Aryloxy- and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

• US 8,987,252 B2
• Filed: 05/08/2008
• Issued: 03/24/2015
• Est. Priority Date: 05/10/2007
• Status: Expired due to Fees

• Current Assignee: Albany Molecular Research Incorporated, Bristol-Myers Squibb Company
• Original Assignee: Albany Molecular Research Incorporated, Bristol-Myers Squibb Company
• Inventors: Liu, Shuang, Yang, Yuh-lin Allen, Sambandam, Aruna, Molino, Bruce F., Olson, Richard E.
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US12/598,912
• Publication Number:
  US 20100210624A1
• Time in Patent Office: 2,511 Days
• Field of Search: 514/213.01, 540/593
• US Class Current: 514/213.01
• 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 aromatic monocyclic or bicyclic carbocycle or heterocycle.

3. The compound according to claim 1, wherein X is substituted aromatic bicyclic carbocycle or heterocycle and R⁴ is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle.

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

OR¹², —

S(O)_nR¹³, C(O)R¹³, —

NR¹⁰R¹¹, —

CN, halogen, and C₁-C₆ alkyl, wherein 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 aromatic bicyclic carbocycle or heterocycle and R⁴ is H, —

OR¹², —

S(O)_nR¹³, C(O)R¹³, —

NR¹⁰R¹¹, —

CN, halogen, and C₁-C₆ alkyl, wherein 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 aromatic monocyclic heterocycle and R⁴ is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle.

7. The compound according to claim 1, wherein:

X is phenyl, 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 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:

R⁴is H, halogen, —

OR¹², —

S(O)_nR¹³, —

CN, —

C(O)R¹³ , —

NR¹⁰R¹¹, or C₁-C₆ alkyl, wherein C₁-C₆ alkyl 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, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 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, 3,3-dimethyl-2-oxoindolinyl, 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, 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, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl, 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 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 phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 6-oxopyridazin-1(6H)-yl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 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, 3,3-dimethyl-2-oxoindolinyl, 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, substituted from 1 to 4 times with substituents as defined in R¹⁴.

12. The compound according to claim 1, wherein:

X is a [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused aromatic bicyclic carbocycle or heterocycle selected from the group consisting of indenyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzooxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl, benzoimidazolyl, benzotriazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, 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, 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, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,2-a]pyrazinyl, 3,3-dimethyl-2-oxoindolinyl, 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, 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 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.

13. The compound according to claim 12, wherein:

R⁴ is H, halogen, —

OR¹², —

S (O)_nR¹³, —

CN, —

C(O)R¹³, —

NR¹⁰R¹¹, or C₁-C₆ alkyl, wherein C₁-C₆alkyl is optionally substituted from 1 to 3 times with substituents as defined in R¹⁵.

14. The compound according to claim 12, wherein R⁴ is phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 6-oxopyridazin-1(6H)-yl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 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, 3,3-dimethyl-2-oxoindolinyl, 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, substituted from 1 to 4 times with substituents as defined in R¹⁴.

15. The compound according to claim 1, wherein:

X is thiophenyl, thiazolyl, pyridinyl, phenyl, naphthyl, benzo[b]thiophenyl, or benzofuranyl, 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, 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, aminopyridinyl, 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, 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, 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, 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, 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.

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

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

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

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

) stereoisomer.

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

21. A compound selected from the group consisting of:

(+)-2-methyl-5-(naphthalen-2-yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-5-(4-chlorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-2-methyl-8-(pyridazin-3-yl)-5-(p-tolyloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-2-methyl-8-(pyridazin-3-yl)-5-(4-(trifluoromethoxy)phenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-5-(3,5-difluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-4-(2-Methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yloxy)benzonitrile;

(+)-5-(3,4-Dichlorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-5-(3,4-Difluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-5-(2,4-Difluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3 ,4,5-tetrahydro- 1H-benzo[c]azepine;

(−

)-2-methyl-5-phenoxy-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c] azepine;

(−

)-2-methyl-8-(pyridazin-3-yl)-5-(pyridin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-5 -(2-flurophenoxy)-2-methyl-8-(pyridazin-3-yl)-2 ,3 ,4,5-tetrahydro- 1H-benzo[c]azepine;

(−

)-5 -(3-flurophenoxy)-2-methyl-8-(pyridazin-3-yl)-2 ,3 ,4,5-tetrahydro- 1H-benzo[c]azepine;

(−

)-5 -(3,5 -difluorophenoxy)-2-methyl-8-(pyridazin-3 -yl)-2,3 ,4,5 -tetrahydro- 1H-benzo[c]azepine;

(+)-2-Methyl-5-(naphthalen- 1 -yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c] azepine;

(+)-2-methyl-8-(6-methylpyridazin-3-yl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-methyl-8 -(6-methylpyridazin-3 -yl)-5 -phenoxy-2,3 ,4,5 -tetrahydro- 1H-benzo[c]azepine;

(−

)-5-(4-fluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-5 -(4-fluorophenoxy)-2-methyl-8 -(pyridazin-3-yl)-2 ,3 ,4,5 -tetrahydro- 1H-benzo[c]azepine;

(−

)-5 -(naphthalen-2-yloxy)-2-methyl-8 -(pyridazin-3-yl)-2 ,3 ,4,5-tetrahydro- 1H-benzo[c]azepine;

(±

)-5-(4-fluorophenoxy)-2-methyl-8-(pyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-benzo [c]azepine;

(±

)-5-(4-fluorophenoxy)-2-methyl- 8-(1H-pyrazol-4-yl)-2 ,3 ,4,5-tetrahydro- 1H-benzo[c] azepine;

(±

)-6-(5-(4-fluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo [c] azepin-8 -yl)pyridazin-3-amine;

(±

)-8-(4-(ethylsulfonyl)piperazin- 1 -yl)-5 -(4-fluorophenoxy)-2-methyl-2,3 ,4,5-tetrahydro- 1H-benzo[c]azepine;

(+)-2-methyl-5 -(4-(trifluoromethyl)phenoxy)-2 ,3 ,4,5-tetrahydro-1 H-benzo [c]azepine;

(−

)-2-methyl-5-(4-(trifluoromethyl)phenoxy)-2,3,4,5-tetrahydro-1H-benzo [c]azepine;

(±

)-5-(4-fluorophenoxy)-2-methyl-8-(pyrazin-2-yl)-2,3,4,5-tetrahydro-1H-benzo [c]azepine;

(±

)-6-(5-(4-fluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo [c] azepin-8 -yl)pyridin-2-amine;

(±

)-6-(5-(4-fluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo [c]azepin-8-yl)pyridazin-3(2H)-one;

(±

)-5-(4-fluorophenoxy)-2-methyl- 8-(4-(methylsulfonyl)phenyl)-2 ,3 ,4,5 -tetrahydro- 1H-benzo[c]azepine;

(±

)-2-(5-(4-fluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo [c] azepin-8 -yl)benzonitrile;

(±

)-8-([1,2 ,4]triazolo [ 1 ,5-a]pyridin-6-yl)-5-(4-fluorophenoxy)-2-methyl-2 ,3 ,4,5 -tetrahydro- 1H-benzo[c]azepine;

(±

)-8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-(4-fluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(±

)-1-(5-(4-fluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridin-2(1H)-one;

(−

)-8-(6-methylpyridazin-3-yl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-methyl-8-(pyridazin-3-yl)-5-(quinolin-7-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-5-(2-chlorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(±

)-2-(5-(3,5-difluorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

(+)-8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3,5-difluorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3,5-difluorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c] azepine;

(±

) 8-(6-(difluoromethoxy)pyridazin-3-yl)-5-(3,5-difluorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(±

)-2-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridazin-3(2H)-one;

(±

)-2-(5-(3,5-difluorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridazin-3(2H)-one;

(+)-8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-8-(6-(difluoromethoxy)pyridazin-3-yl)-5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-8-(6-(difluoromethoxy)pyridazin-3-yl)-5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-6-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridazin-3-amine;

(−

)-6-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridazin-3-amine;

(+)-2-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

(−

)-2-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

1-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridin-2(1H)-one (Enantiomer A);

1-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridin-2(1H)-one (Enantiomer B);

(+)-4-(2-methyl-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzamide;

(−

)-4-(2-methyl-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzamide;

(+)-2-Methyl-8-(4-methylsulfonylphenyl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+2-Methyl-8-(4-methylsulfonylphenyl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-5-(3,5-difluorophenoxy)-2-methyl-8-(4-(methylsulfonyl)phenyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepine;

(−

)-5-(3,5-difluorophenoxy)-2-methyl-8-(4-(methylsulfonyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo [c]azepine;

(+)-4-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzonitrile;

(−

)-4-(5-(3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzonitrile;

(−

)-2-Methyl-5-phenoxy-8-(pyrimidin-2-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-8-(6-aminopyridazin-3-yl)-2-methyl-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+8-(6-aminopyridazin-3-yl)-2-methyl-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+5-(2,3-difluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-5-(3-cyanophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-5-(4-cyanophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-5-(2,5-difluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

and (−

)-5-(2,6-difluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

22. The compound according to claim 21 selected from the group consisting of:

(+)-2-methyl-5-(naphthalen-2-yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-methyl-5-phenoxy-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-methyl-8-(pyridazin-3-yl)-5-(pyridin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-Methyl-5-(naphthalen-1-yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-2-methyl-8-(6-methylpyridazin-3-yl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-methyl-8-(6-methylpyridazin-3-yl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-5-(naphthalen-2-yloxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-8-(6-methylpyridazin-3-yl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-methyl-8-(pyridazin-3-yl)-5-(quinolin-7-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-4-(2-methyl-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzamide;

(−

)-4-(2-methyl-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzamide;

(+)-2-Methyl-8-(4-methylsulfonylphenyl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-Methyl-8-(4-methylsulfonylphenyl)-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(−

)-2-Methyl-5-phenoxy-8-(pyrimidin-2-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepine;

(+)-8-(6-aminopyridazin-3-yl)-2-methyl-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine; and

(−

)-8-(6-aminopyridazin-3-yl)-2-methyl-5-phenoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.