ARYLOXY- AND HETEROARYLOXY-SUBSTITUTED TETRAHYDROBENZAZEPINES AND USE THEREOF TO BLOCK REUPTAKE OF NOREPINEPHRINE, DOPAMINE, AND SEROTONIN

• US 20100210624A1
• Filed: 05/08/2008
• Published: 08/19/2010
• Est. Priority Date: 05/10/2007
• Status: Active Grant

• Current Assignee: Albany Molecular Research Incorporated
• Original Assignee: Albany Molecular Research Incorporated, Bristol-Myers Squibb Company
• Inventors: Yang, Yuh-lin Allen, Molino, Bruce F., Olson, Richard E., Liu, Shuang, Sambandam, Aruna
• Granted Patent: US 8,987,252 B2
• Time in Patent Office: Days
• US Class Current: 514/213.10
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 223/16 Benzazepines; Hydrogenated benzazepines
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The aryloxy- and heteroaryloxy-substituted tetrahydrobenzazepine derivative compounds of the present invention are represented by formulae (I) (A-E) having the following structure where the carbon atom designated * is in the R or S configuration and the substituents X and R¹-R⁹ are as defined herein.

Claims

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

2. The compound according to claim 1, wherein X is substituted phenyl and R⁴ is substituted monocyclic or bicyclic aryl or heteroaryl.

3. The compound according to claim 1, wherein X is substituted bicyclic aryl or heteroaryl and R⁴ is substituted monocyclic or bicyclic aryl or heteroaryl.

4. The compound according to claim 1, wherein X is substituted phenyl and R⁴ is H, —

OR¹², —

S(O)_nR¹³, C(O)R¹³, —

NR¹⁰R¹¹, —

CN, halogen, and C₁-C₆ alkyl, wherein each of the C₁-C₆ alkyl is optionally substituted from 1 to 3 times with substituents as defined in R¹⁵.

5. The compound according to claim 1, wherein X is substituted bicyclic aryl or heteroaryl and R⁴ is H, —

OR¹², —

S(O)_nR¹³, —

C(O)R¹³, —

NR¹⁰R¹¹, —

CN, —

S(O)_nR¹³, halogen, and C₁-C₆ alkyl, wherein each of the C₁-C₆ alkyl is optionally substituted from 1 to 3 times with substituents as defined in R¹⁵.

6. The compound according to claim 1, wherein X is substituted monocyclic heteroaryl and R⁴ is substituted monocyclic or bicyclic aryl or heteroaryl.

7. The compound according to claim 1, wherein:

X is phenyl, optionally substituted from 1 to 4 times with substituents as defined in R¹⁴;

R¹ is H, methyl, ethyl, or isopropyl;

R² is H, methyl, or gem-dimethyl;

R³ is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, difluoromethoxy or trifluoromethoxy;

R⁵ is H, fluoro, chloro, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, hydroxyl or methoxy;

R⁶ is H, fluoro, chloro, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, hydroxyl or methoxy;

R⁷ is H, gem-dimethyl, or C₁-C₄ alkyl, where each of the C₁-C₄ alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R¹⁵;

R⁸ is H, hydroxyl, fluoro, chloro, methyl, C₁-C₃ alkyl optionally substituted with hydroxyl or amino, or amino optionally substituted with C₁-C₃ alkyl; and

R⁹ is H, fluoro, chloro, methyl, hydroxyl, or cyano.

8. The compound according to claim 7, wherein:

R⁴ is H, halogen, —

OR¹², —

S(O)_nR¹³, —

CN, —

C(O)R¹³, —

NR¹⁰R¹¹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇ cycloalkylalkyl, wherein each of the C₁-C₆ 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 in R¹⁵.

9. The compound according to claim 7, wherein R⁴ is phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 6-oxopyridazin-1(6H)-yl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, oxooxazolidin-3-yl, optionally substituted from 1 to 4 times with substituents as defined in R¹⁴.

10. The compound according to claim 1, wherein:

X represents a 5- or 6-membered monocyclic heterocycle selected from the group consisting of pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl, optionally substituted from 1 to 4 times with substituents as defined in R¹⁴;

R¹ is H, methyl, ethyl, or isopropyl;

R² is H, methyl, or gem-dimethyl;

R³ is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, difluoromethoxy or trifluoromethoxy;

R⁵ is H, fluoro, chloro, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, hydroxyl or methoxy;

R⁶ is H, fluoro, chloro, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, hydroxyl or methoxy;

R⁷ is H, gem-dimethyl, or C₁-C₄ alkyl, where each of the C₁-C₄ alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R¹⁵;

R⁸ is H, hydroxyl, fluoro, chloro, methyl, C₁-C₃ alkyl optionally substituted with hydroxyl or amino, or amino optionally substituted with C₁-C₃ alkyl; and

R⁹ is H, fluoro, chloro, methyl, hydroxyl, or cyano.

11. The compound according to claim 10, wherein:

R⁴ is H, halogen, —

OR¹², —

S(O)_nR¹³, —

CN, —

C(O)R¹³, —

NR¹⁰R¹¹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇ cycloalkylalkyl, wherein each of the C₁-C₆ 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 in R¹⁵.

12. The compound according to claim 10, wherein R⁴ is phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 6-oxopyridazin-1(6H)-yl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, oxooxazolidin-3-yl, optionally substituted from 1 to 4 times with substituents as defined in R¹⁴.

13. The compound according to claim 1, wherein:

X is a [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycle or heterocycle selected from the group consisting of indenyl, indanyl, benzofuranyl, benzothiophenyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, indolyl, isoindolyl, indolinyl, benzo[1,3]dioxolyl, benzooxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl, benzoimidazolyl, benzotriazolyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 2,3-dihydro-benzo[1,4]dioxinyl, 4H-chromenyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-c]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, imidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, [1,2,4]triazolo[4,3-a]pyrazinyl, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined in R¹⁴;

R¹ is H, methyl, ethyl, or isopropyl;

R² is H, methyl, or gem-dimethyl;

R³ is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, difluoromethoxy or trifluoromethoxy;

R⁵ is H, fluoro, chloro, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, hydroxyl or methoxy;

R⁶ is H, fluoro, chloro, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, hydroxyl or methoxy;

R⁷ is H, gem-dimethyl, or C₁-C₄ alkyl, where each of the C₁-C₄ alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R¹⁵;

R⁸ is H, hydroxyl, fluoro, chloro, methyl, C₁-C₃ alkyl optionally substituted with hydroxyl or amino, or amino optionally substituted with C₁-C₃ alkyl; and

R⁹ is H, fluoro, chloro, methyl, hydroxyl, or cyano.

14. The compound according to claim 13, wherein:

R⁴ is H, halogen, —

OR¹², —

S(O)_nR¹³, —

CN, —

C(O)R¹³, —

NR¹⁰R¹¹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, or C₄-C₇ cycloalkylalkyl, wherein each of the C₁-C₆ 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 in R¹⁵.

15. The compound according to claim 13, wherein R⁴ is phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 6-oxopyridazin-1(6H)-yl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl and oxooxazolidin-3-yl, optionally substituted from 1 to 4 times with substituents as defined in R¹⁴.

16. The compound according to claim 1, wherein:

X is thiophenyl, thiazolyl, pyridinyl, phenyl, naphthyl, benzo[b]thiophenyl, benzofuranyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, or 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl, optionally substituted with from 1 to 3 substituents selected independently from the group consisting of fluoro, chloro, bromo, methoxy, hydroxyl, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, substituted C₁-C₃ alkyl, methanesulfonyl, carbamoyl, C₁-C₃ alkyl-substituted carbamoyl, and acetamido;

R¹ is H, methyl, ethyl, isopropyl;

R² is H or gem-dimethyl;

R³ is H, chloro or fluoro;

R⁴ is H, methoxy, hydroxyl, methyl, fluoro, bromo, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, acetyl, aminomethyl, 1-aminocyclopropyl, morpholinomethyl, 2-hydroxypropan-2-yl, morpholine-4-carbonyl, 2-morpholinoethoxy, 2-(dimethylamino)ethyl(methyl)amino, 2-hydroxyethylamino, piperidin-1-yl, piperidin-2-yl, pyrrolidin-1-yl, piperidin-4-ol, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(ethylsulfonyl)piperazin-1-yl, 4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl, 4-(pyridin-2-yl)piperazin-1-yl, 4-(pyrimidin-2-yl)piperazin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 6-methylpyridazin-3-yloxy, 6-aminopyridazin-3-yloxy, pyridazin-3-yloxy, pyrazin-2-yloxy, 3-aminopyrazin-2-yloxy, 5-aminopyrazin-2-yloxy, 6-aminopyrazin-2-yloxy, 1,2,4-oxadiazol-3-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrazol-4-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-(methanesulfonyl)phenyl, 3-(methanesulfonyl)phenyl, 2-(methanesulfonyl)phenyl, carbamoylphenyl, pyridinyl, aminopyridinyl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(difluoromethyl)pyridazin-3-yl, 6-((difluoromethoxy)methyl)pyridazin-3-yl, 6-aminopyridazin-3-yl, 6-(methylamino)pyridazin-3-yl, 6-(dimethylamino)pyridazin-3-yl, 6-morpholinopyridazin-3-yl, 6-(4-hydroxypiperidin-1-yl)pyridazin-3-yl, 6-(4-methylpiperazin-1-yl)pyridazin-3-yl, 6-(hydroxymethyl)pyridazin-3-yl, 6-(methoxycarbonyl)pyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5-aminopyrazin-2-yl, 6-aminopyrazin-2-yl, 2-oxopyridin-1(2H)-yl, 2-oxopyrrolidin-1-yl, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxopyridazin-1(6H)-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-3-yl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3,3-dimethyl-2-oxoindolin-5-yl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-methyl-[1,2,4]triazolo[4,3-b]-pyridazinyl, [1,2,4]triazolo[4,3-b]-pyridazinyl, or oxooxazolidin-3-yl;

R⁵ is H, chloro or fluoro;

R⁶ is H, chloro or fluoro;

R⁷ is H;

R⁸ is H, fluoro, methyl, or hydroxyl; and

R⁹ is H or hydroxyl.

17. The compound according to claim 1, wherein the carbon atom designated * is in the R configuration.

18. The compound according to claim 1, wherein the carbon atom designated * is in the S configuration.

19. The compound according to claim 1, wherein the compound is a (+) stereoisomer.

20. The compound according to claim 1, wherein the compound is a (−

) stereoisomer.

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 1.

22. A method of treating a disorder which is created by or is dependent upon decreased availability of norepinephrine, dopamine, or serotonin, said method comprising:

administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

23. The method according to claim 22, further comprising:

administering a therapeutically effective amount of a serotonin 1A receptor antagonist or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23, wherein the serotonin 1A receptor antagonist is WAY 100135 or spiperone.

25. The method according to claim 22, further comprising:

administering a therapeutically effective amount of a selective neurokinin-1 receptor antagonist or a pharmaceutically acceptable salt thereof.

26. The method according to claim 22, further comprising:

administering a therapeutically effective amount of a norepinephrine precursor or a pharmaceutically acceptable salt thereof.

27. The method according to claim 26, wherein the norepinephrine precursor is L-tyrosine or L-phenylalanine.

28. The method according to claim 22, wherein the disorder is selected from the group consisting of:

lower back pain, attention deficit hyperactivity disorder (ADHD), cognition impairment, anxiety disorders, generalized anxiety disorder (GAD), panic disorder, bipolar disorder or manic depression or manic-depressive disorder, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, social phobia, simple phobias, pre-menstrual dysphoric disorder (PMDD), social anxiety disorder (SAD), major depressive disorder (MDD), postnatal depression, dysthymia, depression associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease, or psychosis, supranuclear palsy, eating disorders, obesity, anorexia nervosa, bulimia nervosa, binge eating disorder, analgesia, substance abuse disorders, chemical dependencies, nicotine addiction, cocaine addiction, alcohol and amphetamine addiction, Lesch-Nyhan syndrome, neurodegenerative diseases, Parkinson'"'"'s disease, late luteal phase syndrome or narcolepsy, psychiatric symptoms, anger, rejection sensitivity, movement disorders, extrapyramidal syndrome, Tic disorders, restless leg syndrome (RLS), tardive dyskinesia, supranuclear palsy, sleep related eating disorder (SRED), night eating syndrome (NES), stress urinary incontinence (SUI), migraine, neuropathic pain, diabetic neuropathy, fibromyalgia syndrome (FS), chronic fatigue syndrome (CFS), sexual dysfunction, premature ejaculation, male impotence, and thermoregulatory disorders.