Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof

A method of treating a disorder which is created by decreased availability of serotonin, norepinephrine or dopamine or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, wherein in the disorder is depression, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula (I):

• wherein:
• the carbon atom designated * is in the R or S configuration;
• R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or C4-C7 cycloalkylalkyl, each of which is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of:
• C1-C3 alkyl, halogen, Ar,—CN, —OR9 and —NR9R10;
• R2 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl or C1-C6 haloalkyl;
• R3 is H, halogen, —OR11, —S(O)nR12, —CN, —C(O)R12, —C(O)NR11R12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or C4-C7 cycloalkylalkyl and wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of:
• C1-C3 alkyl, halogen, —CN, —OR9, —NR9R10 and phenyl which is optionally substituted 1-3 times with a substituent selected from the group consisting of:
• halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy, —CN, —OR9, and —NR9R10;
• R4 is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, triazinyl, triazolyl, furanyl, pyranyl, indazolyl, benzimidazolyl, quinolinyl, quinazolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, benzthiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl or thiadiazolyl, wherein the R4 group is optionally substituted with from 1 to 4 R14 substituents;
• R5 and R6 and R7 are each independently selected from the group consisting of:
• H, halogen, —OR11, —NR11R12, —NR11C(O)R12, —NR11C(O)2R12—NR11C(O)NR12R13, —S(O)nR12, —CN, —C(O)R12,—C(O)NR11R12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or C4-C7 cycloalkylalkyl, and wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of:
• C1-C3 alkyl, halogen, —CN, —OR9, —NR9R10 and phenyl which is optionally substituted 1-3 times with a substituent selected from the group consisting of:
• halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy, —CN, —OR9, or NR9R10;
• or R5 and R6 taken together may be —O—C(R12)2—O—,
• R8 is H, halogen or OR11;
• R9 and R10 are each independently selected from the group H, C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R13, phenyl and benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of:
• halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy;
• or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
• R11 is H, C1-C4alkyl, C1-C4 haloalkyl, C1-C4alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R13, phenyl or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;
• R12 is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;
• or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
• R13 is C1-C4 alkyl, C1-C4 haloalkyl or phenyl,
• n is 0, 1, or 2;
• and,
• R14 is independently selected at each occurrence from a substituent selected from the group consisting of:
• halogen, —NO2, —OR11, —NR11R12, —NR11C(O)R12, —NR11C(O)2R12, —NR11C(O)NR12R13, —S(O)nR12, —CN, —C(O)R12, C(O)NR11R12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where C1-C6 alkyl, C2-C6 alkenyl C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C1-C3 alkyl, halogen, Ar, —CN, —OR9, and —NR9R10, or
• an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof.