Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
View Patent ↗The compounds of the present invention are represented by the following aryl- and heteroaryl-substituted tetrahydrobenzazepine and dihydrobenzazapine derivatives having formulae I(A-E) and formula (II): where the carbon atom designated * is in the R or S configuration, and the substituents X and R 1 -R 9 are as defined herein.
1. A compound of formulae I(A-E) having the following structure:
wherein:
the carbon atom designated * is in the R or S configuration; and
X represents a 5- or 6-membered aromatic or nonaromatic monocyclic carbocycle or heterocycle selected from the group consisting of phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ; 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, indanyl, benzofuranyl, benzothiophenyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, isoindolyl, indolinyl, benzo[1,3]dioxolyl, benzooxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl, benzoimidazolyl, benzotriazolyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 2,3-dihydro-benzo[1,4]dioxinyl, 4H-chromenyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, imidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, [1,2,4]triazolo[4,3-a]pyrazinyl, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ;
R 1 is H, 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, each of which is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
R 2 is H, 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, each of which is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; 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 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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 15 ; 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 14 ;
R 4 is H, halogen, —OR 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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, 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 15 ;
R 4 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, wherein 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 13 , and —S(O) n R 13 ; or
R 4 is a monocyclic or bicyclic aryl or heteroaryl selected from the group consisting of phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo [d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ;
provided that for compounds of formula IA, X is substituted phenyl and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl;
provided that for compounds of formula IB, X is substituted bicyclic carbocycle or heterocycle and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl;
provided that for compounds of formula IC, X is substituted phenyl and R 4 is H, —OR 12 , —S(O) n R 13 , C(O)R 13 , —NR 10 R 11 , —CN, halogen, or C 1 -C 6 alkyl, wherein each of the C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
provided that for compounds of formula ID, X is substituted bicyclic carbocycle or heterocycle and R 4 is H, —OR 12 , —S(O) n R 13 , C(O)R 13 , —NR 10 R 11 , —CN, halogen, or C 1 -C 6 alkyl, wherein each of the C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; and
provided that for compounds of formula IE, X is substituted aromatic monocyclic heterocycle and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl;
R 7 is selected from the group consisting of H, —S(O) n R 13 , —C(O)R 13 , 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 15 ;
R 8 is selected from the group consisting of H, halogen, —OR 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —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 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 15 ; or
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 H, halogen, —OR 12 , —SR 10 , C 1 -C 6 alkyl, —CN or —NR 10 R 11 , wherein each of C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
R 10 and R 11 are each independently selected from the group consisting of H, —C(O)R 13 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 4 alkyl, 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 15 ;
R 10 and R 11 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 14 ;
R 10 and R 11 are taken together with the nitrogen to which they are attached to form a saturated or partially saturated monocyclic or fused bicyclic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, thiomorpholine, [1,2]oxazinane, isoxazolidine, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 3-oxomorpholino, 3-oxothiomorpholino, 5,6,7,8-tetrahydroimidazo[1,2-c]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, wherein the heterocycle is attached to the benzazepine core via the nitrogen atom, 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 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , 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 below in R 15 ;
R 10 and R 11 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, wherein 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 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , 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 13 , —C(O)R 13 , 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 below in R 15 ;
R 10 and R 11 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, wherein 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, wherein 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 14 ; or
when R 4 is —NR 10 R 11 or —C(O)NR 10 R 11 , either R 10 or R 11 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, 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, —C(O)R 13 , and —S(O) n R 13 , or either R 10 or R 11 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, wherein 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 13 , and —S(O) n R 13 ;
R 12 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 13 , wherein each of —C 1 -C 4 alkyl, 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 15 ;
R 13 is selected from the group consisting of H, —NR 10 R 11 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 4 alkyl, 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 15 ; or
R 12 and R 13 are each independently 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 below in R 14 ; or
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 piperidine, pyrrolidine, piperazine, 1,4-diazepane, morpholine, thiomorpholine, and other heterocycles containing 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the heterocycle 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 10 , —S(O) n R 10 , —C(O)R 10 , —C(O)NR 10 R 11 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 below in R 15 ;
n is 0, 1, or 2;
R 14 is independently selected at each occurrence from a substituent in the group consisting of halogen, —NO 2 , —OR 12 , —NR 10 R 11 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) n R 13 , —CN, —C(O)R 13 , 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 15 ; and
R 15 is independently selected at each occurrence from a substituent in the group consisting of —CN, halogen, C(O)R 13 , C 1 -C 3 alkyl, —OR 12 , —NR 10 R 11 , —S(O) n R 13 , 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 14 ;
with the following provisos that (1) when R 4 is H or C 1-4 alkoxy, X cannot be phenyl; (2) when R 4 is (a) C 1-6 alkyl, (b) C 1-4 alkoxy, (c) hydroxyl, (d) halogen, or (e) CN, X cannot be a phenyl substituted at the para-position with the same R 4 ; (3) when any one of R 3 , R 4 , R 5 , and R 6 is hydrogen, halogen, perhalomethyl, optionally substituted C 1-6 -alkyl, hydroxy, optionally substituted C 1-4 alkoxy, cyano, amino, optionally substituted mono- or optionally substituted di-C 1-4 alkylamino, acylamino, or carbamoyl, X cannot be furanyl, thienyl, pyrazolyl, tetrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, benzo[d]isoxazolyl, or benzo[d]isothiazolyl; (4) when R 4 is —S(O) n R 13 , n cannot be 0; and (5) when R 9 is a substituted alkyl, R 15 cannot be —NR 10 R 11 ;
or an oxide thereof, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein X is substituted phenyl and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl.
3. The compound according to claim 1 , wherein X is substituted bicyclic carbocycle or heterocycle and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl.
4. The compound according to claim 1 , wherein X is substituted phenyl and R 4 is selected from the group consisting of H, —OR 12 , —S(O) n R 13 , C(O)R 13 , —NR 10 R 11 , —CN, halogen, and C 1 -C 6 alkyl, wherein each of the C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 15 .
5. The compound according to claim 1 , wherein X is substituted bicyclic carbocycle or heterocycle and R 4 is selected from the group consisting of H, —OR 12 , —S(O) n R 13 , C(O)R 13 , —NR 10 R 11 , —CN, halogen, and C 1 -C 6 alkyl, wherein each of the C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 15 .
6. The compound according to claim 1 , wherein X is substituted monocyclic heterocycle and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl.
7. The compound according to claim 1 , wherein:
X is phenyl, optionally substituted from 1 to 4 times with substituents as defined in R 14 ;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 3 is H, methyl, hydroxy, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 5 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or methoxy;
R 6 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or methoxy;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, wherein each of the C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 15 ;
R 8 is H, hydroxy, fluoro, or chloro; and
R 9 is H, fluoro, chloro, methyl, hydroxyl, or cyano.
8. The compound according to claim 7 , wherein:
R 4 is H, halogen, —OR 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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, 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 in R 15 ; or
R 4 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, wherein 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 13 , and —S(O) n R 13 .
9. The compound according to claim 7 , wherein R 4 is phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined in R 14 .
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-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl, optionally substituted from 1 to 4 times with substituents as defined in R 14 ;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 3 is H, methyl, hydroxy, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 5 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, or methoxy;
R 6 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, or methoxy;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, wherein each of the C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 15 ;
R 8 is H, hydroxy, fluoro, or chloro; and
R 9 is H, fluoro, chloro, methyl, hydroxyl, or cyano.
11. The compound according to claim 10 , wherein:
R 4 is H, halogen, —OR 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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, 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 in R 15 ; or
R 4 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, wherein 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 13 , and —S(O) n R 13 .
12. The compound according to claim 10 , wherein R 4 is phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo [d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined in R 14 .
13. The compound according to claim 1 , wherein:
X is a [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycle or heterocycle selected from the group consisting of indenyl, indanyl, benzofuranyl, benzothiophenyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, isoindolyl, indolinyl, benzo[1,3]dioxolyl, benzooxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl, benzoimidazolyl, benzotriazolyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 2,3-dihydro-benzo[1,4]dioxinyl, 4H-chromenyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, imidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, [1,2,4]triazolo[4,3-a]pyrazinyl, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(31/)-yl, optionally substituted from 1 to 4 times with substituents as defined in R 14 ;
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 3 is H, methyl, hydroxy, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 5 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, or methoxy;
R 6 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, or methoxy;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, wherein each of the C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 15 ;
R 8 is H, hydroxy, fluoro, or chloro; and
R 9 is H, fluoro, chloro, methyl, hydroxyl, or cyano.
14. The compound according to claim 13 , wherein:
R 4 is H, halogen —OR 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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, 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 in R 15 ; or
R 4 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, wherein 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 13 , and —S(O) n R 13 .
15. The compound according to claim 13 , wherein R 4 is phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo [d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined in R 14 .
16. The compound according to claim 1 , wherein:
X is thiophenyl, thiazolyl, pyridinyl, phenyl, naphthyl, benzo[b]thiophenyl, benzofuranyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, or 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl, optionally substituted with from 1 to 3 substituents selected independently from the group consisting of halogen, methoxy, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, substituted C 1 -C 3 alkyl, methanesulfonyl, carbamoyl, C 1 -C 3 alkyl—Substituted carbamoyl, and acetamido;
R 1 is H, methyl, ethyl, isopropyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, or benzyl;
R 2 is H or gem-dimethyl;
R 3 is H or fluoro;
R 4 is H, methoxy, hydroxyl, methyl, fluoro, bromo, cyano, trifluoromethyl, 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-pyridazin-3-yloxy, 1,2,4-oxadiazol-3-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrazol-4-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, (methanesulfonyl)phenyl, pyridinyl, aminopyridinyl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(trifluoromethyl)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, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-1,6-dihydropyridazin-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-3-yl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, or 3,3-dimethyl-2-oxoindolin-5-yl;
R 5 is H or fluoro;
R 6 is H or fluoro;
R 7 is H;
R 8 is H, fluoro, or hydroxy; and
R 9 is H or hydroxy.
17. The compound according to claim 1 , wherein the carbon atom designated * is in the R configuration.
18. The compound according to claim 1 , wherein the carbon atom designated * is in the S configuration.
19. The compound according to claim 1 , wherein the compound is a (+) stereoisomer.
20. The compound according to claim 1 , wherein the compound is a (−) stereoisomer.
21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 1 .
22. A compound of formula (II) having the following structure:
wherein:
X represents a 5- or 6-membered aromatic or nonaromatic monocyclic carbocycle or heterocycle selected from the group consisting of phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ; 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, indanyl, benzofuranyl, benzothiophenyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, isoindolyl, indolinyl, benzo[1,3]dioxolyl, benzooxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl, benzoimidazolyl, benzotriazolyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 2,3-dihydro-benzo[1,4]dioxinyl, 4H-chromenyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3b]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, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, imidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, [1,2,4]triazolo[4,3-a]pyrazinyl, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ;
R 1 is H, 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, each of which is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
R 2 is H, 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, each of which is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; 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 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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 15 ; 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 14 ;
R 4 is H, halogen, —OR 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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, 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 15 ;
R 4 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, wherein 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 13 , and —S(O) n R 13 ; or
R 4 is phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo [d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(311)-yl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ;
R 7 is selected from the group consisting of H, —S(O) n R 13 , —C(O)R 13 , 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 15 ; or
R 7 is gem-dimethyl;
R 8 is H or C 1 -C 6 alkyl, wherein each of C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
R 10 and R 11 are each independently selected from the group consisting of H, —C(O)R 13 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 4 alkyl, 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 15 ;
R 10 and R 11 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 14 ;
R 10 and R 11 are taken together with the nitrogen to which they are attached to form a saturated or partially saturated monocyclic or fused bicyclic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, thiomorpholine, [1,2]oxazinane, isoxazolidine, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 3-oxomorpholino, 3-oxothiomorpholino, 5,6,7,8-tetrahydroimidazo[1,2-c]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, wherein the heterocycle is attached to the benzazepine core via the nitrogen atom, 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 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , 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 below in R 15 ;
R 10 and R 11 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, wherein 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 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , 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 13 , —C(O)R 13 , 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 below in R 15 ;
R 10 and R 11 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, wherein 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, wherein 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 14 ; or
when R 4 is —NR 10 R 11 or —C(O)NR 10 R 11 , either R 10 or R 11 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, 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, —C(O)R 13 , and —S(O) n R 13 , or either R 10 or R 11 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, wherein 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 13 , and —S(O) n R 13 ;
R 12 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 13 , wherein each of C 1 -C 4 alkyl, 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 15 ;
R 13 is selected from the group consisting of H, —NR 10 R 11 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 4 alkyl, 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 15 ; or
R 12 and R 13 are each independently 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 below in R 14 ; or
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 piperidine, pyrrolidine, piperazine, 1,4-diazepane, morpholine, thiomorpholine, and other heterocycles containing 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the heterocycle 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 10 , —S(O) n R 10 , —C(O)R 10 , —C(O)NR 10 R 11 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 below in R 15 ;
n is 0, 1, or 2;
R 14 is independently selected at each occurrence from a substituent in the group consisting of halogen, —NO 2 , —OR 12 , —NR 10 R 11 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) n R 13 , —CN, —C(O)R 13 , 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 15 ; and
R 15 is independently selected at each occurrence from a substituent in the group consisting of —CN, halogen, C(O)R 13 , C 1 -C 3 alkyl, —OR 12 , —NR 10 R 11 , —S(O) n R 13 , 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 14 ;
with the following provisos that (1) when R 4 is H, X cannot be phenyl or a phenyl substituted at the para-position with Cl; (2) when R 4 is H, OMe, or O-benzyl, X cannot be a phenyl substituted at the para-position with the same R 4 ; and (3) when R 2 is a 2-(4-nitrophenoxy)ethyl, R 5 cannot be OC(O)NMe 2 ;
or an oxide thereof, or a pharmaceutically acceptable salt thereof.
23. The compound according to claim 22 , wherein:
R 1 is H, methyl, ethyl, or isopropyl;
R 2 is H, methyl, or gem-dimethyl;
R 3 is H, methyl, hydroxy, methoxy, fluoro, chloro, cyano, trifluoromethyl, or trifluoromethoxy;
R 5 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, or methoxy;
R 6 is H, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, or methoxy;
R 7 is H, gem-dimethyl, or C 1 -C 4 alkyl, wherein each of the C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined in R 15 ; and
R 8 is H or C 1 -C 3 alkyl.
24. The compound according to claim 22 , wherein:
X is thiophenyl, thiazolyl, pyridinyl, phenyl, naphthyl, benzo[b]thiophenyl, benzofuranyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl or 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl, optionally substituted with from 1 to 3 substituents selected independently from the group consisting of halogen, methoxy, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, substituted C 1 -C 3 alkyl, methanesulfonyl, carbamoyl, C 1 -C 3 alkyl-substituted carbamoyl, and acetamido;
R 1 is H, methyl, ethyl, isopropyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, or benzyl;
R 2 is H or gem-dimethyl;
R 3 is H or fluoro;
R 4 is H, methoxy, hydroxyl, methyl, fluoro, bromo, cyano, trifluoromethyl, 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-pyridazin-3-yloxy, 1,2,4-oxadiazol-3-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrazol-4-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, (methanesulfonyl)phenyl, pyridinyl, aminopyridinyl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(trifluoromethyl)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, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-1,6-dihydropyridazin-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-3-yl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, or 3,3-dimethyl-2-oxoindolin-5-yl;
R 5 is H or fluoro;
R 6 is H or fluoro;
R 7 is H; and
R 8 is H or C 1 -C 3 alkyl.
25. The compound according to claim 22 , wherein the compound is a (+) stereoisomer.
26. The compound according to claim 22 , wherein the compound is a (−) stereoisomer.
27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 22 .
28. A process for preparation of a product compound of formulae I(A-E) having the following structure:
wherein:
the carbon atom designated * is in the R or S configuration; and
X represents a 5- or 6-membered aromatic or nonaromatic monocyclic carbocycle or heterocycle selected from the group consisting of phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ; 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, indanyl, benzofuranyl, benzothiophenyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, isoindolyl, indolinyl, benzo[1,3]dioxolyl, benzooxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl, benzoimidazolyl, benzotriazolyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 2,3-dihydro-benzo[1,4]dioxinyl, 4H-chromenyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, imidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, [1,2,4]triazolo[4,3-a]pyrazinyl, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ;
R 1 is H, 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, each of which is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
R 2 is H, 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, each of which is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; 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 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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 15 ; 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 14 ;
R 4 is H, halogen, —OR 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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, 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 15 ;
R 4 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, wherein 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 13 , and —S(O) n R 13 ; or
R 4 is a monocyclic or bicyclic aryl or heteroaryl selected from the group consisting of phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo [d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, optionally substituted from 1 to 4 times with substituents as defined below in R 14 ;
provided that for compounds of formula IA, X is substituted phenyl and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl;
provided that for compounds of formula IB, X is substituted bicyclic carbocycle or heterocycle and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl;
provided that for compounds of formula IC, X is substituted phenyl and R 4 is H, —OR 12 , —S(O) n R 13 , C(O)R 13 , —NR 10 R 11 , —CN, halogen, or C 1 -C 6 alkyl, wherein each of the C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
provided that for compounds of formula ID, X is substituted bicyclic carbocycle or heterocycle and R 4 is H, —OR 12 , —S(O) n R 13 , C(O)R 13 , —NR 10 R 11 , —CN, halogen, or C 1 -C 6 alkyl, wherein each of the C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ; and
provided that for compounds of formula IE, X is substituted aromatic monocyclic heterocycle and R 4 is substituted monocyclic or bicyclic aryl or heteroaryl;
R 7 is selected from the group consisting of H, —S(O) n R 13 , —C(O)R 13 , 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 15 ;
R 8 is selected from the group consisting of H, halogen, —OR 12 , —S(O) n R 13 , —CN, —C(O)R 13 , —NR 10 R 11 , 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 15 ; or
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 H, halogen, —OR 12 , —SR 10 , C 1 -C 6 alkyl, —CN, or —NR 10 R 11 , wherein each of C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 15 ;
R 10 and R 11 are each independently selected from the group consisting of H, —C(O)R 13 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 4 alkyl, 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 15 ;
R 10 and R 11 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 14 ;
R 10 and R 11 are taken together with the nitrogen to which they are attached to form a saturated or partially saturated monocyclic or fused bicyclic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, thiomorpholine, [1,2]oxazinane, isoxazolidine, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 3-oxomorpholino, 3-oxothiomorpholino, 5,6,7,8-tetrahydroimidazo[1,2-c]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, wherein the heterocycle is attached to the benzazepine core via the nitrogen atom, 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 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , 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 below in R 15 ;
R 10 and R 11 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, wherein 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 12 , —NR 12 R 13 , —S(O) n R 13 , —C(O)R 13 , 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 13 , —C(O)R 13 , 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 below in R 15 ;
R 10 and R 11 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, wherein 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, wherein 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 14 ; or
when R 4 is —NR 10 R 11 or —C(O)NR 10 R 11 , either R 10 or R 11 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, 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, —C(O)R 13 , and —S(O) n R 13 , or either R 10 or R 11 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, wherein 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 13 , and —S(O) n R 13 ;
R 12 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 13 , wherein each of C 1 -C 4 alkyl, 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 15 ;
R 13 is selected from the group consisting of H, —NR 10 R 11 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 4 alkyl, 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 15 ; or
R 12 and R 13 are each independently 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 below in R 14 ; or
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 piperidine, pyrrolidine, piperazine, 1,4-diazepane, morpholine, thiomorpholine, and other heterocycles containing 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the heterocycle 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 10 , —S(O) n R 10 , —C(O)R 10 , —C(O)NR 10 R 11 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 below in R 15 ;
n is 0, 1, or 2;
R 14 is independently selected at each occurrence from a substituent in the group consisting of halogen, —NO 2 , —OR 12 , —NR 10 R 11 , —NR 12 C(O) 2 R 13 , —S(O) n R 13 , —CN, —C(O)R 13 , 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 15 ; and
R 15 is independently selected at each occurrence from a substituent in the group consisting of —CN, halogen, C(O)R 13 , C 1 -C 3 alkyl, —OR 12 , —NR 10 R 11 , —S(O) n R 13 , 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 14 ;
with the following provisos that (1) when R 4 is H, X cannot be phenyl; (2) when R 4 is (a) C 1-6 alkyl, (b) C 1-4 alkoxy, (c) hydroxyl, (d) halogen, or (e) CN, X cannot be a phenyl substituted at the para-position with the same R 4 ; (3) when any one of R 3 , R 4 , R 5 , and R 6 is hydrogen, halogen, perhalomethyl, optionally substituted C 1-6 -alkyl, hydroxy, optionally substituted C 1-4 alkoxy, cyano, amino, optionally substituted mono- or optionally substituted di-C 1-4 alkylamino, acylamino, or carbamoyl, X cannot be furanyl, thienyl, pyrazolyl, tetrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, benzo[d]isoxazolyl, or benzo[d]isothiazolyl; (4) when R 4 is —S(O) n R 13 , n cannot be 0; and (5) when R 9 is a substituted alkyl, R 15 cannot be —NR 10 R 11 ;
or an oxide thereof, or a pharmaceutically acceptable salt thereof,
said process comprising:
treating an intermediate compound of the formula:
under conditions effective to produce the product compound.