Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

• Main Authors: OLSON, RICHARD E, ISHERWOOD, MATTHEW L, FLEMING, KRISTEN N, GUZZO, PETER R, HU, MIN, CUI, WENGE, ZHA, CONGXIANG, MANNING, DAVID D, NACRO, KASSOUM, MOLINO, BRUCE F, SAMBANDAM, ARUNA, LIU, SHUANG
• Format: Patent
• Language: English
• Published: 16.01.2014
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

A compound of formulae I(A-E) having the following structure: R5* R 4 N, I(A-E) wherein: the carbon atom designated * is in the R or S configuration; X is phenyl, optionally substituted from 1 to 4 times with substituents as defined in R1 4 ; R' is H, methyl, ethyl, or isopropyl; R2 is H, methyl, or gem-dimethyl; R3 is H, methyl, hydroxy, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy; R4 is pyrimidinyl, optionally substituted from 1 to 4 times with substituents as defined below in R5 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or methoxy; R 6 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or methoxy; R7 is H, gem-dimethyl, or CI-C 4 alkyl, wherein each of the CI-C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R'5 ; R is H; R9 is H; R10 and R" are each independently selected from the group consisting of H, -C(O)R, CI-C 4 alkyl, C3 -C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where each of CI-C 6 allyl, C3-C6 cycloalkyl, and C4 -C7 cycloalkylalkyl is optionally substituted from I to 3 times with substituents as defined below in R15; R' 0 and R" are each independently selected from the group consisting of phenyl, benzyl, and other 5- or 6-membered monocyclic heterocycles, where each of the phenyl, benzyl, and 5- or 6-membered monocyclic heterocycle is optionally substituted from 1 to 3 times with substituents as defined below in R14; R'0 and R" are taken together with the nitrogen to which they are attached to form a saturated or partially saturated monocyclic or fused bicyclic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, thiomorpholine, [1,2]oxazinane, isoxazolidine, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 3-oxomorpholino, 3-oxothiomorpholino, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydro-[1,2,4]triazolc[4,3-a]pyrazine, and other monocyclic or fused bicyclic heterocycles containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the heterocycle is attached to the benzazepine core via the nitrogen atom, and is optionally substituted from I to 3 times with a substituent selected 12 independently at each occurrence thereof from the group consisting of halogen, cyano, -OR -NR 2 R1D, -S(O),R' 3 , -C(O)R 3, and Ci-C 4 alkyl, where each of CI-C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R15; R' 0 and R1 are taken together with the nitrogen to which they are attached to form a heterocycle selected from the group consisting of piperazine, 2-oxopiperazinyl, 2-oxo-1,4 diazepanyl, 5-oxo-1,4-diazepanyl, 1,4-diazepane, and other heterocycles containing one additional nitrogen atom in the ring, where the heterocycle is optionally substituted on a ring carbon with from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, -OR , -NR12 R 3 , -S(O),R' 3 , -C(O)R 3 , and CI-C 4 alkyl, or on the additional nitrogen atom from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of S(O)nR'3 , C(O)R 3 , and CI-C 4 alkyl, wherein each of CI-C 4 alkyl is optionally substituted from I to 3 times with substituents as defined below in R15; R'0 and R" are taken together with the nitrogen to which they are attached to form a heterocycle selected from the group consisting of piperazine, 2-oxopiperazinyl, 2-oxo-1,4 diazepanyl, 5-oxo-1,4-diazepanyl, 1,4-diazepane, and other heterocycles containing one additional nitrogen atom in the ring, where the heterocycle is optionally substituted on the additional nitrogen atom with a substituent selected independently at each occurrence thereof from the group consisting of phenyl, benzyl, and 5- or 6-membered aromatic heterocycles containing 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where each of the phenyl, benzyl, and 5- and 6-membered heterocycle is optionally substituted from 1 to 3 times with substituents as defined below in R' 4; R 2 is selected from the group consisting of H, CI-C 4 alkyl, C3-C6 cycloalkyl, C4 -C7 cycloalkylalkyl, and -C(O)R 1 3 , where each of CI-C 6 alkyl, C3 -C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted from I to 3 times with substituents as defined below in R"; R 3 is CI-C 4 alkyl; R' 4 is independently selected at each occurrence from a substituent in the group consisting of halogen, -NO 2, -OR 2 , -NR"R", -NR C(O)2R 3, -NR'2 C(O)NR 2R , -S(O)n R 3, -CN, C(O)R 3 , CI-C 6 alkyl, C2-C6 alkenyl, C2 -C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, wherein each of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R15; and R 5 is independently selected at each occurrence from a substituent in the group consisting of CN, halogen, C(O)R 3 , CI-C 3 alkyl, -OR 2 , -NR' 0R", -S(O)nR13 , aryl, and heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted from I to 4 times with substituents as defined above in R1 4; and n is 0, 1, or 2.