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

1. A compound of formulae I(A-E) having the following structure:

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 R 14 ;

R 1 is H, methyl, ethyl, or isopropyl;

R 2 is H, methyl, or gem-dimethyl;

R 3 is H, methyl, hydroxy, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;

R 4 is pyrimidinyl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ;

R 5 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or methoxy;

R 6 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or methoxy;

R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, wherein each of the C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 15 ;

R 8 is H;

R 9 is H;

R 10 and R 11 are each independently selected from the group consisting of H, —C(O)R 13 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, where each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; or

R 10 and R 11 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 R 14 ; or

R 10 and R 11 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]triazolo[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 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OR 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , and C 1 -C 4 alkyl, where each of C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; or

R 10 and R 11 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 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , and C 1 -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) n R 13 , —C(O)R 13 , and C 1 -C 4 alkyl, wherein each of C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; or

R 10 and R 11 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 14 ;

R 12 is selected from the group consisting of H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and —C(O)R 13 , where each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;

R 13 is C 1 -C 4 alkyl;

R 14 is independently selected at each occurrence from a substituent in the group consisting of halogen, —NO 2 , —OR 12 , —NR 10 R 11 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(o) n R 13 , —CN, —C(O)R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; and

R 15 is independently selected at each occurrence from a substituent in the group consisting of —CN, halogen, C(O)R 13 , C 1 -C 3 alkyl, —OR 12 , —NR 10 R 11 , —S(O) n R 13 , aryl, and heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted from 1 to 4 times with substituents as defined above in R 14 ; and

n is 0, 1, or 2.

2. The compound according to claim 1 , wherein X is phenyl substituted from 1 to 4 times with halogen.

3. The compound according to claim 2 , wherein the halogen is F.

4. The compound according to claim 1 , wherein R 1 is H.

5. The compound according to claim 1 , wherein R 2 is H.

6. The compound according to claim 1 , wherein R 3 is H.

7. The compound according to claim 1 , wherein R 4 is pyrimidin-2-yl.

8. The compound according to claim 1 , R 4 is substituted with —S(O) n R 13 .

9. The compound according to claim 1 , wherein R 5 is H.

10. The compound according to claim 1 , wherein R 6 is H.

11. The compound according to claim 1 , wherein R 7 is gem-dimethyl.

12. The compound according to claim 1 , wherein

R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are H;

R 4 is pyrimidin-2-yl;

R 7 is gem-dimethyl; and

X is phenyl substituted from 1 to 4 times with halogen.

13. The compound according to claim 8 , wherein n is 2 and R 13 is methyl.

14. The compound according to claim 1 , wherein

R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are H;

R 4 is pyrimidin-2-yl substituted with —S(O) n R 13 ;

R 7 is gem-dimethyl; and

X is phenyl substituted from 1 to 4 times with F.