Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
View Patent ↗The aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepine derivative compounds of the present invention are represented by formulae 1(A-D) having the following structure: where the substituents X and R 1 -R 8 are as defined herein.
1. A compound of formulae I(A-D) having the following structure:
wherein:
X represents a 5- or 6-membered aromatic monocyclic carbocycle or heterocycle selected from the group consisting of phenyl, 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 below in R 9 , or other 5- or 6-membered aromatic monocyclic carbocycles or heterocycles containing 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, substituted from 1 to 4 times with substituents as defined below in R 9 ; or
X is a [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused 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, [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 below in R 9 , or other [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycles or heterocycles containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, substituted from 1 to 4 times with substituents as defined below in R 9 ;
R 1 and R 2 are each independently selected from the group consisting of H, 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, each of which is optionally substituted from 1 to 3 times with substituents as defined below in R 10 ; or
R 2 is gem-dimethyl;
R 3 , R 5 , and R 6 are each independently selected from the group consisting of H, halogen, —OR 11 , —NR 12 R 13 , S(O) n R 14 , —CN, —C(O)R 15 , 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 the 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 10 ; or
R 3 , R 5 , and R 6 are each independently a 5- or 6-membered monocyclic carbocycle or heterocycle or a [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycle or heterocycle containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, optionally substituted from 1 to 4 times with substituents as defined below in R 9 ;
R 4 is H, halogen, —OR 11 , —NR 12 R 13 , —S(O) n R 14 , —CN, —C(O)R 15 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 4 -C 7 cycloalkylalkyl, where each of the 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 10 ; or
R 4 is an aromatic monocyclic or bicyclic carbocycle or an aromatic or non-aromatic monocyclic or bicyclic heterocycle selected from the group consisting of phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 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-pynolo[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, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, substituted from 1 to 4 times with substituents as defined below in R 9 , or other 5- or 6-membered monocyclic carbocycles or heterocycles or [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycles or heterocycles containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, substituted from 1 to 4 times with substituents as defined below in R 9 ;
provided that for compounds of formula IA, X is substituted phenyl and R 4 is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle;
provided that for compounds of formula IB, X is substituted aromatic bicyclic carbocycle or heterocycle and R 4 is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle;
provided that for compounds of formula IC, X is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle and R 4 is H, —OR 11 , —NR 12 R 13 , —S(O) n R 14 , —C(O)R 15 , —CN, halogen or C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 10 ; and
provided that for compounds of formula ID, X is substituted aromatic monocyclic heterocycle and R 4 is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle;
R 7 and R 8 are each independently selected from the group consisting of H, 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, each of which is optionally substituted from 1 to 3 times with substituents as defined below in R 10 ; or
R 2 , R 7 , and R 8 are gem-dimethyl, with the proviso that only one of R 7 and R 8 is gem-dimethyl;
R 9 is independently selected at each occurrence from a substituent in the group consisting of halogen, —NO 2 , —CN, —OR 11 , —NR 12 R 13 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) n R 14 , —C(O)R 15 , 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 10 ;
R 10 is independently selected at each occurrence from a substituent in the group consisting of —CN, halogen, C 1 -C 3 alkyl, —OR 11 , —NR 12 R 13 , —S(O) n R 14 , C(O)R 15 , 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 9 ;
R 11 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 15 , wherein 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 above in R 10 ; or
R 11 is selected from the group consisting of phenyl, benzyl, pyridazinyl, pyrimidinyl, pyrazinyl, other 5- or 6-membered aromatic monocyclic heterocycles, and [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycles or heterocycles containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, optionally substituted from 1 to 4 times with substituents as defined above in R 9 ;
R 12 and R 13 are each independently selected from the group consisting of H, —C(O)R 15 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein 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 above in R 10 ;
R 12 and R 13 are each independently selected from the group consisting of phenyl, benzyl, and other 5- or 6-membered monocyclic heterocycles, wherein 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 9 ;
R 12 and R 13 are each independently a bridged bicyclic ring containing 6-12 carbon atoms and optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the bridged bicyclic ring is optionally substituted from 1 to 3 times with substituents selected from the group consisting of C 1 -C 3 alkyl, —S(O) n R 14 , and —C(O)R 15 , with the proviso that only one of R 12 and R 13 is a bridged bicyclic ring;
R 12 and R 13 are taken together with the nitrogen to which they are attached to form a saturated or partially saturated monocyclic or bicyclic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, thiomorpholine, [1,2]oxazinane, isoxazolidine, 2-oxopiperidine, 2-oxopyrrolidine, 3-oxomorpholine, 3-oxothiomorpholine, 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, 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 11 , —NR 12 R 13 , —S(O) n R 14 , —C(O)R 15 , 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 above in R 10 ;
R 12 and R 13 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 11 , —NR 12 R 13 , —S(O) n R 14 , —C(O)R 15 , 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 14 , —C(O)R 15 , 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 above in R 10 ;
R 12 and R 13 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 9 ; or
when R 4 is —NR 12 R 13 or —C(O)NR 12 R 13 , either R 12 or R 13 is a bridged bicyclic ring containing 6-12 carbon atoms and optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where the bridged bicyclic ring is optionally substituted from 1 to 3 times with substituents selected from the group consisting of C 1 -C 3 alkyl, —C(O)R 15 , and —S(O) n R 14 , or either R 12 or R 13 is a C 1 -C 3 alkyl substituted with a bridged bicyclic ring containing 6-12 carbon atoms and optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where the bridged bicyclic ring is optionally substituted from 1 to 3 times with substitutents selected from the group consisting of C 1 -C 3 alkyl, —C(O)R 15 , and —S(O) n R 14 ;
R 14 is selected from the group consisting of H, —NR 12 R 13 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein 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 above in R 10 ; or
R 14 is selected from the group consisting of phenyl, benzyl, pyridazinyl, pyrimidinyl, pyrazinyl, 5- or 6-membered aromatic monocyclic heterocycles, and [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycles or heterocycles containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, optionally substituted from 1 to 4 times with substituents as defined above in R 9 ;
R 15 is selected from the group consisting of H, —OR, —NR 12 R 13 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein 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 above in R 10 ; or
R 15 is selected from the group consisting of phenyl, benzyl, pyridazinyl, pyrimidinyl, pyrazinyl, 5- or 6-membered aromatic monocyclic heterocycles, and [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycles or heterocycles containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, optionally substituted from 1 to 4 times with substituents as defined above in R 9 ;
n is 0, 1 or 2;
with the following proviso that when R 1 is n-propyl, X cannot be 3-(trifluoromethyl)phenyl;
or an oxide of, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein X is substituted phenyl and R 4 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 R 4 is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle.
4. The compound according to claim 1 , wherein X is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle and R 4 is H, —OR 11 , —NR 12 R 13 , —S(O) n R 14 , —C(O)R 15 , —CN, halogen, or C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 .
5. The compound according to claim 1 , wherein X is substituted aromatic monocyclic heterocycle and R 4 is substituted aromatic monocyclic or bicyclic carbocycle or heterocycle.
6. The compound according to claim 1 , wherein:
X is phenyl, substituted from 1 to 4 times with substituents as defined in R 9 ;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 3 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 5 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 6 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, where C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 ; and
R 8 is H, gem-dimethyl, or C 1 -C 4 alkyl, where C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 .
7. The compound according to claim 6 , wherein R 4 is H, halogen, —OR, —NR 12 R 13 , —S(O) n R 14 , —CN, —C(O)R 15 , or C 1 -C 6 alkyl, where C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 .
8. The compound according to claim 6 , wherein R 4 is phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 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, substituted from 1 to 4 times with substituents as defined in R 9 .
9. The compound according to claim 1 , wherein:
X represents a 5- or 6-membered aromatic 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 R 9 ;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 3 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 5 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 6 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, where C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 ; and
R 8 is H, gem-dimethyl, or C 1 -C 4 alkyl, where C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 .
10. The compound according to claim 9 , wherein R 4 is H, halogen, —OR 11 , —NR 12 R 13 , —S(O) n R 14 , —CN, —C(O)R 15 , or C 1 -C 6 alkyl, where C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 .
11. The compound according to claim 9 , wherein R 4 is phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 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, substituted from 1 to 4 times with substituents as defined in R 9 .
12. 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, 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, [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 R 9 ;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 3 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 5 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 6 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, where C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 ; and
R 8 is H, gem-dimethyl, or C 1 -C 4 alkyl, where C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 .
13. The compound according to claim 12 , wherein R 4 is H, halogen, —OR 11 , —NR 12 R 13 , —S(O) n R 14 , —CN, —C(O)R 15 , or C 1 -C 6 alkyl, where C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 .
14. The compound according to claim 12 , wherein R 4 is phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 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, substituted from 1 to 4 times with substituents as defined in R 9 .
15. The compound according to claim 1 , wherein:
X is a 5- or 6-membered aromatic monocyclic carbocycle or heterocycle or a [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycle or heterocycle containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, substituted from 1 to 4 times with substituents as defined in R 9 ;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 4 is H, methyl, hydroxyl, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 3 , R 5 , and R 6 are each independently selected from the group consisting of H, halogen, —OR 11 , —NR 12 R 13 , S(O) n R 14 , —CN, —C(O)R 15 , 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 the 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 10 ; or
R 3 , R 5 , and R 6 are each independently a 5- or 6-membered monocyclic carbocycle or heterocycle or a [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycle or heterocycle containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, optionally substituted from 1 to 4 times with substituents as defined in R 9 , with the proviso that only one of R 3 , R 5 , and R 6 is 5- or 6-membered monocyclic carbocycle or heterocycle or a [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycle or heterocycle;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, where C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 ; and
R 8 is H, gem-dimethyl, or C 1 -C 4 alkyl, where C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 10 .
16. The compound according to claim 1 , wherein:
X is phenyl, pyridinyl, naphthyl, benzo[b]thiophenyl, or benzofuranyl, substituted with from 1 to 3 substituents selected independently from the group consisting of fluoro, chloro, bromo, methoxy, cyano, trifluoromethyl, difluoromethoxy, carbamoyl, C 1 -C 3 alkyl-substituted carbamoyl, trifluoromethoxy, acetamido, methanesulfonyl, and substituted C 1 -C 3 alkyl;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H;
R 3 is H or fluoro;
R 4 is H, methoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, morpholino, piperazinyl, 4-acetylpiperazin-1-yl, 4-(ethylsulfonyl)piperazin-1-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-(methanesulfonyl)phenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 1H-pyrazol-1-yl, 1H-pyrazol-4-yl, oxazol-2-yl, thiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1H-1,2,4-triazol-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-aminopyridin-2-yl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(hydroxymethyl)pyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(difluoromethyl)pyridazin-3-yl, 6-(difluoromethoxy)pyridazin-3-yl, 6-aminopyridazin-3-yl, pyrimidin-2-yl, pyrimidin-2-ylamino, pyrimidin-5-yl, pyrazin-2-yl, 2-oxopyridin-1(2H)-yl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, or [1,2,4]triazolo[4,3-a]pyridin-6-yl;
R 5 is H or fluoro;
R 6 is H or fluoro;
R 7 is H; and
R 8 is H.
17. The compound according to claim 1 , wherein R 9 is independently selected at each occurrence from a substituent in the group consisting of halogen, —CN, —OR 11 , —NR 12 R 13 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) n R 14 , —C(O)R 5 , 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 in R 10 .
18. The compound according to claim 9 , wherein X represents a 5- or 6-membered aromatic monocyclic heterocycle selected from the group consisting of 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 R 9 .
19. A compound selected from the group consisting of:
1-(1-fluoronaphthalen-2-yl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(4-(methylsulfonyl)phenyl)-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(3,5-difluorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(2,4-difluorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-7-(pyridazin-3-yl)-1-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(5-fluoronaphthalen-2-yl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-fluoronaphthalen-2-yl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
3-(4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)benzonitrile;
1-(benzo[d][1,3]dioxol-5-yl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-1-yl)-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(3,4-difluorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(3-fluorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(3,4-dichlorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(2-fluorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(3-chlorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-phenyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(1-(4-chlorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2(1H)-one;
1-(4-chlorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-fluorophenyl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-7-(6-methylpyridazin-3-yl)-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-fluorophenyl)-4-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-methyl-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2(1H)one;
7-(4-(ethylsulfonyl)piperazin-1-yl)-4-methyl-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(pyridin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-N-(pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-amine;
4-methyl-1-(naphthalen-2-yl)-7-(pyrazin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-7-(4-(methanesulfonyl)phenyl)-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(1H-pyrazol-1-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-7-(6-methylpyridazin-3-yl)-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
7-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-methyl-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(pyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-chlorophenyl)-4-methyl-7-(pyrazin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-chlorophenyl)-4-methyl-7-(4-(methylsulfonyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-chlorophenyl)-4-methyl-7-(pyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-chlorophenyl)-4-methyl-7-(pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-(1-(4-chlorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)benzamide;
7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(4-chlorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
7-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-(4-chlorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine; and
6-(1-(4-chlorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridazin-3-amine.
20. The compound according to claim 19 selected from the group consisting of:
1-(benzo[d][1,3]dioxol-5-yl)-4-methyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-1-yl)-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-phenyl-7-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-7-(6-methylpyridazin-3-yl)-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
1-(4-methyl-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)pyridin-2(1H)one;
7-(4-(ethylsulfonyl)piperazin-1-yl)-4-methyl-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(pyridin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-N-(pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-amine;
4-methyl-1-(naphthalen-2-yl)-7-(pyrazin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-7-(4-(methanesulfonyl)phenyl)-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(1H-pyrazol-1-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-7-(6-methylpyridazin-3-yl)-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
7-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-methyl-1-(naphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine;
4-methyl-1-(naphthalen-2-yl)-7-(pyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine; and
4-methyl-1-(naphthalen-2-yl)-7-(pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine.
21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 1 .