ARYL, HETEROARYL, AND HETEROCYCLE SUBSTITUTED TETRAHYDROISOQUINOLINES AND USE THEREOF

• US 20100292242A1
• Filed: 05/11/2010
• Published: 11/18/2010
• Est. Priority Date: 05/12/2009
• Status: Active Grant

• Current Assignee: Consynance Therapeutics Incorporated
• Original Assignee: Albany Molecular Research Incorporated
• Inventors: Molino, Bruce F., Liu, Shuang, Nacro, Kassoum
• Granted Patent: US 9,034,899 B2
• Time in Patent Office: Days
• US Class Current: 514/252.04
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 25/20 Hypnotics; Sedatives
• 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 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 217/02 : with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 217/12 : with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 217/14 : other than aralkyl radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Novel aryl, heteroaryl, and non-aromatic heterocyle substituted tetrahydroisoquinolines are described in the present invention. These compounds are used in the treatment of various neurological and physiological disorders. Methods of making these compounds are also described in the present invention.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein R¹ is H, C₁-C₆ alkyl, or gem-dialkyl of which each alkyl is C₁-C₄.

3. The compound of claim 2, wherein R¹ is H or gem-dimethyl.

4. The compound of claim 1, wherein R² is H, halogen, —

OR¹¹, —

S(O)_nR¹², —

CN, —

C(O)R¹², —

C(O)NR¹¹R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

5. The compound of claim 4, wherein R² is H or F.

6. The compound of claim 1, wherein R³ is phenyl optionally substituted from 1 to 4 times with substituents as defined in R¹⁴.

7. The compound of claim 1, wherein R³ is a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, 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, furo[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, 2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 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, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R¹⁴.

8. The compound of claim 7, wherein R³ is 1,2,4-oxadiazol-3-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 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-(hydroxymethyl)pyridazin-3-yl, 6-methoxypyridazin-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, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxopyridazin-1(6H)-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-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, 3,3-dimethyl-2-oxoindolin-6-yl, 3-methyl-[1,2,4]-triazolo[4,3-b]-pyridazinyl, or [1,2,4]triazolo[4,3-b]-pyridazinyl.

9. The compound of claim 1, wherein R³ is a non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R¹⁴.

10. The compound of claim 1, wherein R⁴ is H, Cl, F, CH₃, OH, or OCH₃.

11. The compound of claim 1, wherein R⁴ is H or F.

12. The compound of claim 1, wherein R⁵, R⁶, and R⁷ are each independently selected from the group consisting of H, halogen, —

OR¹¹, —

NR¹¹R¹², —

NR¹¹C(O)R¹², S(O)_nR¹², —

CN, —

C(O)R¹², —

C(O)NR¹¹R¹², C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

13. The compound of claim 12, wherein R⁷ is H.

14. The compound of claim 13, wherein R⁵ and R⁶ are each H, F, Cl, OH, OCH₃, or CH₃.

15. The compound of claim 14, wherein R⁵ and R⁶ are each Cl.

16. The compound of claim 1, wherein R⁸ is H, OH, CH₃, or F.

17. The compound of claim 1, wherein:

R¹ is H, C₁-C₆ alkyl, or gem-dialkyl of which each alkyl is C₁-C₄;

R² is H, halogen, —

OR¹¹, —

S(O)₂R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl;

R³ is aryl, heteroaryl, or non-aromatic heterocycle;

R⁴ is H, F, or Cl; and

R⁵, R⁶, and R⁷ are each independently H, halogen, —

OR¹¹, —

NR¹¹R¹², —

S(O)₂R¹², —

C(O)R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

18. The compound of claim 1, wherein:

R¹ is H or gem-dimethyl;

R² is H;

R³ is phenyl, or heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, 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, furo[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, 2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 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, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxo-azepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl;

wherein the phenyl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R¹⁴;

R⁴ is H or F;

R⁵ and R⁶ are each independently H, F, Cl, OH, OMe, or Me;

R⁷ is H or F; and

R⁸ is H, OH, or F.

19. The compound of claim 1, wherein:

R¹ is H or gem-dimethyl;

R² is H;

R³ is 1,2,4-oxadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 2-aminopyridinyl, 3-aminopyridinyl, 4-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-(hydroxymethyl)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, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-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, 3-methyl-[1,2,4]triazolo[4,3-b]-pyridazinyl, [1,2,4]triazolo[4,3-b]-pyridazinyl, or oxooxazolidin-3-yl;

R⁴ is H or F;

R⁵ and R⁶ are each independently H, F, Cl, or CH₃;

R⁷ is H; and

R⁸ is H.

20. A compound according to claim 1, selected from the group consisting of:

4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;

7-(6-methylpyridazin-3-yl)-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline;

6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;

6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine;

4-(4-chlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

6-(4-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;

4-(4-chlorophenyl)-7-(6-chloropyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline;

4-(4-chlorophenyl)-1-methyl-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(4-chlorophenyl)-7-(6-methoxypyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-1,1-dimethyl-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-1,1-dimethyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;

3-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;

4-(3,4-dichlorophenyl)-7-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline;

1-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one;

2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one;

4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methylpyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

6-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one;

4-(3,4-dichlorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline;

4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dimethylisoxazole;

4-(4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide;

5-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine;

6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine;

4-(3,4-dichlorophenyl)-6-fluoro-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4]triazolo[1,5-α

]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-6-fluoro-7-(pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;

4-(4-chlorophenyl)-1,1-dimethyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(4-(4-chlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide;

6-(4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;

7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline; and

an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

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. A compound of formula (I):

24. The compound of claim 23, wherein R¹ is C₁-C₆ alkyl or gem-dialkyl.

25. The compound of claim 24, wherein R¹ is gem-dimethyl.

26. The compound of claim 23, wherein R² is H, halogen, —

OR¹¹, —

S(O)_nR¹², —

CN, —

C(O)R¹², —

C(O)NR¹¹R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

27. The compound of claim 26, wherein R² is H or F.

28. The compound of claim 23, wherein R³ is phenyl optionally substituted from 1 to 4 times with substituents as defined in R¹⁴.

29. The compound of claim 23, wherein R³ is a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, 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, furo[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, 2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 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, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R¹⁴.

30. The compound of claim 29, wherein R³ is 1,2,4-oxadiazol-3-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 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-(hydroxymethyl)pyridazin-3-yl, 6-methoxypyridazin-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, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxopyridazin-1(6H)-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-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, 3,3-dimethyl-2-oxoindolin-6-yl, 3-methyl-[1,2,4]triazolo[4,3-b]-pyridazinyl, or [1,2,4]triazolo[4,3-b]-pyridazinyl.

31. The compound of claim 23, wherein R³ is a non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R¹⁴.

32. The compound of claim 23, wherein R⁴ is H, Cl, F, or CH₃.

33. The compound of claim 32, wherein R⁴ is H or F.

34. The compound of claim 23, wherein R⁵, R⁶, and R⁷ are each independently selected from the group consisting of H, halogen, —

OR¹¹, —

NR¹¹C(O)R¹², S(O)_nR¹², —

CN, —

C(O)R¹², —

C(O)NR¹¹R¹², C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

35. The compound of claim 34, wherein R⁷ is H.

36. The compound of claim 35, wherein R⁵ and R⁶ are each H, F, Cl, OH, OCH₃, or CH₃.

37. The compound of claim 36, wherein R⁵ and R⁶ are each Cl.

38. The compound of claim 23, wherein R⁸ is H, OH, CH₃, or F.

39. The compound of claim 23, wherein:

R¹ is C₁-C₆ alkyl or gem-dialkyl of which each alkyl is C₁-C₄;

R² is H, halogen, —

OR¹¹, —

S(O)₂R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl;

R³ is aryl, heteroaryl, or non-aromatic heterocycle;

R⁴ is H, F, or Cl; and

R⁵, R⁶, and R⁷ are each independently H, halogen, —

OR¹¹, —

S(O)₂R¹², —

C(O)R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 23.

41. 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 23 or a pharmaceutically acceptable salt thereof.

42. A compound of formula (I):

43. The compound of claim 42, wherein R¹ is gem-dimethyl.

44. The compound of claim 42, wherein R² is H, halogen, —

OR¹¹, —

S(O)_nR¹², —

CN, —

C(O)R¹², —

C(O)NR¹¹R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

45. The compound of claim 44, wherein R² is H or F.

46. The compound of claim 42, wherein R³ is phenyl optionally substituted from 1 to 4 times with substituents as defined in R¹⁴.

47. The compound of claim 42, wherein R³ is a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, 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, furo[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, 2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 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, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R¹⁴.

48. The compound of claim 47, wherein R³ is 1,2,4-oxadiazol-3-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 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-(hydroxymethyl)pyridazin-3-yl, 6-methoxypyridazin-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, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxopyridazin-1(6H)-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-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, 3,3-dimethyl-2-oxoindolin-6-yl, 3-methyl-[1,2,4]triazolo[4,3-b]-pyridazinyl, or [1,2,4]triazolo[4,3-b]-pyridazinyl.

49. The compound of claim 42, wherein R³ is a non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R¹⁴.

50. The compound of claim 42, wherein R⁴ is H, Cl, F, CH₃, OH, or OCH₃.

51. The compound of claim 50, wherein R⁴ is H or F.

52. The compound of claim 42, wherein R⁵, R⁶, and R⁷ are each independently selected from the group consisting of H, halogen, —

OR¹¹, —

NR¹¹R¹², —

NR¹¹C(O)R¹², —

S(O)_nR¹², —

CN, —

C(O)R¹², —

C(O)NR¹¹R¹², C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

53. The compound of claim 52, wherein R⁷ is H.

54. The compound of claim 53, wherein R⁵ and R⁶ are each H, F, Cl, OH, OCH₃, or CH₃.

55. The compound of claim 54, wherein R⁵ and R⁶ are each Cl.

56. The compound of claim 42, wherein R⁸ is H, OH, CH₃, or F.

57. The compound of claim 42, wherein:

R¹ is gem-dialkyl of which each alkyl is C₁-C₄;

R² is H, halogen, —

OR¹¹, —

S(O)₂R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl;

R³ is aryl, heteroaryl, or non-aromatic heterocycle;

R⁴ is H, F, or Cl; and

R⁵, R⁶, and R⁷ are each independently H, halogen, —

OR¹¹, —

NR¹¹R¹², —

S(O)₂R¹², —

C(O)R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

58. The compound of claim 42, wherein:

R¹ is gem-dimethyl;

R² is H;

R³ is phenyl, or heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, 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, furo[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, 2-oxo-2,3-dihydro-1H-benzo[d]imidazole, 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, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, or non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxo-azepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl;

wherein the phenyl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R¹⁴;

R⁴ is H or F;

R⁵ and R⁶ are each independently H, F, Cl, OH, OMe, or Me;

R⁷ is H or F; and

R⁸ is H, OH, or F.

59. The compound of claim 42, wherein:

R¹ is gem-dimethyl;

R² is H;

R³ is 1,2,4-oxadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 2-aminopyridinyl, 3-aminopyridinyl, 4-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-(hydroxymethyl)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, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-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, 3-methyl-[1,2,4]triazolo[4,3-b]-pyridazinyl, [1,2,4]triazolo[4,3-b]-pyridazinyl, or oxooxazolidin-3-yl;

R⁴ is H or F;

R⁵ and R⁶ are each independently H, F, Cl, or CH₃;

R⁷ is H; and

R⁸ is H.

60. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 42.

61. 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 42 or a pharmaceutically acceptable salt thereof.

62. A compound of formula (I):

63. The compound according to claim 62, wherein R¹ is H, methyl, or gem-dimethyl.

64. The compound according to claim 62, wherein R² is H, F, Cl, CN, Me, CF₃, CF₂H, OMe, OCF₃, OCF₂H, or OH.

65. The compound according to claim 62, wherein R³ is [1,2,4]triazolo[1,5-a]pyridinyl-6-yl which is optionally substituted by R¹⁴.

66. The compound according to claim 62, wherein R⁴ is H, F, Cl, CN, Me, CF₃, CF₂H, OMe, OCF₃, OCF₂H, or OH.

67. The compound according to claim 62, wherein R⁵ to R⁷ is independently, H, F, Cl, CN, Me, CF₃, CF₂H, OMe, OCF₃, OCF₂H, or OH.

68. The compound according to claim 62, wherein R⁸ is H.

69. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 62.

70. 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 62 or a pharmaceutically acceptable salt thereof.

71. A compound of formula (I):

72. The compound according to claim 71, selected from the group consisting of:

7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;

6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2(3H)-one;

and an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

73. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 71.

74. 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 71 or a pharmaceutically acceptable salt thereof.