C(O)R.sup.7 group, a C.sub.1-3-alkylen-C(O)-heterocycloalkyl group which is optionally substituted with C.sub.1-3-alkyl, a C.sub.1-3-alkylen-heterocycloalkyl group which is optionally one or more times substituted with C.sub.1-3-alkyl, a C(O)R.sup.7 group, a C(O)NR.sup.8R.sup.9 group, a C(O)NH(C.sub.5-6-cycloalkylen)-NH.sub.2 group, a C(O)NH-heterocycloalkyl group which is optionally substituted with C.sub.1-3-alkyl a heteroaryl group, R.sup.3 a C.sub.1-3-alkylen-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C.sub.1-3-alkyl, C.sub.1-3-alkoxy, amino, C(O)R.sup.7, C(O)NR.sup.8R.sup.9, a C.sub.1-4-alkylen-heteroaryl group, or R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom ##STR00308## R.sup.4 represents a hydrogen atom, a methyl group, a chlorine atom, R.sup.5 represents a hydrogen atom or a halogen atom R.sup.6 represents a hydrogen atom, a halogen atom, a hydroxy group, a C.sub.1-3 alkoxy group, or a cyano group, R.sup.7 represents a OC.sub.1-4-alkyl group R.sup.8, R.sup.9, represents, independently for each occurrence, a hydrogen atom or a C.sub.1-4-alkyl group, or the salts thereof, the solvates thereof or the solvates of the salts thereof, with the proviso that the following compounds 2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide 2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamide are excluded.

3. The compound according to claim 1, in which R.sup.1 represents a benzyl group wherein the -position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group, a halogen atom, a 4-trifluoromethyl group, R.sup.2 represents a methyl group, a hydroxymethyl group, (CH.sub.2).sub.2OH, C(OH)(CH.sub.3).sub.2, CH(OH)CH.sub.3, C(OH)(CH.sub.3).sub.2, CH(OH)CH.sub.2CH(CH.sub.3).sub.2, CH.sub.2OCH.sub.3, CH.sub.2NH.sub.2, CH.sub.2N(CH.sub.3).sub.2, (CH.sub.2).sub.2NHCH(CH.sub.3).sub.2, CH.sub.2NHCH.sub.2CH(CH.sub.3).sub.2, CH.sub.2NH(CH.sub.2).sub.2OH, CH.sub.2NH-(1,4-cyclohexylen)-NH.sub.2, CH.sub.2NH(CH.sub.2).sub.2-piperidine-4-yl, (CH.sub.2).sub.2NHCH.sub.2-(1-methyl-piperidine-4-yl), CH.sub.2NHCH.sub.2-(3-azabicyclo[3.1.0]hex-6-yl), CH.sub.2NH-(1-ethyl-piperidine-4-yl), CH.sub.2NH-(1-isobutyl-piperidine-4-yl), CH.sub.2NH-(1-phenylmethyl-piperidine-4-yl), CH.sub.2NH-(1-tert.butoxycarbonyl-piperidine-4-yl), CH.sub.2NH-2,2-dimethyl-piperidine-4yl), (CH.sub.2).sub.2NH-(1-methyl-pyrrolidin-3-yl), CH.sub.2NH-(piperidin-4-yl), CH.sub.2NH-(1-methyl-piperidin-4-yl), CH.sub.2NH-(2-methyl-propyl-piperidin-3-yl), CH.sub.2NH-(3-fluoropiperidin-4-yl), CH.sub.2NHCH.sub.2-phenyl, CH.sub.2NHC(O)CH.sub.3, CH.sub.2NHC(O)CH.sub.2-piperidine-4-yl, CH.sub.2NHCH.sub.2C(O)-piperazine-1-yl, CH.sub.2NHC(O)-piperidine-4-yl, CH.sub.2NHS(O).sub.2CH.sub.3, CH.sub.2-(4-cyano-phenyl), CH.sub.2C(O)NHCH.sub.3, CH.sub.2C(O)NH(CH.sub.3).sub.2, CH.sub.2C(O)NHCH(CH.sub.3).sub.2, CH.sub.2C(O)NH(CH.sub.2).sub.2OH, CH.sub.2C(O)NH(CH.sub.2).sub.3OH, CH.sub.2C(O)NH.sub.2, CH.sub.2C(O)N(CH.sub.3).sub.2, CH.sub.2C(O)NHCH.sub.3, CH.sub.2C(O)OCH.sub.3, CH.sub.2C(O)-(morpholine-4-yl), CH.sub.2C(O)-(4-methyl-piperazine-1-yl), CH.sub.2C(O)(N-pyrrolidine), (CH.sub.2).sub.2-(3-methylpiperazine-1-yl), CH.sub.2-(4-methyl-piperazine-1-yl), (CH.sub.2).sub.2-(4-methyl-piperazine-1-yl), CH.sub.2-(morpholine-4-yl), (CH.sub.2).sub.2-(morpholine-4-yl), (CH.sub.2).sub.2-(2,4-dimethylpiperazine-1-yl), (CH.sub.2).sub.2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl), CH.sub.2(N-pyrrolidine), C(O)OCH.sub.3, C(O)NH.sub.2, C(O)NH-(4-amino-cyclohexylen), C(O)NH-(1-methyl-piperidine-4-yl), 1H-1,2,4-triazol-5-yl, 1H-imidazol-2-yl, R.sup.3 a CH.sub.2-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C.sub.1-3-alkyl, C.sub.1-3-alkoxy, amino, C(O)R.sup.7, C(O)NR.sup.8R.sup.9, CH.sub.2-pyridine-4-yl, or R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom ##STR00309## R.sup.4 represents a hydrogen atom, a methyl group, a chlorine atom, R.sup.5 represents a hydrogen atom or a fluorine atom R.sup.6 represents a hydrogen atom, a chlorine atom, a hydroxy group, a C.sub.1-3 alkoxy group, or a cyano group, R.sup.7 represents a methoxy group R.sup.8, R.sup.9, represents, independently for each occurrence, a hydrogen atom or a methyl group, or the salts thereof, the solvates thereof or the solvates of the salts thereof, with the proviso that the following compounds 2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide 2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamide are excluded.

4. The compound according to claim 1, which is selected from the group consisting of: 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(dimethylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-{2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}-4-cyano-D-phenylalaninamide, N-[(2R)-4-amino-1-(4-cyanophenyl)-4-oxobutan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)-2-furyl]benzamide, N-{2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzoyl}-4-cyano-N-methyl-D-phenylalaninamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(isopropylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(2-hydroxyethyl)amino]-4-oxobutan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(3-hydroxypropyl)amino]-4-oxobutan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-oxo-4-(pyrrolidin-1-yl)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(morpholin-4-yl)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(4-methylpiperazin-1-yl)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxy-3-methylbutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-hydroxybutan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-methoxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, methyl N-{2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzoyl}-4-cyano-D-phenylalaninate, 2-chloro-N-[(2R,3R)-1-(4-cyanophenyl)-3-hydroxybutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R,3R)-1-(4-cyanophenyl)-3-hydroxybutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-hydroxy-3-(4-iodophenyl)propan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(1S)-2-(4-cyanophenyl)-1-(1H-imidazol-2-yl)ethyl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(1R)-2-(4-cyanophenyl)-1-(1H-1,2,4-triazol-5-yl)ethyl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(4-methylpiperazin-1-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(morpholin-4-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(2-hydroxyethyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(dimethylamino)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(4-methylpiperazin-1-yl)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(propan-2-ylamino)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(3R)-3-methylpiperazin-1-yl]butan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(3S)-3-methylpiperazin-1-yl]butan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(morpholin-4-yl)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-{2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzoyl}-4-cyano-N-(1-methylpiperidin-4-yl)-D-phenylalaninamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(2S)-2,4-dimethylpiperazin-1-yl]butan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(2R)-2,4-dimethylpiperazin-1-yl]butan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-{[(1-methylpiperidin-4-yl)methyl]amino}butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-{[(3R)-1-methylpyrrolidin-3-yl]amino}butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-{[(3S)-1-methylpyrrolidin-3-yl]amino}butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyano-3-methylphenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyano-5-fluoro-2-methylphenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyano-2-methoxyphenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-(3-amino-4-cyanophenyl)-3-hydroxypropan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-(2-amino-4-cyanophenyl)-3-hydroxypropan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2S)-1-(4-cyanophenyl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)-ethyl]amino}methyl)-2-furyl]benzamide, N-[(2R)-1-(acetylamino)-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(3-cyanophenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R,3R)-1-(4-cyanophenyl)-3-hydroxy-5-methylhexan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R,3S)-1-(4-cyanophenyl)-3-hydroxy-5-methylhexan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-hydroxy-3-(pyridin-4-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-(4-carbamoylphenyl)-3-hydroxypropan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(pyrrolidin-1-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, methyl (3R)-3-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}amino)-4-(4-cyanophenyl)butanoate, methyl 4-[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-furan-2-yl]benzoyl}amino)-3-hydroxypropyl]benzoate, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(methylsulfonyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[2-oxo-2-(piperazin-1-yl)ethyl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzoyl}amino)-3-(4-cyanophenyl)propyl]piperidine-4-carboxamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(piperidin-4-ylacetyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(1-methylpiperidin-4-yl)amino]propan-2-yl})-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-[(1-benzylpiperidin-4-yl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-(benzylamino)-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(2-methylpropyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(1-ethylpiperidin-4-yl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[1-(2-methylpropyl)piperidin-4-yl]amino}-propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, tert-butyl 4-{[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-furan-2-yl]benzoyl}amino)-3-(4-cyanophenyl)propyl]amino}piperidine-1-carboxylate, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[(3S)-1-methylpiperidin-3-yl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-{[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethyl]amino}-3-(4-cyanophenyl)-propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(piperidin-4-ylamino)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[(4R)-2,2-dimethylpiperidin-4-yl]amino}-propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(piperidin-4-ylmethyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[2-(piperidin-4-yl)ethyl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-{5-[({2-[4-(trifluoro-methyl)phenyl]propan-2-yl}amino)methyl]furan-2-yl}benzamide, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-{5-[({(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}amino)methyl]furan-2-yl}benzamide, 2-chloro-N-[(3R,4R)-4-(4-cyanophenyl)piperidin-3-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-3-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2,4-dichloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 4-cyano-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-3-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-methoxy-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyano-3-methylphenyl)-3-hydroxypropan-2-yl]-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-amino-3-(4-cyano-3-methylphenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-(trans-4-aminocyclohexyl)-N-{2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzoyl})-4-cyano-D-phenylalaninamide, N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyano-3-methylphenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzamide, 2-chloro-5-[5-({[(1R)-1-(4-chlorophenyl)ethyl]amino}methyl)furan-2-yl]-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-hydroxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 4-cyano-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-3-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 2-chloro-N-[(2R)-4-(methylamino)-4-oxo-1-phenylbutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-(5-{[(2-phenylpropan-2-yl)amino]methyl}furan-2-yl)benzamide, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[2-(4-methylphenyl)propan-2-yl]amino}methyl)-2-furyl]benzamide, N-{2-chloro-5-[5-({[2-(4-chlorophenyl)propan-2-yl]amino}methyl)-2-furyl]benzoyl}-4-cyano-D-phenylalaninamide, and 2-chloro-N-[(2R)-1-hydroxy-3-phenylpropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, or the salts thereof, the solvates thereof or the solvates of the salts thereof,

5. A process for the preparation of a compound of the formula (I) according to claim 1, comprising the step of allowing an intermediate compound of general formula (VI): ##STR00310## in which R.sup.1, R.sup.4, R.sup.5 and R.sup.6 are as defined, to react with a compound of general formula (VII): ##STR00311## in which R.sup.2 and R.sup.3 are as defined, thus providing a compound of general formula (I): ##STR00312## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined.

6. A compound of formula (I) as defined in claim 1 for the treatment and/or prophylaxis of diseases.

7. A compound of formula (I) according to claim 1 for inhibiting proliferation of a cell, comprising contacting the cell with said compound.

8. A compound for use according to claim 6, wherein the disease is a hyperproliferative disorder.

9. A compound for use according to claim 6, wherein the disease is cancer.

10. A compound for use according to claim 6, wherein the disease is breast cancer or lung cancer.

11. A compound of formula (I) according to claim 1 for the preparation of a pharmaceutical composition.

12. A compound of formula (I) according to claim 1 for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of hyperproliferative disorder.

13. A pharmaceutical composition comprising a compound according to claim 1 in combination with a further anti-cancer agent.

14. A pharmaceutical composition comprising at least a compound according to claim 1 in combination with one or more pharmaceutically suitable excipient.

15. A pharmaceutical composition according to claim 12 for the treatment and/or prophylaxis.

Description

EXAMPLES

Example 1

2-Chloro-N-[(2R)-1-(4-cyanophenyl)-4-(dimethylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide

[0865] ##STR00187##

[0866] To a stirred suspension of 2-Chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzoic acid, 100 mg (0.27 mmol, intermediate 1A) in acetonitrile (1.7 mL) were added triethylamine, 76 L (0.54 mmol) followed by TBTU, 87 mg (0.27 mmol, 1.0 eq.) in acetonitrile (1 mL) at r.t. (solution gets clear). After 15 min, (3R)-3-amino-4-(4-cyanophenyl)-N,N-dimethylbutanamide, 75 mg (0.324 mmol, intermediate 2B) in solution in 0.5 mL of THF was added and the resulting mixture was stirred at r.t. overnight. The reaction mixture was concentrated and then dissolved in MeOH/MeCN (1/9, 1.5 mL) for prep HPLC purification (Basic conditions, method 6). The desired product was isolated as a beige solid, 59 mg (35%).

[0867] LC-MS (Method 5): R.sub.t=2.57 min; (ES+): m/z=583/585 (M+H).sup.+

[0868] .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm]=1.36 (d, 3H), 2.30 (s, 3H), 2.73 (dd, 1H), 2.81 (dd, 1H), 2.95 (s, 3H), 2.97 (dd, 1H), 3.10 (s, 3H), 3.16 (dd, 1H), 3.60 and 3.65 (2d, AB, 2H), 3.77 (q, 1H), 4.75 (m, 1H), 6.30 (d, 1H), 6.72 (d, 1H), 7.15 (d, 2H), 7.22 (d, 2H), 7.40 (d, 1H), 7.46 (d, 1H), 7.50 (d, 2H), 7.66 (m, 3H).

[0869] The following Examples were prepared in analogy of Example 1 by amide coupling of the corresponding intermediates xA and xB:

TABLE-US-00009 Ex- Inter- ample medi- No ates Structure/Name Analytics 2 1A; 6B [00188] N-{2-chloro-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzoyl}-4-cyano-D- phenylalaninamide LC-MS (Method 1): Rt = 2.38 min; MS (ES+): m/z = 541-543 (M + H)+. 1H-NMR (500 MHz, DMSO-d6) [ppm] = 1.24 (d, 3H), 2.27 (s, 3H), 2.96 (dd, 1H), 3.21 (dd, 1H), 3.50 (d, 1H), 3.58 (d, 1H), 3.71 (q, 1H), 4.72 (m, 1H), 6.31 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.20 (br s, 1H), 7.23 (d, 2H), 7.45 (d, 1H), 7.47 (d, 1H), 7.52-7.53 (m, 3H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.70 (d, 1H). 3 1A; 3B [00189] N-[(2R)-4-amino-1-(4- cyanophenyl)-4-oxobutan-2-yl]-2- chloro-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide LC-MS (Method 1): R.sub.t = 2.36 min; MS (ES+): m/z = 555/557 (M + H).sup.+ .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm] = 1.38 (d, 3H), 2.31 (s, 3H), 2.59 (d, 2H), 2.97 (dd, 1H), 3.14 (dd, 1H), 3.62 (d, 1H), 3.67 (d, 1H), 3.80 (q, 1H), 4.73 (m, 1H), 6.30 (d, 1H), 6.73 (d, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.40 (d, 1H), 7.46 (d, 1H), 7.50 (d, 2H), 7.65-7.68 (m, 3H). 4 1A; 15B [00190] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-3-hydroxypropan-2- yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.55 min; MS (ES+): m/z = 528/530 (M + H).sup.+ .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm] = 1.37 (d, 3H), 2.31 (s, 3H), 2.89 (dd, 1H), 3.17 (dd, 1H), 3.60 & 3.66 (2d, AB, 2H), 3.65-3.72 (m, 2H) 3.78 (q, 1H), 4.39-4.44 (m, 1H), 6.29 (d, 1H), 6.73 (d, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.41 (d, 1H), 7.51 (d, 2H), 7.53 (d, 1H), 7.65 (d, 2H), 7.67 (dd, 1H). 5 1A; 4B [00191] N-{2-chloro-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl) furan-2-yl]benzoyl}-4-cyano-N- methyl-D-phenylalaninamide LC-MS (Method 5): R.sub.t = 2.48 min; MS (ES+): m/z = 555/557 (M + H).sup.+ .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm] = 1.37 (d, 3H), 2.31 (s, 3H), 2.75 (s, 3H), 3.09 (dd, 1H), 3.30 (dd, 1H), 3.60 and 3.65 (2d, AB, 2H), 3.78 (q, 1H), 4.87 (dd, 1H), 6.30 (d, 1H), 6.74 (d, 1H), 7.15 (d, 2H), 7.22 (d, 2H), 7.41 (d, 1H), 7.50 (d, 2H), 7.62 (d, 1H), 7.67 (d, 2H), 7.69 (dd, 1H) 6 1A; 14B [00192] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-(isopropylamino)- 4-oxobutan-2-yl]-5-[5-({[(1R)-1- (4-methylphenyl)ethyl]amino} methyl)-2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.66 min; MS (ES+): m/z = 597/599 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.03 (d, 6H), 1.25 (d, 3H), 2.27 (s, 3H), 2.34-2.39 (m, 2H), 2.86 (dd, 1H), 2.97 (dd, 1H), 3.50 (d, 1H), 3.57 (d, 1H), 3.71 (q, 1H), 3.84 (m, 1H), 4.50 (m, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.41 (d, 1H), 7.45-7.46 (m, 3H), 7.66 (dd, 1H), 7.73-7.77 (m, 3H), 8.39 (d, 1H). 7 1A; 7B [00193] 2-chloro-N-{(2R)-1-(4- cyanophenyl)-4-[(2- hydroxyethyl)amino]-4-oxobutan- 2-yl}-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.41 min; MS (ES+): m/z = 599/601 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.27 (s, 3H), 2.41-2.43 (m, 2H), 2.85 (dd, 1H), 2.99 (dd 1H), 3.12-3.16 (m, 2H), 3.39-3.42 (m, 2H), 3.51 (dd, 1H), 3.58 (dd, 1H), 3.71 (m, 1H), 4.51 (m, 1H), 4.64 (t, 1H), 6.31 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.41 (d, 1H), 7.45-7.47 (m, 3H), 7.66 (dd, 1H), 7.76 (m, 2H), 7.91 (t, 1H), 8.42 (d, 1H). 8 1A; 8B [00194] 2-chloro-N-{(2R)-1-(4- cyanophenyl)-4-[(3- hydroxypropyl)amino]-4- oxobutan-2-yl}-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.42 min; MS (ES+): m/z = 613/614 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 1.52-1.58 (m, 2H), 2.27 (s, 3H), 2.39-2.42 (m, 2H), 2.85 (dd, 1H), 2.98 (dd, 1H), 3.10-3.14 (m, 2H), 3.38-3.42 (m, 2H), 3.50 (d, 1H), 3.57 (d, 1H), 3.71 (m, 1H), 4.40 (t, 1H), 4.52 (m, 1H), 6.31 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.40 (d, 1H), 7.44-7.47 (m, 3H), 7.66 (dd, 1H), 7.76 (d, 2H), 7.88 (t, 1H), 8.42 (d, 1H). 9 1A; 9B [00195] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-oxo-4-(pyrrolidin- 1-yl)butan-2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.68 min; MS (ES+): m/z = 609/611 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 1.72-1.78 (m, 2H), 1.83-1.89 (m, 2H), 2.27 (s, 3H), 2.51 (dd, 1H), 2.63 (dd, 1H), 2.89 (dd, 1H), 3.05 (dd, 1H), 3.28-3.31 (m, 2H), 3.38-3.47 (m, 2H), 3.50 (d, 1H), 3.57 (d, 1H), 3.71 (q, 1H), 4.54 (m, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.39 (d, 1H), 7.45- 7.48 (m, 3H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.46 (d, 1H). 10 1A; 10B [00196] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-(morpholin-4-yl)- 4-oxobutan-2-yl]-5-[5-({[(1R)-1- (4-methylphenyl)ethyl]amino} methyl)-2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.59 min; MS (ES+): m/z = 625/627 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.27 (s, 3H), 2.62 (dd, 1H), 2.68 (dd, 1H), 2.86 (dd, 1H), 3.05 (dd, 1H), 3.42-3.62 (m, 8H), 3.38-3.47 (m, 2H), 3.71 (q, 1H), 4.54 (m, 1H), 6.32 (d, 1H), 6.87 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.42 (d, 1H), 7.45 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.46 (d, 1H). 11 1A; 11B [00197] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-(4- methylpiperazin-1-yl)-4-oxobutan- 2-yl]-5-[5-({[(lR)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.12 min; MS (ES+): m/z = 638/640 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.16 (s, 3H), 2.20-2.25 (m, 2H), 2.27 (s, 3H), 2.32-2.36 (m, 2H), 2.60 (dd, 1H), 2.69 (dd, 1H), 2.86 (dd, 1H), 3.04 (dd, 1H), 3.42-3.52 (m, 5H), 3.57 (d, 1H), 3.71 (q, 1H), 4.53 (m, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.42 (d, 1H), 7.45 (d, 1H), 7.47 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.44 (d, 1H). 12 1A; 18B [00198] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-3-hydroxy-3- methylbutan-2-yl]-5-[5-({[(1R)-1- (4-methylphenyl)ethyl]amino} methyl)-2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.44 min; MS (ES+) m/z = 556-558 (M + H).sup.+ .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm] = 1.32 (s, 3H), 1.37 (d, 3H), 1.42 (s, 3H), 2.30 (s, 3H), 2.76 (dd, 1H), 3.35 (dd, 1H), 3.64 & 3.68 (2d, AB, 2H), 3.80 (q, 1H), 4.36 (dd, 1H), 6.31 (d, 1H), 6.68 (d, 1H), 7.13 (d, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.38 (d, 1H), 7.48 (d, 2H), 7.63- 7.66 (m, 3H). 13 1A; 19B [00199] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-hydroxybutan-2- yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.44 min; MS (ES+) m/z = 542-544 (M + H).sup.+ .sup.1H-NMR (500 M-z, CD.sub.3OD) [ppm] = 1.37 (d, 3H), 1.76-180 (m, 1H), 1.88-1.92 (m, 1H), 2.30 (s, 3H), 2.92 (dd, 1H), 3.08 (dd, 1H), 3.62 & 3.67 (2d, AB, 2H), 3.73- 3.76 (m, 2H), 3.79 (q, 1H), 4.48-4.53 (m, 1H), 6.30 (d, 1H), 6.71 (d, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.36 (d, 1H), 7.41 (d, 1H), 7.49 (d, 2H), 7.65-7.68 (m, 3H). 14 1A; 20B [00200] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-3-methoxypropan-2- yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.81 min; MS (ES+) m/z = 542-544 (M + H).sup.+ .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm] = 1.36 (d, 3H), 2.31 (s, 3H), 2.92 (dd, 1H), 3.13 (dd, 1H), 3.41 (s, 3H), 3.50 (dd, 1H), 3.53 (dd, 1H), 3.60 & 3.66 (2d, AB, 2H), 3.78 (q, 1H), 4.49-4.55 (m, 1H), 6.29 (d, 1H), 6.72 (d, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.41 (d, 1H), 7.47 (d, 1H), 7.49 (d, 2H), 7.65-7.69 (m, 3H). 15 1A; 53B [00201] methyl N-{2-chloro-5-[5-({[(1R)- 1-(4-methylphenyl)ethyl]amino} methyl)-2-furyl]benzoyl}-4-cyano- D-phenylalaninate LC-MS (Method 1): R.sub.t = 2.54 min; MS (ES+): m/z = 556/558 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.27 (s, 3H), 3.08 (dd, 1H), 3.29 (dd, 1H), 3.51 (d, 1H), 3.58 (d, 1H), 3.69 (s, 3H), 3.71 (q, 1H), 4.78 (m, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.41 (d, 1H), 7.48 (d, 1H), 7.52 (d, 2H), 7.69 (dd, 1H), 7.78 (d, 2H), 9.01 (d, 1H). 16 (dia#1) and 17 (dia#2) 1A; 22B [00202] Dia#1: LC-MS (Method 5): R.sub.t = 2.50 min; MS (ES+) m/z = 542/544 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.15 (d, 3H), 1.25 (d, 3H), 2.27 (s, 3H), 2.84 (dd, 1H), 3.01 (dd, 1H), 3.52 & 3.60 (2d, AB, 2H), 3.68-3.76 (m, 1H), 3.80-3.88 (m, 1H), 4.13-4.20 (m, 1H), 4.84 (d, 1H), 6.33 (s, 1H), 6.89 (d, 1H), 7.13 (d, 2H), 7.24 (d, 2H), 7.33 (d, 1H), 7.45 (d, 1H), 7.50 (d, 2H), 7.65 (dd, 1H), 7.76 (d, 2H), 8.27 (d, 1H). 1H missing [00203] 2-chloro-N-[(2R,3R)-1-(4- cyanophenyl)-3-hydroxybutan-2- yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide and 2-chloro-N-[(2R,3S)-1-(4- cyanophenyl)-3-hydroxybutan-2- yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide Dia#2: LC-MS (Method 5): R.sub.t = 2.47 min; MS (ES+) m/z = 542/544 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.22 (d, 3H), 1.26 (d, 3H), 2.27 (s, 3H), 2.71 (dd, 1H), 3.25 (dd, 1H), 3.53 & 3.60 (2d, AB, 2H), 3.59-3.66 (m, 1H), 3.68-3.76 (m, 1H), 3.97-4.06 (m, 1H), 4.91 (d, 1H), 6.33 (d, 1H), 6.88 (d, 1H), 7.13 (d, 2H), 7.22 (d, 1H), 7.24 (d, 2H), 7.44 (d, 1H), 7.47 (d, 2H), 7.65 (dd, 1H), 7.75 (d, 2H), 8.32 (d, 1H). 18 1A; 23B [00204] 2-chloro-N-[(2R)-1-hydroxy-3-(4- iodophenyl)propan-2-yl]-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.57 min; MS (ES+): m/z = 629/631 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.27 (s, 3H), 2.65 (dd, 1H), 2.94 (dd, 1H), 3.40 (m, 1H), 3.50 (m, 1H), 3.52 (d, 1H), 3.59 (d, 1H), 3.72 (q, 1H), 4.10 (m, 1H), 4.86 (t, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.10 (d, 2H), 7.12 (d, 2H), 7.24 (d, 2H), 7.43 (d, 1H), 7.46 (d, 1H), 7.63 (d, 2H), 7.66 (dd, 1H), 8.31 (d, 1H). 19 1A; 24B [00205] 2-chloro-N-[2-(4-cyanophenyl)-1- (1H-imidazol-2-yl)ethyl]-5-[5- ({[(1S)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.19 min; MS (ES+): m/z = 564/566 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.24 (d, 3H), 2.27 (s, 3H), 3.22 (dd, 1H), 3.45 (dd, 1H), 3.50 & 3.57 (2d, AB, 2H), 3.71 (m, 1H), 5.43 (m, 1H), 6.31 (d, 1H), 6.87 (br s, 1H), 6.88 (d, 1H), 7.06 (br s, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.43-7.50 (m, 3H), 7.54 (m, 1H), 7.63- 7.78 (m, 3H), 8.97 (d, 1H). 20 1A; 25B [00206] 2-chloro-N-[(1R)-2-(4- cyanophenyl)-1-(1H-1,2,4-triazol- 5-yl)ethyl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.48 min; MS (ES+): m/z = 565/567 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.24 (d, 1H), 1.26 (d, 3H), 2.27 (s, 3H), 3.24 (dd, 1H), 3.41 (br s, 1H), 3.49-3.63 (m, 2H), 3.73 (m, 1H), 5.48 (m, 1H), 6.33 (s, 1H), 6.90 (d, 1H), 7.13 (d, 2H), 7.24 (d, 2H), 7.45 (s, 1H), 7.50 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.51 (br s 1H), 9.03 (br s, 2H), 13.90 (br s, 1H). 21 1A; 26B [00207] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-3-(4- methylpiperazin-1-yl)propan-2- yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.16 min; MS (ES+): m/z = 610/612 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.12 (s, 3H), 2.27 (s, 3H), 2.27-2.50 (m, 10H), 2.74 (dd, 1H), 3.07 (dd, 1H), 3.51 (d, 1H), 3.58 (d, 1H), 3.72 (m, 1H), 4.35 (m, 1H), 6.33 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.40 (m, 1H), 7.45 (d, 1H), 7.47 (d, 2H), 7.66 (dd, 1H), 7.74- 7.77 (m, 2H), 8.31 (d, 1H). .sup.13C-NMR (125 MHz, DMSO-d.sub.6) [ppm] = 20.6, 24.3, 38.3, 43.6, 45.7, 47.6, 52.7, 54.8, 56.4, 61.4, 107.6, 108.8, 108.9, 119.0, 122.8, 124.9, 126.5, 127.9, 128.8, 129.1, 130.0, 130.4, 131.8, 135.6, 137.6, 142.5, 145.2, 150.0, 155.4, 165.5. 22 1A; 27B [00208] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-3-(morpholin-4- yl)propan-2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.26 min; MS (ES+): m/z = 597/599 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.26 (d, 3H), 2.28 (s, 3H), 2.40-2.50 (m, 6H), 2.77 (dd, 1H), 3.08 (dd, 1H), 3.50-3.65 (m, 6H), 3.73 (q, 1H), 4.38 (m, 1H), 6.33 (d, 1H), 6.90 (d, 1H), 7.13 (d, 2H), 7.24 (d, 2H), 7.41 (d, 1H), 7.46 (d, 1H), 7.50 (d, 2H), 7.67 (dd, 1H), 7.77 (d, 2H), 8.36 (d, 1H). .sup.13C-NMR (125 MHz, DMSO-d.sub.6) [ppm] = 20.6, 24.3, 38.2, 43.5, 47.4, 53.4, 56.4, 61.8, 66.3, 107.7, 108.8, 109.1, 119.0, 122.8, 124.9, 126.5, 127.9, 128.8, 129.1, 130.0, 130.4, 131.9, 135.6, 137.6, 142.5, 145.2, 150.0, 155.4, 165.6 23 1A; 28B [00209] 2-chloro-N-{(2R)-1-(4- cyanophenyl)-3-[(2- hydroxyethyl)amino]propan-2-yl}- 5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.18 min; MS (ES+): m/z = 571/573 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.27 (s, 3H), 2.58-2.65 (m, 2H), 2.66-2.72 (m, 2H), 2.79 (dd, 1H), 3.07 (dd, 1H), 3.46 (q, 2H), 3.51 (d, 1H), 3.58 (d, 1H), 3.71 (q, 1H), 4.26 (m, 1H), 4.48 (t, 1H), 6.31 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.42 (d, 1H), 7.46 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.38 (d, 1H). 24 1A; 51B [00210] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-3- (dimethylamino)propan-2-yl]-5- [5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.22 min; MS (ES+): m/z = 555 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.23 (s, 6H), 2.27 (s, 3H), 2.35-2.38 (m, 2H), 2.75 (dd, 1H), 3.11 (dd, 1H), 3.51 & 3.58 (2 d, AB, 2H), 3.72 (m, 1H), 4.30 (m, 1H), 6.31 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.36 (d, 1H), 7.45 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.77 (m, 2H), 8.35 (d, 1H). 25 1A; 29B [00211] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-(4- methylpiperazin-1-yl)butan-2-yl]- 5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.05 min; MS (ES+): m/z = 624/626 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.24 (d, 3H), 1.62 (m, 1H), 1.71 (m, 1H), 2.11 (s, 3H), 2.26 (s, 3H), 2.20-2.42 (m, 10H), 2.84 (dd, 1H), 2.97 (dd, 1H), 3.51 (d, 1H), 3.58 (d, 1H), 3.71 (q, 1H), 4.20 (m, 1H), 6.31 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.33 (d, 1H), 7.46 (d, 1H), 7.47 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.44 (d, 1H). 26 1A; 30B [00212] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4- (isopropylamino)butan-2-yl]-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2 -furyl]benzamide LC-MS (Method 1): R.sub.t = 2.12 min; MS (ES+): m/z = 583/585 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 0.93 (d, 3H), 0.94 (d, 3H), 1.25 (d, 3H), 1.58 (m, 1H), 1.70 (m, 1H), 2.26 (s, 3H), 2.60-2.69 (m, 3H), 2.83 (dd, 1H), 2.96 (dd, 1H), 3.51 (d, 1H), 3.58 (d, 1H), 3.71 (q, 1H), 4.25 (m, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.30 (d, 1H), 7.47 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.44 (d, 1H). 27 1A; 31B [00213] 2-chloro-N-{(2R)-1-(4- cyanophenyl)-4-[(3R)-3- methylpiperazin-1-yl]butan-2-yl}- 5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 12): R.sub.t = 2.94 min; MS (ES+): m/z = 624/626 (M + H).sup.+. UPLC-MS (Method 11): R.sub.t = 1.04 min; MS (ES+): m/z = 624/626 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 0.89 (d, 3H), 1.25 (d, 3H), 1.50 (t, 1H), 1.57-1.84 (m, 3H), 2.27 (s, 3H), 2.30-2.44 (m, 2H), 2.55-2.65 (m, 3H), 2.68 (br s, 1H), 2.74 (m, 1H), 2.83 (dd, 1H), 2.97 (dd, 1H), 3.52 & 3.59 (2d, AB, 2H), 3.71 (q, 1H), 4.21 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.33 (d, 1H), 7.47 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.43 (d, 1H). 28 1A; 32B [00214] 2-chloro-N-{(2R)-1-(4- cyanophenyl)-4-[(3S)-3- methylpiperazin-1-yl]butan-2-yl}- 5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.14 min; MS (ES+): m/z = 624/626 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.87 (d, 3H), 1.25 (d, 3H), 1.46 (t, 1H), 1.64 (m, 1H), 1.71 (m, 1H), 1.82 (m, 1H), 2.27 (s, 3H), 2.33- 2.38 (m, 2H), 2.55-2.67 (m, 4H), 2.75 (m, 1H), 2.85 (dd, 1H), 2.96 (dd, 1H), 3.51 (d, 1H), 3.58 (d, 1H), 3.71 (q, 1H), 4.20 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.34 (d, 1H), 7.47 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.43 (d, 1H). 29 1A; 33B [00215] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-(morpholin-4- yl)butan-2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.16 min; MS (ES+): m/z = 610/612 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 1.65 (m, 1H), 1.74 (m, 1H), 2.27 (s, 3H), 2.33-2.44 (m, 6H), 2.84 (dd, 1H), 2.98 (dd, 1H), 3.50-3.60 (m, 6H), 3.71 (q, 1H), 4.23 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.32 (d, 1H), 7.47 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.41 (d, 1H). 30 1A; 47B [00216] N-{2-chloro-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzoyl}-4-cyano-N-(1- methylpiperidin-4-yl)-D- phenylalaninamide LC-MS (Method 1): R.sub.t = 2.21 min; MS (ES+): m/z = 638/640 (M + H).sup.+, 520/522 (M + H 118).sup.+ .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 1.29-1.38 (m, 1H), 1.39-1.48 (m, 1H), 1.61-1.68 (m, 1H), 1.69-1.77 (m, 1H), 1.89-2.00 (m, 2H), 2.15 (s, 3H), 2.27 (s, 3H), 2.62-2.73 (m, 2H), 2.97 (dd, 1H), 3.11 (dd, 1H), 3.52 (m, 1H), 3.50 & 3.58 (2 d, AB, 2H), 3.71 (q, 1H), 4.74 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.13 (d, 2H), 7.24 (d, 2H), 7.43 (d, 1H), 7.45 (d, 1H), 7.51 (d, 2H), 7.67 (dd, 1H), 7.77 (d, 2H), 7.94 (d, 1H), 8.74 (d, 1H) 31 1A; 34B [00217] 2-chloro-N-{(2R)-1-(4- cyanophenyl)-4-[(2S)-2,4- dimethylpiperazin-1-yl]butan-2- yl}-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.13 min; MS (ES+): m/z = 638/640 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.93 (d, 3H), 1.25 (d, 3H), 1.57 (m, 1H), 1.71- 1.77 (m, 2H), 2.03 (m, 1H), 2.09 (s, 3H), 2.15-2.24 (m, 2H), 2.27 (s, 3H), 2.33 (m, 1H), 2.46-2.54 (m, 2H), 2.73 (m, 1H), 2.79-2.83 (m, 2H), 2.98 (dd, 1H), 3.51 (d, 1H), 3.58 (d, 1H), 3.71 (q, 1H), 4.19 (m, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.29 (d, 1H), 7.46 (d, 1H), 7.47 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.44 (d, 1H). 32 1A; 35B [00218] 2-chloro-N-{(2R)-1-(4- cyanophenyl)-4-[(2R)-2,4- dimethylpiperazin-1-yl]butan-2- yl}-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.12 min; MS (ES+): m/z = 638/640 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.94 (d, 3H), 1.25 (d, 3H), 1.60 (m, 1H), 1.65- 1.72 (m, 2H), 1.97 (m, 1H), 2.08 (s, 3H), 2.15 (m, 1H), 2.27 (s, 3H), 2.29-2.32 (m, 2H), 2.46-2.50 (m, 2H), 2.67 (m, 1H), 2.79 (m, 1H), 2.86 (dd, 1H), 2.96 (dd, 1H), 3.51 (d, 1H), 3.58 (d, 1H), 3.71 (q, 1H), 4.21 (m, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.34 (d, 1H), 7.46 (d, 1H), 7.48 (d, 2H), 7.67 (dd, 1H), 7.77 (d, 2H), 8.46 (d, 1H). 33 1A; 36B [00219] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-{[(1- methylpiperidin-4- yl)methyl]amino}butan-2-yl]-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.13 min; MS (ES+): m/z = 652/654 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.01-1.10 (m, 2H), 1.23 (m, 1H), 1.25 (d, 3H), 1.57-1.61 (m, 3H), 1.70-1.75 (m, 3H), 2.09 (s, 3H), 2.26 (s, 3H), 2.33 (d, 2H), 2.58-2.68 (m, 4H), 2.83 (dd, 1H), 2.96 (dd, 1H), 3.52 (d, 1H), 3.59 (d, 1H), 3.71 (q, 1H), 4.24 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.30 (d, 1H), 7.47 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.46 (d, 1H). 34 1A; 37B [00220] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-{[(3R)-1- methylpyrrolidin-3- yl]amino}butan-2-yl]-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.15 min; MS (ES+): m/z = 624/626 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.25 (d, 3H), 1.46 (m, 1H), 1.60 (m, 1H), 1.69 (m, 1H), 1.92 (m, 1H), 2.14 (m, 1H), 2.18 (s, 3H), 2.27 (s, 3H), 2.36-2.41 (m, 2H), 2.58-2.64 (m, 3H), 2.83 (dd, 1H), 2.96 (dd, 1H), 3.17 (m, 1H), 3.52 (d, 1H), 3.59 (d, 1H), 3.71 (q, 1H), 4.23 (m, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.12 (d,2H), 7.24 (d, 2H), 7.30 (d, 1H), 7.46 (d, 1H), 7.48 (d, 2H), 7.67 (dd, 1H), 7.77 (d, 2H), 8.43 (d, 1H). 35 1A; 38B [00221] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-{[(3S)-1- methylpyrrolidin-3- yl]amino}butan-2-yl]-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.11 min; MS (ES+): m/z = 624/626 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.25 (d, 3H), 1.42 (m, 1H), 1.59 (m, 1H), 1.69 (m, 1H), 1.92 (m, 1H), 2.13 (m, 1H), 2.17 (s, 3H), 2.27 (s, 3H), 2.35-2.38 (m, 2H), 2.56-2.61 (m, 3H), 2.82 (dd, 1H), 2.96 (dd, 1H), 3.13 (m, 1H), 3.52 (d, 1H), 3.59 (d, 1H), 3.71 (q, 1H), 4.24 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.30 (d, 1H), 7.47 (d, 1H), 7.48 (d, 2H), 7.67 (dd, 1H), 7.77 (d, 2H), 8.43 (d, 1H). 36 1A; 39B [00222] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-4-(6-methyl-2,6- diazaspiro[3.3]hept-2-yl)butan-2- yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.12 min; MS (ES+): m/z = 636/638 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 1.44-1.52 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 2.40-2.43 (m, 2H), 2.81 (dd, 1H), 2.93 (dd, 1H), 3.08 (s, 4H), 3.10 (s, 4H), 3.51 (d, 1H), 3.58 (d, 1H), 3.71 (q, 1H), 4.16 (m, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.32 (d, 1H), 7.46 (d, 2H), 7.47 (d, 1H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.40 (d, 1H). 37 1A; 40B [00223] 2-chloro-N-[(2R)-1-(4-cyano-3- methylphenyl)-3-hydroxypropan- 2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.42 min; MS (ES+): m/z = 542/544 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.24 (d, 3H), 2.27 (s, 3H), 2.43 (s, 3H), 2.74 (dd, 1H), 3.04 (dd, 1H), 3.41 (m, 1H), 3.49 (d, 1H), 3.54 (m, 1H), 3.56 (d, 1H), 3.71 (q, 1H), 4.15 (m, 1H), 4.92 (t, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.29 (d, 1H), 7.36 (s, 1H), 7.46-7.47 (m, 2H), 7.66 (dd, 1H), 7.68 (d, 1H), 8.36 (d, 1H). 38 1A; 41B [00224] 2-chloro-N-[(2R)-1-(4-cyano-5- fluoro-2-methylphenyl)-3- hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.48 min; MS (ES+): m/z = 560/562 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.24 (d, 3H), 2.27 (s, 3H), 2.35 (s, 3H), 2.70 (dd, 1H), 3.11 (dd, 1H), 3.44 (m, 1H), 3.50 (d, 1H), 3.56 (d, 1H), 3.59 (m, 1H), 3.71 (q, 1H), 4.20 (m, 1H), 5.01 (t, 1H), 6.32 (d, 1H), 6.91 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.33 (d, 1H), 7.46-7.48 (m, 2H), 7.67 (dd, 1H), 7.71 (d, 1H), 8.40 (d, 1H). 39 1A; 42B [00225] 2-chloro-N-[(2R)-1-(4-cyano-2- methoxyphenyl)-3- hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): Rt = 2.42 min; MS (ES+): m/z = 558/560 (M + H)+. 1H-NMR (500 MHz, DMSO-d6) [ppm] = 1.25 (d, 3H), 2.27 (s, 3H), 2.66 (dd, 1H), 3.08 (dd, 1H), 3.43 (m, 1H), 3.50 (d, 1H), 3.53 (m, 1H), 3.57 (d, 1H), 3.71 (q, 1H), 3.86 (s, 3H), 4.26 (m, 1H), 4.88 (t, 1H), 6.31 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.36 (dd, 1H), 7.39-7.42 (m, 3H), 7.45 (d, 1H), 7.65 (dd, 1H), 8.25 (d, 1H). 40 1A; 43B [00226] N-[(2R)-1-(3-amino-4- cyanophenyl)-3-hydroxypropan-2- yl]-2-chloro-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.33 min; MS (ES+): m/z = 543/545 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.24 (d, 3H), 2.27 (s, 3H), 2.61 (dd, 1H), 2.86 (dd, 1H), 3.39 (m, 1H), 3.48-3.52 (m, 2H), 3.57 (d, 1H), 3.71 (q, 1H), 4.09 (m, 1H), 4.85 (t, 1H), 5.93 (s, 2H), 6.31 (d, 1H), 6.54 (dd, 1H), 6.70 (s, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.29 (d, 1H), 7.47 (d, 1H), 7.49 (d, 1H), 7.66 (dd, 1H), 8.32 (d, 1H). 41 1A; 44B [00227] N-[(2R)-1-(2-amino-4- cyanophenyl)-3-hydroxypropan-2- yl]-2-chloro-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.39 min; MS (ES+): m/z = 543/545 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.24 (d, 3H), 2.27 (s, 3H), 2.70 (dd, 1H), 2.80 (dd, 1H), 3.45 (m, 1H), 3.49 (d, 1H), 3.54 (m, 1H), 3.57 (d, 1H), 3.70 (q, 1H), 4.07 (m, 1H), 4.88 (t, 1H), 5.63 (s, 2H), 6.31 (d, 1H), 6.89 (dd, 1H), 6.92 (d, 1H), 6.95 (d, 1H), 7.12 (d, 2H), 7.16 (d, 1H), 7.23 (d, 2H), 7.49 (d, 1H), 7.58 (d, 1H), 7.68 (dd, 1H), 8.49 (d, 1H). 42 1A; 16B [00228] 2-chloro-N-[(2S)-1-(4- cyanophenyl)propan-2-yl]-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): Rt = 2.54 min; MS (ES+): m/z = 512/514 (M + H)+. 1H-NMR (500 MHz, MeOD) [ppm] = 1.30 (d, 3H), 1.37 (d, 3H), 2.31 (s, 3H), 2.93-3.00 (m, 2H), 3.60 & 3.67 (2 d, AB, 2H), 3.79 (q, 1H), 4.43 (m, 1H), 6.30 (d, 1H), 6.73 (d, 1H), 7.15 (d, 2H), 7.22 (d, 2H), 7.44 (d, 1H), 7.49 (m, 3H), 7.65- 7.70 (m, 3H). 43 1A; 17B [00229] N-[(2R)-1-acetamido-3-(4- cyanophenyl)propan-2-yl]-2- chloro-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.42 min; MS (ES+): m/z = 569/571 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 1.85 (s, 3H), 2.27 (s, 3H), 2.77 (dd, 1H), 2.97 (dd, 1H), 3.28 (m, 2H), 3.52 & 3.56 (2 d, AB, 2H), 3.70 (q, 1H), 4.26 (m, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.44-7.49 (m, 4H), 7.64 (dd, 1H), 7.76 (d, 2H), 7.97 (t, 1H), 8.34 (d, 1H). 44 1A; 21B [00230] 2-chloro-N-[(2R)-1-(3- cyanophenyl)-3-hydroxypropan-2- yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 5): R.sub.t = 2.58 min; MS (ES+) m/z = 528-530 (M + H).sup.+ .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm] = 1.36 (d, 3H), 2.31 (s, 3H), 2.85 (dd, 1H), 3.15 (dd, 1H), 3.59 & 3.65 (2d, AB, 2H), 3.67 (dd, 1H), 3.71 (dd, 1H), 3.77 (q, 1H), 4.36- 4.41 (m, 1H), 6.29 (d, 1H), 6.75 (d, 1H), 7.15 (d, 2H), 7.22 (d, 2H), 7.41 (d, 1H), 7.48 (t, 1H), 7.55-7.57 (m, 2H), 7.65 (d, 1H), 7.67-7.69 (m, 2H). 45 1A; 45B [00231] 2-chloro-N-[(2R,3R)-1-(4- cyanophenyl)-3-hydroxy-5- methylhexan-2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.66 min; MS (ES+) m/z = 584/586 (M + H).sup.+ LC-MS (Method 10): R.sub.t = 9.91 min; MS (ES+): m/z = 584/586 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO- d6) [ppm] = 0.85 (d, 3H), 0.87 (d, 3H), 1.26 (d, 3H), 1.28-1.42 (m, 2H), 1.79 (m, 1H), 2.26 (s, 3H), 2.84 (dd, 1H), 3.01 (dd, 1H), 3.52 & 3.59 (2d, AB, 2H), 3.70 (m, 2H), 4.17 (m, 1H), 4.77 (d, 1H), 6.32 (d, 1H), 6.82 (d, 1H), 7.11 (d, 2H), 7.23 (d, 2H), 7.30 (d, 1H), 7.45 (d, 1H), 7.50 (d, 2H), 7.66 (dd, 1H), 7.75 (d,2H), 8.24 (d, 1H) 46 1A; 46B [00232] 2-chloro-N-[(2R,3S)-1-(4- cyanophenyl)-3-hydroxy-5- methylhexan-2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.63 min; MS (ES+) m/z = 584/586 (M + H).sup.+ LC-MS (Method 10): R.sub.t = 9.71 min; MS (ES+): m/z = 584/586 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO- d6) [ppm] = 0.86 (d, 3H), 0.91 (d, 3H), 1.25 (d, 3H), 1.34 (m, 1H), 1.45 (m, 1H), 1.83 (m, 1H), 2.27 (s, 3H), 2.71 (dd, 1H), 3.23 (dd, 1H), 3.51 (m, 1H), 3.52 & 3.60 (2d, AB, 2H), 3.71 (q, 1H), 4.01 (m, 1H), 4.80 (d, 1H), 6.32 (d, 1H), 6.85 (d, 1H), 7.11 (d, 2H), 7.21 (d, 1H), 7.23 (d, 2H), 7.44 (d, 1H), 7.46 (d, 2H), 7.65 (dd, 1H), 7.75 (d, 2H), 8.32 (d, 1H) 47 1A; 48B [00233] 2-chloro-N-[(2R)-1-hydroxy-3- (pyridin-4-yl)propan-2-yl]-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 5): Rt = 2.33 min; MS (ES+) m/z = 504-506 (M + H)+ 1H-NMR (500 MHz, CD3OD) [ppm] = 1.36 (d, 3H), 2.31 (s, 3H), 2.86 (dd, 1H), 3.15 (dd, 1H), 3.59 & 3.64 (2d, AB, 2H), 3.67 (dd, 1H), 3.71 (dd, 1H), 3.77 (q, 1H), 4.44-4.49 (m, 1H), 6.28 (d, 1H), 6.73 (d, 1H), 7.15 (d, 2H), 7.22 (d, 2H), 7.39-7.41 (m, 3H), 7.53 (d, 1H), 7.67 (dd, 1H), 8.44 (d, 2H). 48 1A; 49B [00234] N-[(2R)-1-(4-carbamoylphenyl)-3- hydroxypropan-2-yl]-2-chloro-5- [5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.22 min; MS (ES+): m/z = 546/548 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.24 (d, 3H), 2.27 (s, 3H), 2.76 (dd, 1H), 3.03 (dd, 1H), 3.42 (m, 1H), 3.49-3.55 (m, 2H), 3.57 (d, 1H), 3.71 (q, 1H), 4.16 (m, 1H), 4.87 (t, 1H), 6.31 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23-7.25 (m, 3H), 7.35 (d, 2H), 7.45-7.47 (m, 2H), 7.65 (dd, 1H), 7.82 (d, 2H), 7.89 (br s, 1H), 8.35 (d, 1H). 49 1A; 50B [00235] 2-chloro-N-[(2R)-1-(4- cyanophenyl)-3-(pyrrolidin-1- yl)propan-2-yl]-5-[5-({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzamide LC-MS (Method 1): R.sub.t = 2.18 min; MS (ES+): m/z = 581/583 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.25 (d, 3H), 1.67- 1.72 (m, 4H), 2.27 (s, 3H), 2.51-2.55 (m, 5H), 2.59 (dd, 1H), 2.76 (m, 1H), 3.12 (dd, 1H), 3.51 (d, 1H), 3.57 (d, 1H), 3.72 (m, 1H), 4.29 (m, 1H), 6.32 (m, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.37 (t, 1H), 7.45 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.75-7.77 (m, 2H), 8.35 (d, 1H) 50 1A; 52B [00236] methyl (3R)-3-({2-chloro-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzoyl}amino)-4-(4- cyanophenyl)butanoate LC-MS (Method 1): R.sub.t = 2.50 min; MS (ES+): m/z = 570/572 (M + H).sup.+. .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm] = 1.36 (d, 3H), 2.31 (s, 3H), 2.68 (dd, 1H), 2.70 (dd, 1H), 2.97 (dd, 1H), 3.11 (dd, 1H), 3.60 & 3.67 (2 d, AB, 2H), 3.70 (s, 3H), 3.79 (q, 1H), 4.74 (m, 1H), 6.30 (d, 1H), 6.72 (d, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.40 (d, 1H), 7.44 (d, 1H), 7.50 (d, 2H), 7.64-7.69 (m, 3H). 51 [00237] methyl 4-[(2R)-2-({2-chloro-5-[5- ({[(1R)-1-(4- methylphenyl)ethyl]amino}methyl)- 2-furyl]benzoyl}amino)-3- hydroxypropyl]benzoate LC-MS (Method 1): R.sub.t = 2.43 min; MS (ES+): m/z = 561/563 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO- d.sub.6) [ppm] = 1.25 (d, 3H), 2.27 (s, 3H), 2.78 (dd, 1H), 3.07 (dd, 1H), 3.42 (m, 1H), 3.50-3.56 (m, 2H), 3.58 (d, 1H), 3.71 (m, 1H), 3.83 (s, 3H), 4.17 (m, 1H), 4.90 (t, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.43-7.46 (m, 4H), 7.65 (dd, 1H), 7.89 (d, 2H), 8.35 (d, 1H).

Example 53

N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0870] ##STR00238##

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0871] ##STR00239##

[0872] To a stirred solution of intermediate 1A, 1.80 g (4.87 mmol) in tetrahydrofuran (80 mL) and DMF (4 mL) was added triethylamine, 0.67 mL (4.87 mmol) followed by TBTU, 1.64 g (5.11 mmol, 1.05 eq.). The mixture was stirred for 30 min at r.t., and then amine intermediate 52B, 1.66 g (4.87 mmol, 1 eq.) and triethylamine, 2.0 mL (14.6 mmol, 3.0 eq.) were added. The resulting mixture was stirred at r.t. for 16 h. Most of the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate and washed with sat. aq. sodium hydrogen carbonate, brine and then dried over sodium sulfate. The solution was concentrated and the residue purified by flash chromatography on silica (dichloromethane/methanol, 1/0>100/4) to give the product, 2.8 g (82%) as beige solid.

[0873] LC-MS (Method 1): R.sub.t=2.66 min; MS (ES+): nm/z=657/659 (M+H).sup.+

[0874] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]=1.31 (d, 3H), 2.27 (s, 3H), 2.86 (dd, 1H), 3.14 (dd, 1H), 3.66 (br s, 2H), 3.78-3.90 (m, 3H), 4.61 (m, 1H), 6.40 (br s, 1H), 6.86 (d, 1H), 7.14 (d, 2H), 7.27-7.30 (m, 3H), 7.38 (d, 1H), 7.50 (d, 2H), 7.61 (dd, 1H), 7.75 (d, 2H), 7.80 (m, 2H), 7.88 (m, 2H), 8.52 (d, 1H).

N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0875] To a stirred solution of 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]-amino}methyl)-2-furyl]benzamide, 205 mg (0.31 mmol) in absolute ethanol (5 mL) was added hydrazine, 1.56 mL (1M in THF, 1.56 mmol, 5 eq.). The resulting solution was stirred at 35 C. for 16 h, and then at 70 C. for 3 h. The solvent was then removed in vacuum, the residue triturated in ethyl acetate and filtered. The filtrate was concentrated and the residue obtained was purified by preparative TLC on silica (dichloromethane/ammonia 7N in methanol, 100/2 to 100/4) to give the product, 110 mg (66%) as an off white solid.

[0876] LC-MS (Method 1): R.sub.t=2.13 min; MS (ES+): m/z=527/529 (M+H).sup.+

[0877] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]=1.25 (d, 3H), 1.65 (br s, 2H), 2.27 (s, 3H), 2.67 (d, 2H), 2.77 (dd, 1H), 3.05 (dd, 1H), 3.51 & 3.57 (2 d, AB, 2H), 3.71 (q, 1H), 4.10 (m, 1H), 6.31 (d, 1H), 6.91 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.42 (d, 1H), 7.46 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.34 (d, 1H).

Example 54

2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(methylsulfonyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0878] ##STR00240##

[0879] To a solution of Example 53, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 70 mg (0.133 mmol) in THF (1.5 mL) cooled to 0 C., was added successively triethylamine, 0.019 L (0.139 mmol, 1.05 eq.) and methanesulfonyl chloride, 0.010 mL (0.133 mmol, 1.0 eq.). The reaction mixture was stirred at 0 C. for 1 h. Ethyl acetate and an aqueous saturated sodium hydrogenocarbonate solution were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2). The combined organics were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (dichloromethane/methanol: 96/4) to provide the product, 68 mg (81%) as an off-white solid.

[0880] LC-MS (Method 1): R.sub.t=2.49 min; MS (ES+): m/z=605/607 (M+H).sup.+

[0881] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]=1.26 (d, 3H), 2.27 (s, 3H), 2.78 (dd, 1H), 2.96 (s, 3H), 3.09 (dd, 1H), 3.11-3.21 (m, 2H), 3.28 (s, 1H), 3.51 & 3.56 (2 d, AB, 2H), 3.67-3.75 (m, 1H), 4.28 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.27 (t, 1H), 7.45 (d, 1H), 7.49 (d, 2H), 7.53 (d, 1H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.43 (d, 1H)

Example 55

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[2-oxo-2-(piperazin-1-yl)ethyl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0882] ##STR00241##

Tert-butyl 4-{N-[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzo}amino)-3-(4-cyanophenyl)propyl]glycyl}piperazine-1-carboxylate

[0883] ##STR00242##

[0884] To a stirred solution of Example 53, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 125 mg (0.237 mmol) in acetonitrile (5.0 mL) was added triethylamine, 50 L (0.356 mmol, 1.5 eq) and tert-butyl 4-(bromoacetyl)piperazine-1-carboxylate, 95 mg (0.31 mmol, 1.3 eq.). The mixture was stirred at r.t. for 24 h. The mixture was diluted with ethyl acetate (20 mL) and the organic layer was washed successively with aq. sat. sodium hydrogen carbonate, water, brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (eluent: dichloromethane/ammonia 7N in methanol, 97/3) to give an impure fraction that was purified by preparative TLC (eluent: dichloromethane/ammonia 7N in methanol, 97.5/2.5) to give the pure product, 52 mg (29%) as an off-white solid.

[0885] LC-MS (Method 1): R.sub.t=2.50 min; MS (ES+): m/z=753/755 (M+H).sup.+, 535/537 (M+H218).sup.+

[0886] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 1.40 (s, 9H), 2.27 (s, 3H), 2.65-2.72 (m, 2H), 2.80 (dd, 1H), 3.05 (dd, 1H), 3.24-3.35 (m, 5H), 3.35-3.48 (m, 5H), 3.50 & 3.58 (2 d, AB, 2H), 3.70 (m, 1H), 4.27 (m, 1H), 6.32 (d, 1H), 6.92 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.44-7.51 (m, 4H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.40 (d, 1H).

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[2-oxo-2-(piperazin-1-yl)ethyl]amino} propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0887] To a stirred solution of tert-butyl 4-{N-[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}amino)-3-(4-cyanophenyl)propyl]-glycyl}piperazine-1-carboxylate, 52 mg (0.069 mmol) in dichloromethane (1.5 mL) and dioxane (1.5 mL) was added slowly hydrochloric acid, 0.173 mL (4M in 1,4-dioxane, 0.69 mmol, 10 eq.) at 0 C. and the resulting mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated to dryness. The resulting solid was partitioned between aq. sat. sodium hydrogen carbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (silica, DCM/ammonia 7N in methanol, 96/4) to give an impure product that was purified a second time by preparative TLC (silica, DCM/ammonia 7N in methanol, 97/3) to give the pure product, 31 mg (69%) as an off white solid.

[0888] LC-MS (Method 1): R.sub.t=2.08 min; MS (ES+): m/z=653/655 (M+H).sup.+; 535/537 (M118+H).sup.+

[0889] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 2.27 (s, 3H), 2.60-2.71 (m, 6H), 2.80 (dd, 1H), 3.06 (dd, 1H), 3.31-3.46 (m, 6H), 3.51 & 3.58 (2 d, AB, 2H), 3.71 (q, 1H), 4.28 (m, 1H), 6.31 (d, 1H), 6.93 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.44-7.51 (m, 4H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.41 (d, 1H).

Example 56

N-[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}amino)-3-(4-cyanophenyl)propyl]piperidine-4-carboxamide

[0890] ##STR00243##

Tert-butyl 4-{[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}amino)-3-(4-cyanophenyl)propyl]carbamoyl}piperidine-1-carboxylate

[0891] ##STR00244##

[0892] To a stirred solution of N-Boc-isonipecotic acid, 53 mg (0.228 mmol) in tetrahydrofuran (3 mL) were added TBTU, 73 mg (0.228 mmol, 1.0 eq.) and triethylamine, 0.095 mL (0.683 mmol, 3.0 eq.) at r.t. After 20 min, Example 53, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 120 mg (0.228 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 5 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed successively with water, aq. sat. sodium hydrogen carbonate, brine, dried over sodium sulfate and concentrated. The residue (156 mg) was purified by preparative TLC (eluent: dichloromethane/methanol, 97/3) to give the product, 110 mg (62%) as a light yellow solid.

[0893] LC-MS (Method 1): R.sub.t=2.66 min; MS (ES+): m/z=738/740 (M+H).sup.+

[0894] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 1.36 (s, 9H), 1.32-1.47 (m, 3H), 1.61-1.72 (m, 2H), 2.27 (s, 3H), 2.28-2.33 (m, 1H), 2.70 (m, 2H), 2.76 (dd, 1H), 2.95 (dd, 1H), 3.21-3.35 (m, 2H), 3.51 & 3.57 (2 d, AB, 2H), 3.71 (q, 1H), 3.84-3.96 (m, 2H), 4.30 (m, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.41-7.48 (m, 3H), 7.51 (d, 1H), 7.65 (dd, 1H), 7.76 (d, 2H), 7.96 (t, 1H), 8.34 (d, 1H)

N-[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]-benzoyl}amino)-3-(4-cyanophenyl)propyl]piperidine-4-carboxamide

[0895] To a stirred solution of tert-butyl 4-{[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)-2-furyl]benzoyl}amino)-3-(4-cyanophenyl)propyl]-carbamoyl}piperidine-1-carboxylate, 110 mg (0.149 mmol) in dichloromethane (4 mL) was added slowly hydrochloric acid, 0.37 mL (4M in 1,4-dioxane, 1.49 mmol, 10 eq.) at 0 C. and the resulting mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated to dryness. The resulting solid was partitioned between aq. sat. sodium hydrogen carbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (silica, DCM/ammonia 7N in methanol, 94/6) to give the product, 58 mg (60%) as an off-white solid.

[0896] LC-MS (Method 1): R.sub.t=2.18 min; MS (ES+): m/z=638/640 (M+H).sup.+; 520/522 (M118+H).sup.+

[0897] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 1.39-1.49 (m, 2H), 1.54-1.63 (m, 2H), 2.13-2.21 (m, 1H), 2.27 (s, 3H), 2.37-2.45 (m, 2H), 2.76 (dd, 1H), 2.86-2.93 (m, 2H), 2.95 (dd, 1H), 3.19-3.28 (m, 2H), 3.50 & 3.58 (2 d, AB, 2H), 3.71 (q, 1H), 4.29 (m, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.45-7.51 (m, 4H), 7.66 (dd, 1H), 7.76 (d, 2H), 7.83 (t, 1H), 8.34 (d, 1H).

Example 57

2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(piperidin-4-ylacetyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0898] ##STR00245##

[0899] Using the same procedures as described for Example 56

[0900] LC-MS (Method 1): R.sub.t=2.19 min; MS (ES+): m/z=652/654 (M+H); 534/536 (M118+H).sup.+

[0901] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=0.93-1.05 (m, 2H), 1.25 (d, 3H), 1.48-1.56 (m, 2H), 1.70-1.80 (m, 1H), 1.95-2.05 (m, 2H), 2.27 (s, 3H), 2.30-2.40 (m, 2H), 2.76 (dd, 1H), 2.77-2.86 (m, 2H), 2.96 (dd, 1H), 3.27 (m, 2H), 3.51 & 3.58 (2 d, AB, 2H), 3.71 (q, 1H), 4.27 (m, 1H), 6.33 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.43-7.48 (m, 3H), 7.50 (d, 1H), 7.65 (dd, 1H), 7.76 (d, 2H), 7.94 (t, 1H), 8.34 (d, 1H)

Example 58

2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(1-methylpiperidin-4-yl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0902] ##STR00246##

[0903] To a stirred solution of Example 53, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 75 mg (0.14 mmol) and acetic acid, 16 L (0.28 mmol, 2.0 eq) in THF (2 mL) was added 1-methyl-4-piperidone, 18 mg (0.16 mmol, 1.1 eq). The mixture was stirred at r.t. for 30 min and then sodium triacetoxyborohydride, 45 mg (0.21 mmol, 1.5 eq.) was added. The mixture was stirred at r.t. for 16 h, and then diluted with ethyl acetate (20 mL) and the organic layer was washed successively with aq. sat. sodium hydrogen carbonate, water, brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (eluent: dichloromethane/ammonia 7N in methanol, 97/3) to give the product, 50 mg (56%) as a white solid.

[0904] LC-MS (Method 1): R.sub.t=2.07 min; MS (ES+): m/z=624 (M+H).sup.+.

[0905] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H and m, overlap, 2H), 1.75 (m, 2H), 1.88 (m, 2H), 2.13 (s, 3H), 2.28 (s, 3H), 2.36 (m, 1H), 2.65-2.70 (m, 4H), 2.79 (dd, 1H), 3.09 (dd, 1H), 3.51 & 3.58 (2 d, AB, 2H), 3.72 (q, 1H), 4.24 (m, 1H), 6.33 (d, 1H), 6.91 (d, 1H), 7.13 (d, 2H), 7.24 (d, 2H), 7.40 (d, 1H), 7.48 (d, 1H), 7.49 (d, 2H), 7.68 (dd, 1H), 7.77 (d, 2H), 8.37 (d, 1H).

[0906] The following examples were prepared using the same procedure, from corresponding commercially available starting material as indicated.

TABLE-US-00010 Example Starting No material Structure/Name Analytics 59 1-benzylpiperidin- 4-one [00247] LC-MS (Method 1): R.sub.t = 2.14 min; MS (ES+): m/z = 700.7 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.24 (d, 3H), 1.27 (m, 2H), 1.75 (m, 2H), 1.96 (t, 2H), 2.26 (s, 3H), 2.42 (m, 1H), 2.65-2.75 (m, 4H), 2.78 (dd, 1H), 3.08 (dd, 1H), 3.42 (s, 2H), 3.51 & 3.57 (2d, AB, 2H), 3.70 (q, 1H), 4.22 (m, 1H), 6.31 (d, 1H), 6.90 (d, 1H), 7.11 (d, 2H), 7.21-7.32 (m, 7H), 7.38 (d, 1H), 7.46 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.35 (d, 1H). 60 Benzaldehyde [00248] LC-MS (Method 1): R.sub.t = 2.34 min; MS (ES+): m/z = 617 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.26 (d, 3H), 2.28 (s, 3H), 2.64 (m, 2H), 2.81 (dd, 1H), 3.11 (dd, 1H), 3.58 (m, 2H), 3.74 (m, 3H), 4.35 (m, 1H), 6.33 (br s, 1H), 6.90 (d, 1H), 7.13 (d, 2H), 7.25 (m, 3H), 7.30-7.41 (m, 5H), 7.47 (m, 3H), 7.67 (dd, 1H), 7.76 (d, 2H), 8.39 (d, 1H). 61 2-methylpropanal [00249] LC-MS (Method 1): R.sub.t = 2.34 min; MS (ES+): m/z = 583/585 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.86 (d, 6H), 1.25 (d, 3H), 1.64 (m, 1H), 2.27 (s, 3H), 2.30-2.42 (m, 2H), 2.65 (m, 2H), 2.78 (dd, 1H), 3.07 (dd, 1H), 3.50 & 3.57 (2d, AB, 2H), 3.71 (q, 1H), 4.27 (m, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.11 (d, 2H), 7.23 (d, 2H), 7.39 (d, 1H), 7.45 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.36 (d, 1H). 62 1-ethylpiperidin- 4-one [00250] LC-MS (Method 1): R.sub.t = 1.99 min; MS (ES+): m/z = 638/640 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.97 (t, 3H), 1.22 (m, 2H), 1.25 (d, 3H), 1.61 (br s, 1H), 1.74 (m, 2H), 1.86 (m, 2H), 2.24-2.29 (m, 2H and s, overlap, 3H), 2.39 (m, 1H), 2.68 (d, 2H), 2.75-2.81 (m, 3H), 3.09 (dd, 1H), 3.50 & 3.58 (2d, AB, 2H), 3.71 (q, 1H), 4.22 (m, 1H), 6.31 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.39 (d, 1H), 7.47 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.36 (d, 1H). 63 1-isobutylpiperidin- 4-one [00251] LC-MS (Method 1): R.sub.t = 2.02 min; MS (ES+): m/z = 666/668 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.84 (d, 6H), 1.25 (m, 5H), 1.60-1.75 (m, 4H), 1.85 (t, 2H), 1.98 (d, 2H), 2.28 (s, 3H), 2.38 (m, 1H), 2.68- 2.74 (m, 4H), 2.77 (dd, 1H), 3.10 (dd, 1H), 3.50 & 3.58 (2d, AB, 2H), 3.72 (m, 1H), 4.23 (m, 1H), 6.32 (d, 1H), 6.91 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.40 (d, 1H), 7.47 (d. 1H), 7.48 (d, 2H), 7.67 (dd, 1H), 7.77 (d, 2H), 8.36 (d, 1H) 64 tert-butyl 4- oxopiperidine- 1-carboxylate [00252] LC-MS (Method 1): R.sub.t = 2.33 min; MS (ES+): m/z = 710 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.12 (m, 2H), 1.25 (d, 3H), 1.40 (s, 9H), 1.75 (m, 3H), 2.28 (s, 3H), 2.61 (m, 1H), 2.70 (d, 2H), 2.76-2.82 (m, 3H), 3.10 (dd, 1H), 3.50 & 3.58 (2d, AB, 2H), 3.72 (m, 1H), 3.80 (br d, 2H), 4.24 (m, 1H), 6.33 (d, 1H), 6.91 (d, 1H), 7.13 (d, 2H), 7.24 (d, 2H), 7.39 (d, 1H), 7.48 (d, 1H), 7.49 (d, 2H), 7.68 (dd, 1H), 7.77 (d, 2H), 8.37 (d, 1H). 65 1-methylpiperidin- 3-one [00253] LC-MS (Method 1): R.sub.t = 2.24 min; MS (ES+): m/z = 624/626 (M + H).sup.+, 506/508 (M + H-118).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.00 (m, 1H), 1.25 (d, 3H), 1.42 (m, 1H), 1.55-1.78 (m, 4H), 1.85 (m, 1H), 2.11-2.13 (2s, 3H), 2.27 (s, 3H), 2.54-2.75 (m, 4H), 2.78 (dd, 1H), 3.07 (dd, 1H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (q, 1H), 4.20 (m, 1H), 6.32 (d, 1H), 6.90 & 6.91 (2d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.38 & 7.40 (2d, 1H), 7.45-7.50 (m, 3H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.36 & 8.38 (2d, 1H). 66.sup.Boc tert-butyl (1R,5S,6r)- 6-formyl-3-azabicyclo [3.1.0]hexane-3-carboxy- late [419572-19-3] [00254] LC-MS (Method 1): R.sub.t = 2.50 min; MS (ES+): m/z = 722/724 (M + H).sup.+, 604/606 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.6 (m, 1H), 1.25 (d, 3H), 1.35 (m, 1H), 1.36 (s, 9H), 1.77 (m, 1H), 2.27 (s, 3H), 2.47 (m, 2H), 2.62-2.71 (m, 2H), 2.80 (dd, 1H), 3.06 (dd, 1H), 3.18-3.28 (m, 2H), 3.39 (t, 2H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (q, 1H), 4.27 (m, 1H), 6.32 (d, 1H), 6.91 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.40 (d, 1H), 7.45-7.51 (m, 3H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.37 (d, 1H).

Example 66

N-[(2R)-1-{[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethyl]amino}-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0907] ##STR00255##

[0908] To a stirred solution of, tert-butyl (1R,5S,6r)-6-({[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}amino)-3-(4-cyanophenyl)propyl]amino}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate, 82 mg (0.114 mmol) in dichloromethane (2 mL) was added slowly hydrochloric acid, 0.28 mL (4M in 1,4-dioxane, 1.265 mmol, 10 eq.) at 0 C. and the resulting mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated to dryness. The resulting solid was partitioned between aq. sat. sodium hydrogen carbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (silica, DCM/ammonia 7N in methanol, 94/6) to give the product, 66 mg (89%) as a beige solid.

[0909] LC-MS (Method 1): R.sub.t=2.27 min; MS (ES+): m/z=622/624 (M+H).sup.+; 504/506 (M118+H).sup.+

[0910] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=0.8 (m, 1H), 1.12-1.20 (m, 2H), 1.24 (m, 1H), 1.25 (d, 3H), 1.36 (m, 1H), 2.27 (s, 3H), 2.60 (dd, 2H), 2.65-2.68 (m, 2H), 2.75-2.82 (m, 3H), 3.06 (dd, 1H), 3.26-3.31 (m, 2H), 3.51 & 3.58 (2 d, AB, 2H), 3.71 (q, 1H), 4.26 (m, 1H), 6.32 (d, 1H), 6.91 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.38 (d, 1H), 7.45-7.51 (m, 3H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.37 (d, 1H).

[0911] The following examples were prepared using the same procedure, from corresponding N-Boc intermediates as indicated. The N-Boc intermediates were prepared in analogy to Example 55 and 56, from the corresponding commercially available starting material and Example 53 as indicated.

TABLE-US-00011 Example Inter- No mediate Structure/Name Analytics 67 64 [00256] LC-MS (Method 1): R.sub.t = 1.97 min; MS (ES+): m/z = 610/612 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.10-1.25 (m, 3H), 1.25 (d, 3H), 1.76 (m, 2H), 2.26 (s, 3H), 2.53 (m, overlap with DMSO signal, 1H), 2.68 (d, 2H), 2.77 (dd, 1H), 2.96 (br d, 2H), 3.09 (dd, 1H), 3.35-3.50 (m, 1H), 3.50 & 3.57 (2d, AB, 2H), 3.71 (q, 1H), 4.22 (m, 1H), 6.31 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.38 (d, 1H), 7.46 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.37 (d, 1H). 68 68.sup.Boc [00257] LC-MS (Method 1): R.sub.t = 2.11 min; MS (ES+): m/z = 638/640 (M + H)+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.85-1.00 (m, 2H), 1.02 (m, 6H), 1.25 (d, 3H), 1.62 (br d, 1H), 1.77 (t, 1H), 2.27 (s, 3H), 2.57-2.83 (m, 6H), 3.07 (m, 1H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (q, 1H), 4.22 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.38 (d, 1H), 7.45-7.50 (m, 3H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.34 & 8.35 (2d, 1H, epimer 1 & 2). The product was obtained as a 1/1 mixture of epimers. 68.sup.Boc tert-butyl 2,2-dimethyl- 4-oxopiperidine-1- carboxylate [00258] LC-MS (Method 1): R.sub.t = 2.49 min; MS (ES+): m/z = 738/740 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.15 (m, 1H), 1.24 (s, 3H), 1.26 (d, 3H), 1.33 (m, 2H), 1.40 (s, 9H), 1.44 (s, 3H), 1.65 (m, 1H), 1.87 (m, 1H), 2.28 (s, 3H), 2.65-2.84 (m, 3H), 3.06-3.13 (m, 2H), 3.52 & 3.59 (2d, AB, 2H), 3.65 (m, 1H), 3.72 (q, 1H), 4.24 (m, 1H), 6.32 (d, 1H), 6.91 (d, 1H), 7.13 (d, 2H), 7.24 (d, 2H), 7.40 (br s, IH), 7.48 (d, 1H), 7.49 (d, 2H), 7.67 (br d, 1H), 7.77 (d, 2H), 8.37 & 8.38 (2d, 1H, epimer 1 & 2). The product was obtained as a 1/1 mixture of epimers. 69 69.sup.Boc [00259] LC-MS (Method 1): R.sub.t = 2.11 min; MS (ES+): m/z = 624/626 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.00 (m, 2H), 1.23 (m, 1H), 1.24 (d, 3H), 1.38 (m, 1H), 1.61 (m, 2H), 2.27 (s, 3H), 2.34- 2.45 (m, 4H), 2.63 (m, 1H), 2.77 (dd, 1H), 2.88 (br d, 2H), 3.06 (dd, 1H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (q, 1H), 4.26 (m, 1H), 6.32 (d, 1H), 6.89 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.38 (d, 1H), 7.46 (d, 1H), 7.47 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.35 (d, 1H). 69.sup.Boc tert-butyl 4-formylpiperidine- 1-carboxylate [00260] LC-MS (Method 1): R.sub.t = 2.59 min; MS (ES+): m/z = 724/726 (M + H).sup.+. 70 70.sup.Boc [00261] LC-MS (Method 1): R.sub.t = 2.06 min; MS (ES+): m/z = 638/640 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.18 (m, 2H), 1.25 (d, 3H), 1.34 (q, 2H), 1.55 (m, 1H), 1.73 (br d, 2H), 2.27 (s, 3H), 2.50-2.72 (m, 6H), 2.77 (dd, 1H), 3.07 (dd, 1H), 3.12 (br d, 2H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (q, 1H), 4.27 (m, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.38 (d, 1H), 7.46 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.36 (d, 1H). 70.sup.Boc tert-butyl 4-(2-oxoethyl) piperidine-1-carboxylate [00262] LC-MS (Method 1): R.sub.t = 2.71 min; MS (ES+): m/z = 738/740 (M + H).sup.+. 71 71.sup.Boc Diastereomer 1 [00263] LC-MS (Method 1): R.sub.t = 2.10 min; MS (ES+): m/z = 624/626 (M + H).sup.+; 506/508 (M-118 + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.24 (m, 1H), 1.25 (d, 3H), 1.38- 1.49 (m, 6H), 1.50-1.60 (m, 2H), 2.27 (s, 3H), 2.55- 2.75 (m, 5H), 2.79 (dd, 1H), 3.11 (dd, 1H), 3.51 & 3.58 (2d, AB, 2H), 3.70 (q, 1H), 4.24 (m, 1 H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.37 (d, 1H), 7.45-7.51 (m, 3H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.38 (d, 1H) 72 72.sup.Boc Diastereomer 2 [00264] LC-MS (Method 1): R.sub.t = 2.14 min; MS (ES+): m/z = 624/626 (M + H).sup.+; 506/508 (M-118 + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.00 (m, 4H), 1.25 (d, 3H), 1.71 (m, 2H), 1.80 (m, 2H), 2.27 (s, 3H), 2.36 (m, 1H), 2.47 (m, 1H), 2.66 (m, 2H), 2.77 (dd, 1H), 3.07 (dd, 1H), 3.50 & 3.58 (2d, AB, 2H), 3.71 (q, 1H), 4.22 (m, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.23 (d, 2H), 7.38 (d, 1H), 7.46 (d, 1H), 7.48 (d, 2H), 7.66 (dd, 1H), 7.76 (d, 2H), 8.35 (d, IH). 71/72.sup.Boc tert-butyl (4-oxocyclohexyl) carbamate [00265] Two isomers were isolated (cis and trans). The relative stereochemistry was not assigned. Diastereomer 1: LC-MS (Method 1): R.sub.t = 2.45 min; MS (ES+): m/z = 724/726 (M + H).sup.+, 606/608 (M-118 + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.25 (d, 3H), 1.37 (s, 9H), 1.39- 1.64 (m, 9H), 2.27 (s, 3H), 2.56-2.70 (m, 3H), 2.78 (dd, 1H), 3.12 (dd, 1H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (m, 1H), 4.24 (m, 1H), 6.32 (d, 1H), 6.64 (br d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.38 (d, 1H), 7.45- 7.51 (m, 3H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.37 (d, 1H) Diastereomer 2: LC-MS (Method 1): R.sub.t = 2.40 min; MS (ES+): m/z = 724/726 (M + H).sup.+, 606/608 (M-118 + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 0.96- 1.09 (m, 2H), 1.10-1.20 (m, 2H), 1.25 (d, 3H), 1.37 (s, 9H), 1.67-1.90 (m, 4H), 2.27 (s, 3H), 2.33 (m, 1H), 2.64-2.71 (m, 2H), 2.77 (dd, 1H), 3.08 (dd, 1H), 3.16 (m, 1H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (m, 1H), 4.22 (m, 1H), 6.32 (d, 1H), 6.66 (br d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.38 (d, 1H), 7.45-7.51 (m, 3H), 7.66 (dd, 1H), 7.77 (d, 2H), 8.36 (d, 1H) 73 73.sup.Boc [00266] LC-MS (Method 1): R.sub.t = 2.17 min; MS (ES+): m/z = 628/630 (M + H).sup.+; 510/512 (M-118 + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.25 (d, 3H), 1.32-1.43 (m, 1H), 1.55-1.66 (m, 1H), 2.27 (s, 3H), 2.38-2.92 (m, 7H), 3.03-3.13 (m, 2H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (q, 1H), 4.24 (m, 1H), 4.56 & 4.67 (2d, 1H), 6.32 (d, 1H), 6.90 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.38 (t, 1H), 7.45-7.51 (m, 3H), 7.66 (d, 1H), 7.76 (d, 2H), 8.40 (d, 1H). The product was obtained as a 1/1 mixture of epimers. 73.sup.Boc tert-butyl 3-fluoro-4- oxopiperidine-1- carboxylate [211108-50-8] [00267] LC-MS (Method 1): R.sub.t = 2.41 min; MS (ES+): m/z = 728/730 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.25 (d, 3H), 1.39 (s, 9H), 1.68 (m, 1H), 1.79 (m, 1H), 2.27 (s, 3H), 2.62-2.86 (m, 5H), 3.05-3.19 (m, 2H), 3.51 & 3.58 (2d, AB, 2H), 3.71 (m, 1H), 3.91 (m, 1H), 4.13 (m, 1H), 4.24 (m, 1H), 4.69 & 4.80 (2d, 1H), 6.32 (d, 1H), 6.91 (d, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.38 (s, 1H), 7.45-7.51 (m, 3H), 7.67 (d, 1H), 7.77 (d, 2H), 8.40 (d, 1H). The product was obtained as a 1/1 mixture of epimers.

Example 74

N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-{5-[({2-[4-(trifluoro-methyl)phenyl]propan-2-yl}amino)methyl]-2-furyl}benzamide

[0912] ##STR00268##

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-propan-2-yl]-5-{5-[({2-[4-trifluoromethyl)phenyl]propan-2-}amino)methyl]-2-furyl}benzamide

[0913] ##STR00269##

[0914] A suspension of intermediate 4A, 2-chloro-5-{5-[({2-[4-(trifluoromethyl)-phenyl]propan-2-yl}amino)methyl]-2-furyl}benzoic acid, 75 mg (0.17 mmol) in acetonitrile (2 mL) was treated with triethylamine, 48 L (0.34 mmol) and TBTU, 83 mg (0.26 mmol). The orange solution was then stirred at r.t. for 45 minutes before addition of intermediate 52B, 4-[(2R)-2-amino-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]benzonitrile hydrochloride (1:1), 88 mg (0.26 mmol). The reaction medium was stirred at r.t. for 17 h. The reaction medium was concentrated to dryness. The residue was taken up in dichloromethane and washed with aq. sat. bicarbonate solution, aq. 1 N hydrochloric acid solution and water before being dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (eluent: dichloromethane/ethyl acetate, 1/0 to 6/4) to afford the product, 77 mg (53%) as an orange solid.

[0915] LC-MS (Method 1): R.sub.t=2.87 min; MS (ES+) m/z=725/727 (M+H).sup.+

[0916] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]=1.48 (s, 6H), 2.87 (dd, 1H), 3.14 (dd, 1H), 3.51 (s, 2H), 3.79-3.87 (m, 2H), 4.59 (m, 1H), 6.39 (d, 1H), 6.84 (d, 1H), 7.29 (d, 1H), 7.36 (d, 1H), 7.50 (d, 2H), 7.61 (dd, 1H), 7.68 (d, 2H), 7.75 (d, 2H), 7.78-7.80 (m, 4H), 7.86-7.88 (m, 2H), 8.52 (d, 1H).

N-[(2R)-1-amino-3-4-cyanophenyl)propan-2-yl]-2-chloro-5-{5-[({2-[4-(trifluoro-methyl)phenyl]propan-2-yl}amino)methyl]-2-furyl}benzamide

[0917] To a stirred solution of 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propan-2-yl]-5-{5-[({2-[4-(trifluoromethyl)phenyl]propan-2-yl}-amino)methyl]-2-furyl}benzamide, 75 mg (0.10 mmol) in absolute ethanol (1.7 mL) was added hydrazine, 0.52 mL (1M in THF, 0.52 mmol, 5 eq.). The resulting solution was stirred at 70 C. for 3 h. The reaction medium (yellow suspension) was filtered and rinsed with ethyl acetate. The filtrate was concentrated and the residue obtained (60 mg) was purified by preparative TLC on silica (dichloromethane/ammonia 7N in methanol, 95/5) to give the product, 36 mg (57%) as an off white solid.

[0918] LC-MS (Method 1): R.sub.t=0.46 & 2.25 min; MS (ES+): m/z=595/597 (M+H).sup.+

[0919] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]=1.46 (s, 6H), 1.84 (br s, 2H), 2.67 (d, 2H), 2.77 (dd, 2H), 3.05 (dd, 1H), 3.47 (s, 2H), 4.09-4.13 (m, 1H), 6.35 (d, 1H), 6.90 (d, 1H), 7.43 (d, 1H), 7.46-7.49 (m, 3H), 7.65-7.68 (m, 3H), 7.75-7.78 (m, 4H), 8.35 (d, 1H).

Example 75

N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-{5-[({(1R)-1-1-[4-(trifluoromethyl)phenyl]ethyl}amino)methyl]-2-furyl}benzamide

[0920] ##STR00270##

[0921] Obtained through the same sequence as described for example 74, starting from (1R)-1-[4-(trifluoromethyl)phenyl]ethylamine in the synthesis of intermediate 4A.

[0922] LC-MS (Method 1): R.sub.t=2.24 min; MS (ES+): m/z=581/583 (M+H).sup.+

[0923] .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm]=1.40 (d, 3H), 2.79-2.93 (m, 3H), 3.11 (dd, 1H), 3.65 & 3.69 (2d, AB, 2H), 3.92 (q, 1H), 4.37-4.43 (m, 1H), 6.29 (d, 1H), 6.71 (d, 1H), 7.42 (d, 1H), 7.46 (d, 1H), 7.50 (d, 2H), 7.55 (d, 2H), 7.62 (d, 2H), 7.67 (m, 3H).

Example 76

Cis-chloro-N-[4-(4-cyanophenyl)piperidin-3-yl]-5-[5-({[(1R)-1-(4-methylphenyl)-ethyl]amino}methyl)-2-furyl]benzamide

[0924] ##STR00271##

Tert-butyl 6-(4-cyanophenyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0925] ##STR00272##

[0926] To a cooled (0 C.) solution of tert-butyl 4-(4-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, 498 mg (1.75 mmol) in dichloromethane (8 mL) was added m-chloroperoxybenzoic acid, 647 mg (2.63 mmol, 1.5 eq.). The reaction mixture was stirred at r.t. overnight. A mixture of aqueous saturated sodium thiosulfate solution and aqueous saturated sodium hydrogen carbonate solution was added to the mixture. After 20 min stirring, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organics were washed with water, brine, dried over sodium sulfate, filtered and concentrated to dryness. The oily residue (560 mg) was purified by chromatography on silica gel (40 g column, cyclohexane/ethyl acetate: 95/5 to 60/40) to provide the pure epoxide, 400 mg (72%) as a light yellow oil.

[0927] LC-MS (Method 1): R.sub.t=3.53 min; MS (ES+) m/z=245 (M+H56).sup.+, 201 (M+H-Boc).sup.+

[0928] .sup.1H-NMR (500 MHz, CDCl.sub.3) [ppm]=1.48 (s, 9H), 2.15 (br d, 1H), 2.41-2.50 (m, 1H), 3.13-3.21 (m, 2H), 3.68 (br d, 1H), 3.79 (br s, 1H), 3.97-4.16 (m, 1H), 7.47 (d, 2H), 7.67 (d, 2H)

[0929] R.sub.f=0.46 (cyclohexane/ettyl acetate: 70/30)

Tert-butyl 4-(4-cyanophenyl)-3-hydroxypiperidine-1-carboxylate

[0930] ##STR00273##

[0931] A solution of tert-butyl (1R,6R)-6-(4-cyanophenyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate, 400 mg (1.33 mmol) in methanol (25 mL) and triethylamine, 1.48 mL (10.65 mmol, 8.0 eq.) was passed through a 10% w/w Pd/C cartridge on a H-Cube apparatus (pH2=10 bars, flow=0.5 mL/min, 25 C.). The reaction mixture was concentrated under reduced pressure to give the product, 390 mg (97%) as an off-white solid.

[0932] LC-MS (Method 1): R.sub.t=3.23 min; MS (ES+): m/z=247 (M+H-56).sup.+

[0933] .sup.1H-NMR (500 MHz, CDCl.sub.3) [ppm]=1.48 (s, 9H), 1.63 (brd, 2H), 2.19-2.30 (m, 1H), 2.79-2.89 (m, 2H), 3.02 (d, 1H), 3.98 (s, 1H), 4.31 (br d, 2H), 7.41 (d, 2H), 7.63 (dd, 2H)

[0934] R.sub.f=0.26 (cyclohexane/ethyl acetate: 70/30)

Tert-butyl 4-(4-cyanophenyl)-3-oxopiperidine-1-carboxylate

[0935] ##STR00274##

[0936] To a solution of tert-butyl 4-(4-cyanophenyl)-3-hydroxypiperidine-1-carboxylate, 500 mg (1.65 mmol) in dichloromethane (32 mL) was added Dess-Martin periodinane, 842 mg (1.98 mmol, 1.2 eq). The reaction mixture was stirred at r.t. for 2.5 h. The heterogeneous reaction was treated with a mixture of aqueous saturated sodium thiosulfate solution and aqueous saturated sodium hydrogen carbonate solution. After stirring for 20 min, the phases were separated and the aqueous phase was extracted with dichloromethane (4), dried over sodium sulfate, filtered and concentrated to dryness. The oily residue was purified by chromatography on silica gel (column 12 g, cyclohexane/ethyl acetate: 95/5 to 40/60) to provide the product, 355 mg (68%) as a yellow oil.

[0937] LC-MS (Method 1): R.sub.t=3.09 & 3.35 min; MS (ES+): m/z=301 (M+H).sup.+.

[0938] .sup.1H-NMR (500 MHz, CDCl.sub.3) [ppm]=1.49 (s, 9H), 2.17-2.27 (m, 1H), 2.29-2.37 (m, 1H), 3.48-3.58 (m, 1H), 3.71 (dd, 1H), 3.95-4.13 (m, 2H), 4.26 (d, 1H), 7.25 (d, 2H), 7.65 (d, 2H).

Tert-butyl 3-amino-4-(4-cyanophenyl)piperidine-1-carboxylate

[0939] ##STR00275##

[0940] Under argon, tert-butyl 4-(4-cyanophenyl)-3-oxopiperidine-1-carboxylate, 150 mg (0.50 mmol) was dissolved in anhydrous methanol, 5 mL, and cooled at 0 C. Ammonium acetate, 385 mg (dried by azeotropic evaporation with toluene, 5.0 mmol, 10 eq.) was added. The resulting mixture was stirred at 0 C. 30 min, then sodium cyanoborohydride, 47 mg (0.75 mmol, 1.5 eq.) was added and the mixture stirred at r.t. for 5 h and then at 50 C. for 2 h. The reaction mixture was then stored at 20 C. for 3 days. The mixture was concentrated, the residue partitioned between ethyl acetate and aq. 1M sodium hydroxide solution. The aqueous phase was extracted using ethyl acetate. The combined organic phases were concentrated, the residue was partitioned between MTBE and a 0.5 N hydrochloric acid solution. The phase were separated and the aqueous phase was extracted with MTBE. The acidic solution was then made basic using 2N sodium hydroxide, and extracted using ethyl acetate. The organic phase obtained was dried over sodium sulfate and concentrated to give the crude expected amine, 65 mg (39%). The crude product was used without further purification.

[0941] LC-MS (Method 1): R.sub.t=2.10 & 2.21 min; MS (ES+): m/z=302 (M+H).sup.+, 246 (M+HtBu)+

Tert-butyl 3-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl-2-furyl]-benzoyl}amino)-4-(4-cyanophenyl)piperidine-1-carboxylate

[0942] ##STR00276##

[0943] To a stirred solution of intermediate 1A, 2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoic acid, 75 mg (0.203 mmol) in tetrahydrofuran (2.0 mL) were added TBTU, 65 mg (0.203 mmol, 1 eq.) and triethylamine, 0.11 mL (0.811 mmol, 4 eq.) at r.t. After 20 min, tert-butyl 3-amino-4-(4-cyanophenyl)piperidine-1-carboxylate (mixture of cis and trans isomers), 64 mg (0.213 mmol, 1.05 eq.) was added and the resulting mixture was stirred at r.t. for 16 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed successively with aq. sat. sodium hydrogen carbonate, water, brine, dried over sodium sulfate and concentrated. The residue (142 mg) was purified by preparative TLC (eluent: dichloromethane/methanol, 97/3). The product obtained was contaminated with residual tetramethylurea, thus it was taken up in MTBE (20 mL) and washed with a 1/1 mixture of aq. sat. sodium hydrogen carbonate and water (410 mL), then with brine, dried over sodium sulfate, filtered an concentrated to give the desired product, 70 mg (51%) as an off-white solid. The product was obtained as a mixture of cis and trans stereoisomers. .sup.1H-NMR analysis showed a 85/15 ratio of cis/trans stereoisomers.

[0944] LC-MS (Method 1): R.sub.t=2.78 min; MS (ES+): m/z=653/655 (M+H).sup.+

[0945] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]=1.25 (d, 3H), 1.35 (m, 1H), 1.45 (s, 9H), 1.64-1.76 (m, 1H), 1.78-1.85 (m, 1H), 2.27 (s, 3H), 2.74-2.94 (m, 2H), 3.50 & 3.57 (2d, AB, 2H), 3.71 (m, 1H), 4.00-4.15 (m, 2H), 4.25 (m, 1H), 6.30 (t, 1H), 6.86 (d, 1H), 7.13 (d, 2H), 7.21 (t, 1H), 7.24 (d, 2H), 7.40 (d, 1H), 7.51 (d, 2H), 7.62 (dd, 1H), 7.77 (dd, 2H), 8.44 (d, 1H).

Trans-chloro-N-[4-(4-cyanophenyl)piperidin-3-yl]-5-[5-({[(1R)-1-(4-methylphenyl)-ethyl]amino}methyl)-2-furyl]benzamide and cis-chloro-N-[4-(4-cyanophenyl)piperidin-3-yl]-5-[5-({[(1R)-1-(4-methylphenyl)-ethyl]amino}methyl)-2-furyl]benzamide

[0946] To a stirred solution of tert-butyl 3-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]-amino}methyl)-2-furyl]benzoyl}amino)-4-(4-cyanophenyl)piperidine-1-carboxylate, 70 mg (0.107 mmol) in dichloromethane (3 mL) was added slowly hydrochloric acid, 0.27 mL (4M in 1,4-dioxane, 1.07 mmol, 10 eq.) at 0 C. and the resulting mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated to dryness. The resulting solid was partitioned between aq. sat. sodium hydrogen carbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate (4). The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (silica, DCM/ammonia 7N in methanol, 96/4) to give the trans isomer, 36 mg (60%, 1/1 mixture of stereoisomers) as an off-white solid.

[0947] LC-MS (Method 1): R.sub.t=2.15 min; MS (ES+): m/z=553/555 (M+H); 435/437 (M118+H).sup.+

[0948] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 1.59-1.70 (m, 1H), 1.72-1.79 (m, 1H), 2.27 (s, 3H), 2.43 (t, 1H), 2.50-2.56 (m, 1H), 2.79 (td, 1H), 2.98 (br d, 1H), 3.15 (dd, 1H), 3.50 & 3.57 (2 d, AB, 2H), 3.70 (quint, 1H), 4.10 (m, 1H), 6.30 (app t, 1H), 6.84 (d, 1H), 7.12 (d, 2H), 7.16 (d, 1H), 7.23 (d, 2H), 7.39 (d, 1H), 7.48 (app dd, 2H), 7.61 (app dd, 1H), 7.77 (app dd, 2H), 8.28 (d, 1H)

and the cis isomer, 3.3 mg (5%, 1/1 mixture of stereoisomers), as an off-white solid,

[0949] LC-MS (Method 1): R.sub.t=2.22 min; MS (ES+): m/z=553/555 (M+H).sup.+; 435/437 (M118+H).sup.+,

[0950] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 1.50-1.56 (m, 1H), 2.07-2.19 (m, 1H), 2.26 (s, 3H), 2.57-2.62 (m, 1H), 2.89-3.99 (m, 2H), 3.03-3.08 (br d, 1H), 3.16 (dt, 1H), 3.53 & 3.60 (2 d, AB, 2H), 3.72 (quint, 1H), 4.36 (m, 1H), 6.32 (app t, 1H), 6.89 (app dd, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.27 (app t, 1H), 7.43 (d, 1H), 7.51 (d, 2H), 7.64 (m, 1H), 7.77 (app dd, 2H), 8.39 (app dd, 1H).

[0951] 2D NMR COSY analysis allowed to assign the cis stereochemistry thanks to the multiplicity and .sup.3J coupling constant of proton signals on cyclohexane ring especially proton on the same C as phenyl group (HC-Ph):

trans isomer: =2.79 ppm=td, .sup.3J=12.8 Hz, 4.6 Hz, two axial-axial J.
cis-isomer: =3.16 ppm, dt, .sup.3J=13.3 Hz, 3.6 Hz, one axial-axial J.

Example 77

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-3-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0952] ##STR00277##

[0953] To a stirred solution of intermediate 3A, 2-chloro-3-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoic acid, 42 mg (0.11 mmol) in tetrahydrofuran (3 mL) were added TBTU, 38 mg (0.12 mmol, 1.1 eq.) and triethylamine, 0.045 mL (0.33 mmol, 3 eq.) at r.t. After 20 min, 15B, 4-[(2R)-2-amino-3-hydroxypropyl]benzonitrile hydrochloride (1:1), 21 mg (0.12 mmol, 1.1 eq.) was added and the resulting mixture was stirred at r.t. for 16 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed successively with aq. sat. sodium hydrogen carbonate, water, brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (eluent: dichloromethane/7N ammonia in methanol, 97/3) to give the product, 40 mg (66%) as a beige solid.

[0954] LC-MS (Method 1): R.sub.t=2.46 min; MS (ES+): m/z=546/548 (M+H).sup.+.

[0955] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 2.27 (s, 3H), 2.77 (dd, 1H), 3.08 (dd, 1H), 3.44 (m, 1H), 3.50-3.60 (m, 3H), 3.70 (q, 1H), 4.19 (m, 1H), 4.95 (t, 1H), 6.34 (d, 1H), 7.02 (d, 1H), 7.12 (d, 2H), 7.22 (d, 2H), 7.31 (d, 1H), 7.48 (d, 2H), 7.71 (dd, 1H), 7.76 (d, 2H), 8.47 (d, 1H).

Example 78

2,4-dichloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0956] ##STR00278##

[0957] To a stirred solution of intermediate 5A, 2,4-dichloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoic acid, 75 mg (0.186 mmol) in tetrahydrofuran (1.9 mL) were added TBTU, 63 mg (0.195 mmol, 1.05 eq.) and triethylamine, 78 L (0.557 mmol, 3 eq.) at r.t. After 20 min, 15B, 4-[(2R)-2-amino-3-hydroxypropyl]benzonitrile hydrochloride (1:1), 43 mg (0.204 mmol, 1.1 eq.) was added and the resulting mixture was stirred at r.t. for 2 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (40 mL). The organic layer was washed successively with aq. sat. sodium hydrogen carbonate, water, brine, dried over sodium sulfate and concentrated. The residue (94 mg, orange oil) was purified by preparative TLC (eluent: dichloromethane/methanol, 95/5) to give the product, 50 mg (48%) as an orange foam.

[0958] LC-MS (Method 1): R.sub.t=2.49 min; MS (ES+): m/z=562/564 (M+H).sup.+.

[0959] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 2.26 (s, 3H), 2.77 (dd, 1H), 3.08 (dd, 1H), 3.43 (m, 1H), 3.51-3.57 (m, 2H), 3.61 (d, 1H), 3.73 (q, 1H), 4.18 (m, 1H), 4.95 (t, 1H), 6.40 (d, 1H), 7.11-7.12 (m, 3H), 7.24 (d, 2H), 7.47 (d, 2H), 7.63 (s, 1H), 7.71 (s, 1H), 7.73 (d, 2H), 8.44 (d, 1H).

Example 79

4-cyano-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-3-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0960] ##STR00279##

[0961] To a stirred solution of intermediate 6A, 4-cyano-3-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoic acid, 50 mg (0.139 mmol) in tetrahydrofuran (1.4 mL) were added TBTU, 47 mg (0.146 mmol, 1.05 eq.) and triethylamine, 58 L (0.416 mmol, 3 eq.) at r.t. After 30 min, 15B, 4-[(2R)-2-amino-3-hydroxypropyl]benzonitrile hydrochloride (1:1), 30 mg (0.139 mmol) was added and the resulting mixture was stirred at r.t. for 2 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed successively with aq. 1N hydrochloric acid, aq. sat. sodium hydrogen carbonate, water (2) and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane/methanol, 95/5) to give the product, 54 mg (75%) as a light yellow foam.

[0962] LC-MS (Method 1): R.sub.t=2.39 min; MS (ES+): m/z=519 (M+H).sup.+.

[0963] 1H-NMR (500 MHz, DMSO-d6) [ppm]=1.26 (d, 3H), 2.26 (s, 3H), 2.88 (dd, 1H), 3.06 (dd, 1H), 3.46-3.65 (m, 4H), 3.76 (m, 1H), 4.22 (m, 1H), 4.94 (t, 1H), 6.47 (d, 1H), 7.12 (d, 2H), 7.20 (d, 1H), 7.25 (d, 2H), 7.46 (d, 2H), 7.71 (d, 2H), 7.75 (dd, 1H), 7.97 (d, 1H), 8.14 (d, 1H), 8.55 (d, 1H).

Example 80

N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-methoxy-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0964] ##STR00280##

[0965] To a stirred solution of intermediate 7A, 4-methoxy-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoic acid, 55 mg (0.145 mmol) in tetrahydrofuran (1.5 mL) were added TBTU, 49 mg (0.152 mmol, 1.05 eq.) and triethylamine, 61 L (0.435 mmol, 3 eq.) at r.t. After 20 min, 15B, 4-[(2R)-2-amino-3-hydroxypropyl]benzonitrile hydrochloride (1:1), 34 mg (0.159 mmol, 1.1 eq.) was added and the resulting mixture was stirred at r.t. for 4 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed successively with aq. sat. sodium hydrogen carbonate, water, brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (eluent: dichloromethane/methanol, 95/5) to give the product, 35 mg (43%) as an orange foam.

[0966] LC-MS (Method 1): R.sub.t=2.40 min; MS (ES+): m/z=538 (M+H).sup.+.

[0967] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.27 (d, 3H), 2.14 (s, 3H), 2.27 (s, 3H), 2.77 (dd, 1H), 3.09 (dd, 1H), 3.44 (m, 1H), 3.53 (m, 1H), 3.54 (d, 1H), 3.60 (d, 1H), 3.76 (q, 1H), 3.90 (s, 3H), 4.21 (m, 1H), 4.90 (t, 1H), 6.28 (d, 1H), 6.78 (d, 1H), 6.91 (s, 1H), 7.13 (d, 2H), 7.26 (d, 2H), 7.48 (d, 2H), 7.54 (s, 1H), 7.74 (d, 2H), 8.02 (d, 1H).

Example 81

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0968] ##STR00281##

[0969] To a stirred solution of intermediate 8A, 2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoic acid, 36 mg (90 mol) in tetrahydrofuran (1.8 mL) were added TBTU, 30 mg (95 mol, 1.05 eq.) and triethylamine, 38 L (0.27 mmol, 3 eq.) at r.t. After 20 min, 15B, 4-[(2R)-2-amino-3-hydroxypropyl]benzonitrile hydrochloride (1:1), 21 mg (99 mol, 1.1 eq.) was added and the resulting mixture was stirred at r.t. for 2 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed successively with aq. sat. sodium hydrogen carbonate, water, brine, dried over sodium sulfate and concentrated. The residue (55 mg, orange oil) was purified by preparative TLC (eluent: dichloromethane/methanol, 95/5) to give the product, 36 mg (72%) as an orange foam.

[0970] LC-MS (Method 1): R.sub.t=2.45 min; MS (ES+): m/z=558/560 (M+H).sup.+.

[0971] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 2.26 (s, 3H), 2.78 (dd, 1H), 3.09 (dd, 1H), 3.41 (m, 1H), 3.51-3.56 (m, 2H), 3.59 (d, 1H), 3.73 (q, 1H), 3.94 (s, 3H), 4.16 (m, 1H), 4.92 (t, 1H), 6.31 (d, 1H), 6.85 (d, 1H), 7.12 (d, 2H), 7.15 (s, 1H), 7.24 (d, 2H), 7.48 (d, 2H), 7.56 (s, 1H), 7.73 (d, 2H), 8.22 (d, 1H).

[0972] The following examples were prepared using the same procedure, from corresponding amines as indicated.

ammonia 7N in methanol as eluent.

TABLE-US-00012 Example No Amine Structure/ Name Analytics 83.sup.Phthal. 52B [00282] LC-MS (Method 1): R.sub.t = 2.65 min; MS (ES+): m/z = 687/689 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.28 (d, 3H), 2.24 (s, 3H), 2.87 (dd, 1H), 3.12 (dd, 1H), 3.62 (d, 1H), 3.66 (d, 1H), 3.76- 3.85 (m, 3H), 3.90 (s, 3H), 4.57 (m, 1H), 6.33 (d, 1H), 6.84 (d, 1H), 7.06 (s, 1H), 7.11 (d, 2H), 7.27 (d, 2H), 7.46 (s, 1H), 7.50 (d, 2H), 7.73 (d, 2H), 7.76-7.78 (m, 2H), 7.85-7.86 (m, 2H), 8.39 (d, 1H). 85.sup.Boc 57B.sup.Boc [00283] LC-MS (Method 1): R.sub.t = 2.82 min; MS (ES+): m/z = 768/770 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.12- 1.28 (m, 4H), 1.25 (d, 3H), 1.8 (s, 9H), 1.69-1.84 (m, 4H), 2.26 (s, 3H), 2.97 (dd, 1H), 3.11 (dd, 1H), 3.19 (m, 1H), 3.46 (m, 1H), 3.52 & 3.60 (2d, AB, 2H), 3.72 (q, 1H), 3.94 (s, 3H), 4.65-4.72 (m, 1H), 6.31 (d, 1H), 6.71 (d, 1H), 6.86 (d, 1H), 7.12 (d, 2H), 7.15 (s, 1H), 7.24 (d, 2H), 7.50 (d, 2H), 7.59 (s, 1H), 7.74 (d, 2H), 7.91 (d, 1H), 8.56 (d, 1H) 82 40B [00284] LC-MS (Method 1): R.sub.t = 2.54 min; MS (ES+): m/z = 572/574 (M + H).sup.+ .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.25 (d, 3H), 2.26 (s, 3H), 2.41 (s, 3H), 2.75 (dd, 1H), 3.04 (dd, 1H), 3.38-344 (m, 1H), 3.49-3.61 (m, 3H), 3.72 (q, 1H), 3.94 (s, 3H), 4.14 (m, 1H), 4.91 (t, 1H), 6.31 (d, 1H), 6.86 (d, 1H), 7.12 (d, 2H), 7.17 (s, 1H), 7.23 (d, 2H), 7.28 (d, 1H), 7.35 (s, 1H), 7.58 (s, 1H), 7.66 (d, 2H), 8.23 (d, 1H). 84.sup.Phthal. 56B [00285] LC-MS (Method 1): R.sub.t = 2.75 min; MS (ES+): m/z = 701/703 (M + H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm] = 1.27 (d, 3H), 2.24 (s, 3H), 2.40 (s, 3H), 2.86 (dd, 1H), 3.05 (dd, 1H), 3.63 (m, 2H), 3.75-3.82 (m, 3H), 3.90 (s, 3H), 4.58 (m, 1H), 6.33 (d, 1H), 6.85 (d, 1H), 7.07 (s, 1H), 7.11 (d, 2H), 7.27 (d, 2H), 7.30 (d, 1H), 7.36 (s, 1H), 7.49 (s, 1H), 7.65 (d, 1H), 7.76 (m, 2H), 7.85 (m, 2H), 8.41 (d, 1H).

Example 83

N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0973] ##STR00286##

[0974] To a stirred solution of 83.sup.Phthal, 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propan-2-yl]-4-methoxy-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)-2-furyl]benzamide, 362 mg (0.527 mmol) in absolute ethanol (8 mL) was added hydrazine, 2.6 mL (1M in tetrahydrofuran, 2.63 mmol, 5 eq.) and the mixture was stirred at 70 C. for 4 h. The solvent was then removed in vacuum, the residue was triturated in dichloromethane and filtered. The filtrate was concentrated and the residue (306 mg, orange oil) was purified by flash column chromatography on silica gel (eluent: dichloromethane/7N ammonia in methanol, 98/2) to give the product, 254 mg (79%) as an orange solid.

[0975] LC-MS (Method 1): R.sub.t=2.17 min; MS (ES+): m/z=557/559 (M+H).sup.+.

[0976] .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm]=1.37 (d, 3H), 2.29 (s, 3H), 2.80 (dd, 1H), 2.85-2.90 (m, 2H), 3.10 (dd, 1H), 3.66 (m, 2H), 3.80 (q, 1H), 3.97 (s, 3H), 4.36 (m, 1H), 6.30 (d, 1H), 6.88 (d, 1H), 7.11 (s, 1H), 7.14 (d, 2H), 7.24 (d, 2H), 7.49 (d, 2H), 7.62 (d, 2H), 7.68 (s, 1H).

Example 84

N-[(2R)-1-amino-3-(4-cyano-3-methylphenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[0977] ##STR00287##

[0978] To a stirred solution of example 84.sup.Phthal, 2-chloro-N-[(2R)-1-(4-cyano-3-methylphenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propan-2-yl]-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, 200 mg (0.527 mmol) in absolute ethanol (5 mL) was added hydrazine, 1.4 mL (1M in tetrahydrofuran, 1.4 mmol, 5 eq.) and the mixture was stirred at 70 C. for 4 h. The solvent was then removed in vacuum, the residue was triturated in ethyl acetate and filtered through celite to removed the solid. The filtrate was diluted with ethyl acetate and washed with aq. sat. sodium hydrogen carbonate, water (4), brine, dried over sodium sulfate and concentrated to give the crude product, 159 mg (97%) as a brown sticky solid. A pure sample has been obtained by preparative TLC purification (eluent: dichloromethane/7N ammonia in methanol, 97/3 to 96/4, 2 migrations).

[0979] LC-MS (Method 1): R.sub.t=2.20 min; MS (ES+): m/z=571/573 (M+H).sup.+.

[0980] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 2.25 (s, 3H), 2.41 (s, 3H), 2.64 (d, 2H), 2.73 (dd, 1H), 2.99 (dd, 1H), 3.55 (m, 2H), 3.71 (q, 1H), 3.95 (s, 3H), 4.04 (m, 1H), 6.31 (d, 1H), 6.86 (d, 1H), 7.11 (d, 2H), 7.18 (s, 1H), 7.23 (d, 2H), 7.28 (d, 1H), 7.34 (s, 1H), 7.56 (s, 1H), 7.65 (d, 1H), 8.23 (d, 1H).

Example 85

N-(trans-4-aminocyclohexyl)-N-{2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}-4-cyano-D-phenylalanin-amide

[0981] ##STR00288##

[0982] To a stirred solution of example 85.sup.Boc, N-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-N-{2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}-4-cyano-D-phenylalaninamide, 42 mg (0.055 mmol) in dichloromethane (3 mL) was added slowly hydrochloric acid, 0.14 mL (4M in 1,4-dioxane, 0.547 mmol, 10 eq.) at 0 C. and the resulting mixture was stirred at r.t. for 16 h. More hydrochloric acid, 0.14 mL (4M in 1,4-dioxane, 0.547 mmol, 10 eq.) was added and the reaction mixture was stirred for 24 h. The volatiles were removed under reduced pressure and the residue was treated with aq. sat. sodium hydrogen carbonate and ethyl acetate. The aqueous phase was extracted using ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (dichloromethane/7N ammonia in methanol: 96/4) to give the product, 18 mg (47%) as a beige solid.

[0983] LC-MS (Method 1): R.sub.t=2.23 min; MS (ES+): m/z=668 (M+H).sup.+, 533 (M135+H).sup.+

[0984] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.02-1.27 (m, 5H), 1.25 (d, 3H), 1.68-1.82 (m, 4H), 2.27 (s, 3H), 2.48-2.47 (m, 2H), 2.97 (dd, 1H), 3.10 (dd, 1H), 3.47 (m, 1H), 3.52 & 3.60 (2d, AB, 2H), 3.70 (q, 1H), 3.95 (s, 3H), 4.70 (m, 1H), 6.31 (d, 1H), 6.86 (d, 1H), 7.12 (d, 2H), 7.15 (s, 1H), 7.24 (d, 2H), 7.50 (d, 2H), 7.59 (s, 1H), 7.75 (d, 2H), 7.86 (d, 1H), 8.56 (d, 1H)

Example 86

N-[(2R)-1-[(4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, dia #1

[0985] ##STR00289##

Tert-butyl-(trans-4-{[(2R)-2-({2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)-ethyl]amino}methyl)-2-furyl]benzoyl}amino)-3-(4-cyanophenyl)propyl]amino}cyclo-hexyl) carbamate and tert-butyl-(cis-4-{[(2R)-2-({2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)-ethyl]amino}methyl)-2-furyl]benzoyl}amino)-3-(4-cyanophenyl)propyl]amino}cyclo-hexyl)carbamate

[0986] ##STR00290##

[0987] To a stirred solution of example 83, N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]-benzamide, 100 mg (0.18 mmol) in dichloromethane (2 mL) was added 4-N-Boc-aminocyclohexanone, 50 mg (0.233 mmol, 1.3 eq.) followed by acetic acid, 51 L (0.90 mmol, 5 eq.) and the mixture was stirred at r.t. for 30 min. Sodium triacetoxyborohydride, 57 mg (0.27 mmol, 1.5 eq.) was added in one portion and the resulting mixture was stirred at r.t. for 18 h. The mixture was poured into aq. sat. sodium hydrogen carbonate and extracted with dichloromethane (3). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue (257 mg, orange oil) was purified by preparative TLC (eluent: dichloromethane/7N ammonia in methanol, 97:3) to give the two disatereomers:

Dia #1, 45 mg (32%) as an orange solid; LC-MS (Method 1): R.sub.t=2.37 min; MS (ES+): m/z=754/756 (M+H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 1.37 (s, 9H), 1.40-1.46 (m, 4H), 1.51-1.58 (m, 4H), 2.26 (s, 3H), 2.60-2.64 (m, 3H), 2.77 (dd, 1H), 3.11 (dd, 1H), 3.29 (m, 1H), 3.53 (d, 1H), 3.59 (d, 1H), 3.72 (q, 1H), 3.94 (s, 3H), 4.22 (m, 1H), 6.31 (d, 1H), 6.63 (br d, 1H), 6.86 (d, 1H), 7.11 (d, 2H), 7.16 (s, 1H), 7.24 (d, 2H), 7.48 (d, 2H), 7.51 (s, 1H), 7.74 (d, 2H), 8.25 (d, 1H).
Dia #2, 48 mg (35%) as an orange solid; LC-MS (Method 1): R.sub.t=2.31 min; MS (ES+): m/z=754/756 (M+H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=0.97-1.06 (m, 2H), 1.11-1.18 (m, 2H), 1.25 (d, 3H), 1.37 (s, 9H), 1.72-1.75 (m, 2H), 1.81-1.86 (m, 2H), 2.26 (s, 3H), 2.31 (m, 1H), 2.63-2.67 (m, 2H), 2.76 (dd, 1H), 3.06 (dd, 1H), 3.16 (m, 1H), 3.53 (d, 1H), 3.59 (d, 1H), 3.73 (q, 1H), 3.94 (s, 3H), 4.19 (m, 1H), 6.31 (d, 1H), 6.67 (br d, 1H), 6.86 (d, 1H), 7.11 (d, 2H), 7.16 (s, 1H), 7.24 (d, 2H), 7.47 (d, 2H), 7.52 (s, 1H), 7.73 (d, 2H), 8.23 (d, 1H).

N-[(2R)-1-[(4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, Dia #1

[0988] To a stirred suspension of, tert-butyl-(4-{[(2R)-2-({2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}amino)-3-(4-cyanophenyl)propyl]amino}cyclohexyl)carbamate, dia #1, 44 mg (58 mol) in dichloromethane (0.5 mL) was added slowly hydrochloric acid, 0.15 mL (4M in 1,4-dioxane, 0.58 mmol, 10 eq.) at 0 C. and the resulting mixture was stirred at r.t. for 48 h.

[0989] The volatiles were removed under reduced pressure and the residue was triturated in methyl tert-butyl ether, filtered, washed with methyl tert-butyl ether and dried under reduced pressure. The impure product obtained was treated with aq. sat. sodium hydrogen carbonate and ethyl acetate. The aqueous phase was extracted using ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (eluent: dichloromethane/methanol, 96:4) to give the product, 16 mg (41%) as a beige solid.

[0990] LC-MS (Method 1): R.sub.t=2.03 min; MS (ES+): m/z=654/656 (M+H).sup.+.

[0991] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 1.38-1.47 (m, 5H), 1.50-1.60 (m, 3H), 2.26 (s, 3H), 2.57 (m, 1H), 2.63-2.66 (m, 2H), 2.71 (m, 1H), 2.78 (dd, 1H), 3.09 (dd, 1H), 3.53 (d, 1H), 3.60 (d, 1H), 3.73 (q, 1H), 3.94 (s, 3H), 4.23 (m, 1H), 6.31 (d, 1H), 6.86 (d, 1H), 7.11 (d, 2H), 7.17 (s, 1H), 7.24 (d, 2H), 7.48 (d, 2H), 7.51 (s, 1H), 7.74 (d, 2H), 8.25 (d, 1H).

Example 87

N-[(2R)-1-[(4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide, Dia #2

[0992] ##STR00291##

[0993] Using the same procedure as for example 86 dia #1:

[0994] LC-MS (Method 1): R.sub.t=2.00 min; MS (ES+): m/z=654/656 (M+H).sup.+.

[0995] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=0.98-1.10 (m, 4H), 1.25 (d, 3H), 1.70-1.85 (m, 4H), 2.26 (s, 3H), 2.31 (m, 1H), 2.63-2.70 (m, 2H), 2.77 (dd, 1H), 3.06 (dd, 1H), 3.15 (m, 1H), 3.53 (d, 1H), 3.60 (d, 1H), 3.72 (q, 1H), 3.94 (s, 3H), 4.20 (m, 1H), 6.31 (d, 1H), 6.86 (d, 1H), 7.11 (d, 2H), 7.16 (s, 1H), 7.24 (d, 2H), 7.47 (d, 2H), 7.52 (s, 1H), 7.73 (d, 2H), 8.23 (d, 1H).

Example 88

N-[(2R)-1-[(4-aminocyclohexyl)amino]-3-(4-cyano-3-methylphenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]-benzamide, Dia #1

[0996] ##STR00292##

Tert-butyl trans-N-[4-[[(2R)-2-[[2-chloro-4-methoxy-5-[5-[[[(1R)-1-(p-tolyl)ethyl]-amino]methyl]-2-furyl]benzoyl]amino]-3-(4-cyano-3-methyl-phenyl)propyl]amino]-cyclohexyl]carbamate and tert-butyl cis-N-[4[[(2R)-2-[[2-chloro-4-methoxy-5-[5-[[[(1R)-1-(p-tolyl)ethyl]amino]-methyl]-2-furyl]benzoyl]amino]-3-(4-cyano-3-methyl-phenyl)propyl]amino]cyclohexyl]carbamate

[0997] ##STR00293##

[0998] Example 84 was reacted with 4-N-Boc-aminocyclohexanone using the same procedure described in example 86 to deliver 2 diastereomers

Dia #1, 33 mg (23%), orange solid; LC-MS (Method 1): R.sub.t=2.70 min; MS (ES+): m/z=768/770 (M+H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.26 (d, 3H), 1.38 (s, 9H), 1.40-1.65 (m, 8H), 2.27 (s, 3H), 2.42 (s, 3H), 2.57-2.67 (m, 4H), 2.75 (dd, 1H), 3.07 (dd, 1H), 3.52 & 3.58 (2 d, AB, 2H), 3.73 (q, 1H), 3.96 (s, 3H), 4.20 (m, 1H), 6.33 (d, 1H), 6.64 (br s 1H), 6.88 (d, 1H), 7.12 (d, 2H), 7.19 (s, 1H), 7.24 (d, 2H), 7.30 (d, 1H), 7.36 (s, 1H), 7.55 (s, 1H), 7.67 (d, 1H), 8.27 (d, 1H).
Dia #2, 44 mg (31%), orange solid; LC-MS (Method 1): R.sub.t=2.71 min; MS (ES+): m/z=768/770 (M+H).sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=0.95-1.20 (m, 4H), 1.25 (d, 3H), 1.37 (s, 9H), 1.70-1.90 (m, 4H), 2.26 (s, 3H), 2.30 (m, 1H), 2.41 (s, 3H), 2.64 (m, 2H), 2.73 (dd, 1H), 3.00 (dd, 1H), 3.17 (m, 1H), 3.52 & 3.58 (2 d, AB, 2H), 3.73 (q, 1H), 3.95 (s, 3H), 4.16 (m, 1H), 6.31 (d, 1H), 6.66 (d, 1H), 6.88 (d, 1H), 7.11 (d, 2H), 7.18 (s, 1H), 7.24 (d, 2H), 7.27 (d, 1H), 7.34 (s, 1H), 7.54 (s, 1H), 7.66 (d, 1H), 8.23 (d, 1H).

N-[(2R)-1-[(4-aminocyclohexyl)amino]-3-(4-cyano-3-methylphenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]-benzamide, Dia #1

[0999] Diastereomer #1 was deprotected by the same procedure as described in for example 86 to deliver 13 mg of the title compound:

[1000] LC-MS (Method 1): R.sub.t=2.20 min; MS (ES+): m/z=668/670 (M+H).sup.+.

[1001] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.15 (d, 3H), 1.37-1.46 (m, 5H), 1.48-1.58 (m, 3H), 2.26 (s, 3H), 2.41 (s, 3H), 2.50-2.73 (m, 4H), 2.75 (dd, 1H), 3.04 (dd, 1H), 3.52 & 3.58 (2d, AB, 2H), 3.73 (q, 1H), 3.95 (s, 3H), 4.20 (m, 1H), 6.32 (d, 1H), 6.87 (d, 1H), 7.11 (d, 2H), 7.18 (s, 1H), 7.24 (d, 2H), 7.29 (d, 1H), 7.35 (s, 1H), 7.54 (s, 1H), 7.66 (d, 1H), 8.26 (d, 1H).

Example 89

2-Chloro-5-[5-({[(1R)-1-(4-chlorophenyl)ethyl]amino}methyl)-2-furyl]-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]benzamide

[1002] ##STR00294##

2-chloro-5-(5-formyl-2-furyl)benzoic acid

[1003] ##STR00295##

[1004] To a solution of ester ethyl 2-chloro-5-(5-formylfuran-2-yl)benzoate, 2.0 g (7.17 mmol) in THF (290 mL) at 0 C. was added lithium hydroxide, 361 mg (8.61 mmol, 1.2 eq) in water (70 mL). The solution was stirred at 0 C. for 6 h, then stored at 4 C. overnight. LC-MS analysis showed full conversion. The mixture was diluted with water (70 mL), then acidified using 1N hydrochloric acid aqueous solution. The aqueous phase was extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated to an orange solid. The solid was triturated in ethyl acetate, filtered, rinse with ethyl acetate and dried under reduced pressure to give the product, 1.25 g (64%) as an orange solid.

[1005] LC-MS (Method 1): Rt=2.99 min; MS (ES): m/z=249/251 (MH)

[1006] 1H-NMR (500 MHz, DMSO-d6) [ppm]=7.44 (d, 1H), 7.66 (d, 1H), 7.69 (d, 1H), 8.01 (dd, 1H), 8.23 (d, 1H), 9.64 (s, 1H), 13.70 (br s, 1H)

2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-(5-formyl-2-furyl)benzamide

[1007] ##STR00296##

[1008] To a stirred solution of acid 2-chloro-5-(5-formyl-2-furyl)benzoic acid, 1.34 g (4.81 mmol) in tetrahydrofuran (75 mL) was added TBTU, 1.70 g (5.29 mmol) followed by triethylamine, 1.34 mL (9.62 mmol) at r.t. and the resulting mixture was stirred 15 min at r.t. (a solid formed). Then amine (3R)-3-amino-4-(4-cyanophenyl)-N-methylbutanamide, 1.15 g (5.29 mmol) was added. The mixture was stirred at r.t. overnight. The mixture was diluted in ethyl acetate (500 mL) and washed successively with aq. 1N hydrochloric acid (100 mL), aq. sat. sodium hydrogen carbonate (100 mL), water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. The solid obtained was triturated in ethyl acetate, filtered, washed with ethyl acetate, then with pentane and dried under reduced pressure to give the product, 1.05 g (46%) as yellow solid.

[1009] LC-MS (Method 1): Rt=2.81 min; MS (ES+): m/z=450/452 (M+H)+.

[1010] 1H NMR (DMSO-d6): 2.35-2.45 (m, 2H), 2.60 (d, 3H), 2.88 (dd, 1H), 2.99 (dd, 1H), 4.51 (m, 1H), 7.34 (d, 1H), 7.47 (d, 2H), 7.59 (d, 1H), 7.61 (d, 1H), 7.68 (d, 1H), 7.80-7.85 (m, 3H), 7.90 (dd, 1H), 8.49 (d, 1H), 9.66 (s, 1H).

[1011] Rf=0.12 (ethyl acetate), 0.5 (DCM/methanol 95/5).

2-chloro-5-[5-({[(1R)-1-(4-chlorophenyl)ethyl]amino}methyl)-2-furyl]-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]benzamide

[1012] 2-Chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-(5-formyl-2-furyl)benzamide, 100 mg (0.222 mmol) was suspended in methanol (3 mL). (1R)-1-(4-chlorophenyl)ethanamine, 37 L (0.267 mmol, 1.2 eq.) was added, followed by acetic acid, 13 L (0.222 mmol, 1.0 eq.). The suspension was stirred at r.t. for 20 min, and then sodium cyanoborohydride, 21 mg (0.333 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 16 h. LC-MS analysis showed around 42% expected product and 48% of acetal along with small amount of aldehyde and aldehyde reduction. The reaction medium was filtered, rinsed with DMF (0.5 mL) and the filtrate was purified by preparative LC-MS followed by preparative TLC (dichloromethane/methanol 98/2>97/3) to provide the product, 12.3 mg (9%) as a beige solid.

[1013] LC-MS (Method 5): R.sub.t=2.53 min; MS (ES+): m/z=589/591 (M+H)+

[1014] .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm]=1.37 (d, 3H), 2.52-2.60 (m, 2H), 2.74 (s, 3H), 2.98 (dd, 1H), 3.11 (dd, 1H), 3.63 & 3.68 (2 d, AB, 2H), 3.82 (q, 1H), 4.71 (m, 1H), 6.30 (d, 1H), 6.71 (d, 1H), 7.30-7.36 (m, 4H), 7.40 (d, 1H), 7.43 (d, 1H), 7.50 (d, 2H), 7.64-7.69 (in, 3H).

Example 90

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-hydroxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[1015] ##STR00297##

5-bromo-2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-hydroxybenzamide

[1016] ##STR00298##

[1017] To a stirred solution of 5-bromo-2-chloro-4-hydroxybenzoic acid, 100 mg (0.40 mmol) in tetrahydrofuran (4 mL) were added TBTU, 134 mg (0.42 mmol, 1.05 eq.) and triethylamine, 0.17 mL (1.2 mmol, 3 eq.) at r.t. After 20 min 4-[(2R)-2-amino-3-hydroxypropyl]benzonitrile hydrochloride (1:1), 93 mg (0.44 mmol, 1.1 eq.) was added and the resulting mixture was stirred at r.t. for 16 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed successively with aq. sat. sodium hydrogen carbonate, water, brine, dried over sodium sulfate and concentrated. The residue (155 mg, light yellow solid) was triturated in methyl tert-butyl ether, filtered, washed with methyl tert-butyl ether and dried to give the product, 77 mg (46%) as a white solid.

[1018] LC-MS (Method 1): R.sub.t=2.70 min; MS (ES+): m/z=409/411 (M+H).sup.+.

[1019] .sup.1H-NMR (500 MHz, CD.sub.3OD) [ppm]=2.86 (dd, 1H), 3.13 (dd, 1H), 3.61-3.67 (m, 2H), 4.34 (m, 1H), 6.89 (s, 1H), 7.40 (s, 1H), 7.48 (d, 2H), 7.66 (d, 2H).

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-5-(5-formyl-2-furyl)-4-hydroxybenzamide

[1020] ##STR00299##

[1021] To a stirred solution of 5-bromo-2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-hydroxybenzamide, 75 mg (0.183 mmol), 5-formylfuran-2-ylboronic acid, 38 mg (0.275 mmol, 1.5 eq.) and [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane, 22 mg (27 mol, 15 mol %) in degazed tetrahydrofuran (1.2 mL) was added a solution of sodium carbonate, 39 mg (0.366 mmol, 2.0 eq.) in degazed water (0.6 mL) and the resulting mixture was stirred at 50 C. for 18 h. After cooling to r.t., the solvent was removed under reduced pressure, water and ethyl acetate were added and the phases were separated. The aqueous layer was extracted with ethyl acetate (2), the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, 92 mg (85%) as a dark brown solid that was used without further purification.

[1022] LC-MS (Method 1): R.sub.t=2.71 min; MS (ES+): m/z=425/427 (M+H).sup.+.

2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-hydroxy-5-[5-({[(1R)-1-4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide

[1023] To a stirred solution of 2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-5-(5-formyl-2-furyl)-4-hydroxybenzamide, 91 mg (0.152 mmol) in a mixture of dichloromethane (1.5 mL) and N,N-dimethylformamide (0.30 mL) were added (R)-1-4-tolylethanamine, 25 L (0.167 mmol, 1.1 eq.) followed by acetic acid, 44 L (0.76 mmol, 5 eq.) and the mixture was stirred at r.t. for 30 min. Sodium triacetoxyborohydride, 48 mg (0.228 mmol, 1.5 eq.) was added in one portion and the resulting mixture was stirred at r.t. for 18 h. The mixture was poured into aq. sat. sodium hydrogen carbonate and extracted with dichloromethane (3). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue (149 mg, brown oil) was purified by preparative TLC (eluent: dichloromethane/7N ammonia in methanol, 95:5) to give the product, 29 mg (35%) as an orange solid.

[1024] LC-MS (Method 1): R.sub.t=2.34 min; MS (ES+): m/z=544/546 (M+H).sup.+.

[1025] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]=1.25 (d, 3H), 2.26 (s, 3H), 2.78 (dd, 1H), 3.08 (dd, 1H), 3.40 (m, 1H), 3.51-3.54 (m, 2H), 3.59 (d, 1H), 3.73 (q, 1H), 4.15 (m, 1H), 4.91 (t, 1H), 6.29 (d, 1H), 6.88 (d, 1H), 6.92 (s, 1H), 7.12 (d, 2H), 7.24 (d, 2H), 7.47 (d, 2H), 7.52 (s, 1H), 7.73 (d, 2H), 8.15 (d, 1H).

[1026] The following Examples were prepared in analogy of Example 1 by amide coupling of of intermediates xA or the corresponding dimethyl derivatives and of 1A and xB or commercially available amines:

TABLE-US-00013 Example Interme- Structure/Name Analytics No diates 91 6A; 1B [00300] LC-MS (Method 1): Rt = 2.40 min; MS (ES+): m/z = 560 (M + H)+. 1H-NMR (500 MHz, DMSO-d6) [ppm] = 1.27 (d, 3H), 2.27 (s, 3H), 2.42 (d, 2H), 2.56 (d, 3H), 2.93 (dd, 1H), 2.98 (dd, 1H), 3.59 (d, 1H), 3.64 (d, 1H), 3.77 (m, 1H), 4.53 (m, 1H), 6.48 (d, 1H), 7.12 (d, 2H), 7.20 (d, 1H), 7.25 (d, 2H), 7.42 (d, 2H), 7.69-7.73 (m, 3H), 7.83 (m, 1H), 7.98 (d, 1H), 8.09 (d, 1H), 8.63 (d, 1H). 92 1A (3R)-3-amino-N- methyl-4-phenyl- butanamide [00301] MS: m/z = 544/546 [M + H]+ 1H-NMR (MeOD, 500 MHz): 1.37 (d, 3H), 2.31 (s, 3H), 2.52 (d, 2H), 2.73 (s, 3H), 2.90 (dd, 1H) 2.99 (dd, 1H), 3.60 and 3.65 (2d, AB, 2H), 3.77 (q, 1H), 4.67 (m, 1H), 6.30 (d, 1H), 6.70 (d, 1H), 7.10-7.35 (m, 9H), 7.39 (d, 1H), 7.41 (d, 1H), 7.65 (d, 1H). 93 2-phenylpropan-2-amine 1B [00302] LC-MS (Method 5): Rt = 2.45 min; MS (ES+) m/z = 569-571 (M + H)+ 1H-NMR (500 MHz, CD3OD) [ppm] = 1.54 (s, 6H), 2.55 (d, 2H), 2.74 (s, 3H), 2.94 (dd, 1H), 3.10 (dd, 1H), 3.51 (s, 2H), 4.69-4.74 (m, 1H), 6.29 (d, 1H), 6.70 (d, 1H), 7.21-7.4 (m, 1H), 7.35 (t, 2H), 7.40 (d, 1H), 7.44 (d, 1H), 7.50 (d, 2H), 7.53 (dd, 2H), 7.66-7.68 (m, 3H). 94 2-(4-methylphenyl)propan- 2-amine 1B [00303] LC-MS (Method 1): Rt = 2.44 min; MS (ES+): m/z = 583/585 (M + H)+ 1H-NMR (500 MHz, CD3OD) [ppm] = 1.52 (s, 6H), 2.30 (s, 3H), 2.56 (d, 2H), 2.74 (s, 3H), 2.98 (dd, 1H) 3.11 (dd, 1H), 3.50 (s, 2H), 4.71 (m, 1H), 6.28 (d, 1H), 6.70 (d, 1H), 7.16 (d, 2H), 7.38-7.42 (m, 3H), 7.43 (d, 1H), 7.50 (d, 2H), 7.64- 7.68 (m, 3H). 95 2-(4-chlorophenyl)propan- 2-amine 6B [00304] LC-MS (Method 1): Rt = 2.46 min; MS (ES+) m/z = 575-577 (M + H)+ 1H-NMR (500 MHz, CD3OD) [ppm] = 1.52 (s, 6H), 3.08 (dd, 1H), 3.35 (dd, 1H), 3.52 (s, 2H), 4.94 (dd, 1H), 6.28 (d, 1H), 6.71 (d, 1H), 7.33 (d, 2H), 7.42 (d, 1H), 7.51-7.53 (m, 4H), 7.57 (d, 1H), 7.66-7.69 (m, 3H). 96 1A (R)-3-amino-3-phenyl- propan-1-ol [00305] LC-MS (Method 1): Rt = 2.43 min; MS (ES+): m/z = 503-505 (M + H)+. 1H-NMR (500 MHz, DMSO-d6) [ppm] = 1.25 (d, 3H), 2.27 (s, 3H), 2.71 (dd, 1H), 2.98 (dd, 1H), 3.41 (m, 1H), 3.49-3.54 (m, 2H), 3.57 (d, 1H), 3.71 (q, 1H), 4.12 (m, 1H), 4.83 (t, 1H), 6.32 (d, 1H), 6.88 (d, 1H), 7.13 (d, 2H), 7.17 (m, 1H), 7.24 (d, 2H), 7.28-7.29 (m, 4H), 7.43 (d, 1H), 7.45 (d, 1H), 7.65 (dd, 1H), 8.31 (d, 1H).

B. Assessment of the Physiological Activity

[1027] The ability of the compounds described in the present invention to disrupt the interaction between ATAD2 and acetylated Histone H4 (Ac-H4) was used as quantitative measure of their ATAD2-binding affinities.

[1028] To this end a TR-FRET assay which detects the binding of an Ac-H4-derived synthetic peptide (purchased from e.g. Biosyntan (Berlin, Germany)) of sequence HSGRGKGGGGKGLGK(Ac)GGAKRHRK-Biotin to recombinant, N-terminally GST-tagged ATAD2 bromodomain amino acids 981-1108. The protein was produced in-house via E. coli expression followed by GSH-Sepharose affinity- and Superdex S200-size exclusion chromatography purification.

[1029] Typically, 11 different concentrations of each compound (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 M, 0.51 M, 1.7 M, 5.9 M and 20 M) were tested in duplicate within the same microtiter plate. To this end, 100-fold concentrated compound solutions (in DMSO) were previously prepared with a Precision Pippeting System (BioTek) by serial dilution (1:3.4) of 2 mM stocks in clear, low-volume 384-well microtiter source plates (Greiner Bio-One). Subsequently, 50 nl of compounds were transferred into black, low-volume test plates from the same supplier using a Hummingbird capillary based liquid handling instrument (Digilab). Tests were started by the addition of 2 l of 2.5-fold concentrated ATAD2 solution (25 nM=10 nM final concentration in the 5 l assay volume) in aqueous assay buffer [50 mM HEPES pH 7.5, 50 mM potassium fluoride (KF), 100 mM sodium chloride (NaCl), 0.25 mM CHAPS, 0.05% bovine serum albumine (BSA) and 1 mM dithiothreitol (DTT)] to the compounds in the test plate with a Multidrop dispenser (Thermo-Fisher). Test plates were then incubated 10 at 22 C., in order to allow pre-equilibration of putative compound-ATAD2 complexes. Subsequently, 3 l of a 1.67-fold concentrated solution containing Ac-H4 peptide (83.5 nM=50 nM final concentration) and TR-FRET detection reagents [16.7 nM Anti-GST-XL665 (Cisbio), =10 nM final concentration and 4.17 nM Lance EU W-1024 Streptavidin Europium Chelate (Perkin-Elmer)=2.5 nM final concentration were dispensed into the plates.

[1030] The mixture was further incubated in the dark for 1 hour at 22 C. Finally the inhibition of the formation of ATAD2/Ac-H4 complexes was assessed by measurement of the resonance energy transfer from the Streptavidin-Eu-Chelate to the anti-GST-XL665 antibody present in the reaction. To this end, the fluorescence emissions at 622 nm and 665 nm after excitation at 337 nm were measured in a TR-FRET reader, e.g. a Rubystar or Pherastar (both from BMG Lab Technologies) or a Viewlux (Perkin-Elmer) and the ratio of the emissions at 665 nm and at 622 nm was taken as indicator for the amount of ATAD2/Ac-H4 complexes in equilibrium.

[1031] The data were normalized using two sets of control wells (16 each). The first accounted for 100% ATAD2/Ac-H4 binding (0% inhibition), and contained all reaction components but DMSO instead of inhibitors. The second represented 0% ATAD2/Ac-H4 binding (100% inhibition), and included all assay components except ATAD2. IC50 values were calculated by fitting the normalized inhibition data to a 4-parameter logistic equation using either Screener software (Genedata) or a Bayer-proprietary analysis software.

TABLE-US-00014 Example No IC50 [M] 1 7.40E7 2 9.49E7 3 9.27E7 4 3.93E7 5 1.89E6 6 6.56E7 7 8.32E7 8 8.98E7 9 7.49E7 10 6.74E7 11 8.22E7 12 6.68E7 13 3.86E7 14 8.91E7 15 8.12E7 16 5.70E7 17 3.41E7 18 1.13E6 19 6.40E7 20 7.29E7 21 5.80E7 22 8.54E7 23 5.61E7 24 5.98E7 25 3.52E7 26 3.31E7 27 1.16E7 28 1.48E7 29 6.75E7 30 2.53E7 31 2.97E7 32 1.30E7 33 1.84E7 34 4.23E7 35 4.66E7 36 1.86E7 37 4.43E7 38 3.65E7 39 5.85E7 40 7.81E7 41 7.59E7 42 1.10E6 43 1.71E6 44 1.60E6 45 1.80E6 46 1.10E6 47 2.10E6 48 1.08E6 49 1.76E6 50 1.26E6 51 8.10E7 53 2.73E7 54 7.05E7 55 2.74E7 56 5.10E7 57 5.20E7 58 1.72E7 59 6.25E7 60 1.90E6 61 7.98E7 62 3.32E7 63 3.20E7 64 1.18E6 65 1.21E7 66 2.45E7 67 2.65E7 68 1.09E7 69 1.12E7 70 8.58E8 71 1.07E7 72 1.38E7 73 1.32E7 74 6.71E7 75 5.67E7 76 4.41E7 77 5.98E7 78 1.23E6 79 1.40E6 80 4.07E7 81 3.01E7 82 3.50E7 83 2.33E7 84 2.70E7 85 4.15E7 86 1.66E7 87 2.16E7 88 1.28E7 89 2.06E6 90 3.67E7 91 13.4E6 92 8.37E6 93 7.69E6 94 2.98E6 95 2.82E6 96 2.65E6

Cell Proliferation Assay

[1032] Previous reports demonstrated that ATAD2 is required for the cancer cell proliferation and growth and proposed ATAD2 as a therapeutic target for cancer. Consequently, down-regulation of ATAD2 by RNAi was shown to inhibit the proliferation and invasiveness of breast cancer cells (Kalashnikova et al., 2010, Cancer Res, 70: (22), 9402-9412; Revenko et al., 2010, Mol Cell Biol, 30: (22), 5260-5272), endometrial cancer cells (Raeder et al., 2013, PlosOne, 8: (2), e54873), ovarian cancer cells (Wan et al., 2014, Asian Pac J Cancer Prev, 15: (6) 2777-2783), liver cancer cells (Wu et al., 2014, BMC Cancer, 14: (107), 1-11), prostate cancer cells (Zou et al., 2009, Cancer Res, 69: (8) 3339-3346), cervical cancer cells (Zheng et al., 2015, Oncology Reports, 33: (5), 2337-2344), osteosarcoma (Ciro et al., 2009, Cancer Res, 69: (21), 8491-8498) and to promote apoptotic cancer cell death (Caron et al., 2010, Oncogene, 29: (37), 5171-5181).

[1033] The effect of ATAD2 inhibitory compounds on cancer cell proliferation might be measured as below. For example; MCF7 breast cancer cells might be seeded into 96-well microtiter plates at 2000 cells/well in 90 l cell culture media (RPMI 1640, 10% FCS, 2 mM L-Glutamine, 10 g/ml human Insulin, 100 M Estradiol) and incubated for 24 h at 37 C. and 5% CO.sub.2. Note, the culturing conditions might vary from cell line to cell line depending on their standard culturing conditions. Compounds might be then delivered to the microtiter assay plates and, following a 72 h long incubation period at 37 C. and 5% CO.sub.2, the viability of the cells might be measured with addition of alamarBlue (Invitrogen) to the medium in Victor X3 Multilabel Plate Reader (Perkin Elmer).

TABLE-US-00015 MCF7 NCl-H526 breast cancer lung cancer Example No GI50 [M] GI50 [M] 71 3.18 M 1.25 M 86 3.2 M 2.40 M 36 1.28 M 1.29 M 53 2.51 M 3.6 M 33 1.42 M 1.25 M 66 3.76 M 5.10 M 90 10.8 M 19.1 M 81 10.4 M 10.2 M 4 11.5 M 15.4 M 42 11.9 M >30 M
GI50 means half-maximal growth inhibition.

[1034] Thus according to the data shown above the compound of the present invention are suitable for the treatment of breast cancer and lung cancer.