US2002198190A1PendingUtilityA1
Tetracyclic azepinoindole compounds
Est. expiryApr 23, 2019(expired)· nominal 20-yr term from priority
Inventors:Jackson B. Hester, Jr.Bruce N. RogersEric Jon JacobsenMichael EnnisBrad AckerSusan L. Vander VeldeKristine E. Frank
A61P 37/04A61P 25/18A61P 25/22C07D 487/16A61P 25/24C07D 513/16C07D 498/16C07D 471/16
52
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Claims
Abstract
The present invention provides compounds of formula I: wherein R 1 , R 2 , X and Y have any of the values defined in the specification, as well as pharmaceutical compositions comprising the compounds. The invention also provides therapeutic methods as well as processes and intermediates useful for preparing compounds of formula (I).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula I:
wherein,
each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b , wherein any C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, or C 1-7 alkanoyloxy of R 1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, —S(O) m R e , —S(O) m NR a R b , NR c R d , or —C(═O)NR a R b ;
R 2 is hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, arylcarbonyl, aryl, (aryl)C 1-7 alkyl, C 1-7 alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or (aryl)C 1-7 alkoxycarbonyl;
X and Y together are a 2, 3, or 4 membered saturated or partially unsaturated chain comprising one or more carbon atoms and optionally comprising one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O) 2 —), or NR f in the chain; wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), —NR q R r , —S(O) p R s , or —OR t , or with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl; or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring; or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain (e.g. —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —) forming a ring that is fused to the ring comprising X and Y;
each m is independently 0, 1, or 2;
n is 0, 1,2, or 3;
p is 0, 1, or 2;
each R a and R b is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R a and R b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R c and R d is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; or R c and R d together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R e is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
R f is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, or is a bond to a 2, 3, or 4 membered alkylene chain that forms a ring that is fused to the ring comprising X and Y;
each R q and R r is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R q and R r together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
R s is C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; and
R t is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
wherein any aryl or heteroaryl ring of R 1 , R 2 , X, Y, R a -R f , or R q -R t is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, phenyl, sulfonyl, NR j R k , or —C(═O)NR j R k ,; wherein each R j and R k is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, arylcarbonyl, or aryloxycarbonyl; or R j and R k together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
or a pharmaceutically acceptable salt thereof;
provided Y is not oxy, thio, sulfinyl, or NR f ; and
provided X and Y together are not a 2-membered unsaturated chain; and
provided no carbon of X and Y is bonded to more than one oxy, thio, sulfinyl, or NR f .
2 . The compound of claim 1 wherein each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b , wherein any C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, or C 1-7 alkanoyloxy of R 1 is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, —S(O) m R e , —S(O) m NR a R b , NR c Rd or —C(═O)NR a R b .
3 . The compound of claim 1 wherein each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b , wherein any C 1-7 alkyl or C 1-7 alkoxy of R 1 is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, —S(O) m R, S(O) m NR a R b , NR c R d , or —C(═O)NR a R b .
4 . The compound of claim 1 wherein each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b , wherein any C 1-7 alkyl is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, —S(O) m R e , —S(O) m NR a R b , NR c R d , or —C(═O)NR a R b .
5 . The compound of claim 1 wherein each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b .
6 . The compound of claim 1 wherein each R 1 is independently C 1-7 alkyl, C 1-7 alkoxy, trifluoromethyl, or halo.
7 . The compound of claim 1 wherein n is 1 and R 1 is C 1-7 alkyl, C 1-7 alkoxy, or halo.
8 . The compound of claim 1 wherein n is 1 and R 1 is methyl, methoxy, chloro, or fluoro.
9 . The compound of claim 1 wherein R 2 is hydrogen.
10 . The compound of claim 1 wherein n is 1, 2, or 3.
11 . The compound of claim 1 wherein n is 0.
12 . The compound of claim 1 wherein X and Y together are a 2, 3, or 4 membered saturated or partially unsaturated chain comprising one or more carbon atoms and optionally comprising one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —), or NR f in the chain; wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), —NR q R r , —S(O) p R s , or —OR t , or with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-17 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl.
13 . The compound of claim 1 wherein X and Y together are a 2, 3, or 4 membered saturated or partially unsaturated chain comprising one or more carbon atoms and optionally comprising one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O) 2 —), or NR f in the chain; wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), NR q R r , —S(O) p R s , or —OR t .
14 . The compound of claim 1 wherein X and Y together are a 2, 3, or 4 membered saturated or partially unsaturated chain comprising one or more carbon atoms and optionally comprising one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O) 2 —), or NR f in the chain; wherein the chain is optionally substituted on each carbon with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl.
15 . The compound of claim 1 wherein X and Y together are a 2, 3, or 4 membered chain comprising one or more carbon atoms and optionally comprising one oxy, thio, sulfinyl, sulfonyl, or NR f in the chain; wherein the chain is optionally substituted on each carbon with oxo (═O), hydroxy, (aryl)oxy, heteroaryl(oxy) or C 1-7 alkoxy, or with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl; and wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain forming a ring that is fused to the ring comprising X and Y.
16 . The compound of claim 1 wherein X and Y together are a 2, 3, or 4 membered carbon chain wherein the chain is optionally substituted on each carbon with oxo, hydroxy, (aryl)oxy, heteroaryl(oxy) or C 1-7 alkoxy, or with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl.
17 . The compound of claim 1 wherein X and Y together are a 2 or 3 membered carbon chain optionally substituted on each carbon with oxo or hydroxy, or with one or two C 1-7 alkyl.
18 . The compound of claim 1 wherein X is —O—, —S—, or —C(R g )(R h )—, wherein R g and R h are each independently hydrogen, C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl or (aryl)oxyC 1-7 alkyl, or R g and R h together are oxo.
19 . The compound of claim 1 wherein Y is —C(R g )(R h )—, —C(R g )(R h )C(R g )(R h )—, —C(R g )(R h )C(R g )(R h )C(R g )(R h )—, —C(R g )(R h )C(═O)—, —C(R g )(R h )C(R g )(R h )C(═O)—, —C(═O)C(R g )(R h )—, or —C(═O)C(R g )(R h )C(R g )(R h )—, and each R g and R h is independently hydrogen or C 1-7 alkyl.
20 . The compound of claim 1 wherein X is —O—, —S—, or —C(R g )(R h )—; and Y is —C(R g )(R h )C(═O)—, or —C(R g )(R h )C(R g )(R h )—, wherein each R g and R h is independently hydrogen or C 1-7 alkyl.
21 . The compound of claim 1 wherein X is —O— or —S—; and Y is —C(R g )(R h )C(═O)—, —C(═O)C(R g )(R h )—, or —C(R g )(R h )C(R g )(R h )—, wherein each R g and R h is independently hydrogen or C 1-7 alkyl.
22 . The compound of claim 1 wherein X and Y together are ——CH(R g )CH 2 —, —CH(R g )CH(R g )CH 2 —, —CH(R g )CH(R g )CH(R g )CH 2 —, —C(R g )═C(R g )CH 2 —, —CH═CHCH(R g )CH 2 —, —CH(R g )CH═CHCH 2 —, —O—CH 2 CH 2 —, —O—CH 2 CH(R g )CH 2 —, —S—CH 2 CH 2 —, —S—CH 2 CH(R g )CH 2 —, —S(O)—CH 2 CH 2 —, —S(O)—CH 2 CH(R g )CH 2 —, —S(O) 2 —CH 2 CH 2 —, —S(O) 2 —CH 2 CH(R g )CH 2 —, —NR f CH 2 CH 2 —, —NR f CH 2 CH(R g )CH 2 —, —CH 2 C(═O)—, —CH(R g )CH 2 C(═O)—, —CH(R g )CH(R g )CH 2 C(═O)—, —CH 2 OC(═O)—, —CH(R g )CH 2 OC(═O)—, —OCH 2 C(═O)—, or —OCH 2 CH 2 C(═O)—; wherein each R g is independently —NR q R r , —S(O) p R s , or —OR t .
23 . The compound of claim 1 wherein X and Y together are ——CH(R g )CH(R g )—, —CH(R g )CH(R g )CH(R g )—, —CH(R g )CH(R g )CH(R g )CH(R g )—, —CH═CHCH(R g )—, —C(R g )═C(R g )CH(R g )CH(R g )—, —CH(R g )C(R g )═C(R g )CH(R g )—, —O—CH(R g )CH(R g )—, —O—CH(R g )CH(R g )CH(R g )—, —S—CH(R g )CH(R g )—, —S—CH(R g )CH(R g )CH(R g )—, —S(O)—CH(R g )CH(R g )—, —S(O)—CH(R g )CH(R g )CH(R g )—, —S(O) 2 —CH(R g )CH(R g )—, —S(O) 2 —CH(R g )CH(R g )CH(R g )—, —NR f CH(R g )CH(R g )—, —NR f CH(R g )CH(R g )CH(R g )—, —CH(R g )C(═O)—, —CH(R g )CH(R g )C(═O)—, —CH(R g )CH(R g )CH(R g )C(═O)—, —CH(R g )OC(═O)—, —CH(R g )CH(R g )OC(═O)—, —OCH(R g )C(═O)—, or —OCH(R g )CH(R g )C(═O)—; wherein each R g is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, (aryl)oxy, heteroaryl(oxy), or (aryl)oxyC 1-7 alkyl.
24 . The compound of claim 1 wherein X and Y together are ——CH(R g )CH(R g )—, —CH(R g )CH(R g )CH(R g )—, —C(R g )═C(R g )CH(R g )—, —O—CH(R g )CH(R g )—, —S—CH(R g )CH(R g )—, —S(O)—CH(R g )CH(R g )—, —S(O) 2 —CH(R g )CH(R g )—, —NR f —CH(R g )CH(R g )—, —CH(R g )C(═O)—, —CH(R g )CH(R g )C(═O)—, —CH(R g )OC(═O)—, —OCH(R g )C(═O)—; wherein each R g is independently hydrogen or C 1-7 alkyl.
25 . The compound of claim 1 wherein X and Y together are ——CH(R g )CH 2 —, —CH(R g )CH(R g )CH 2 —, or —O—CH 2 CH 2 —, wherein each R g is independently —NR q R r , —S(O) p R s , —OR t , C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl.
26 . The compound of claim 1 wherein X and Y together are ——C(═O)CH 2 —, —CH 2 C(═O)—, —C(═S)CH 2 —, —CH 2 C(═S)—, —C(═O)CH 2 CH 2 —, —CH 2 C(═O)CH 2 —, —CH 2 CH 2 C(═O)—, —C(═S)CH 2 CH 2 —, —CH 2 C(═S)CH 2 —, or —CH 2 CH 2 C(═S)—.
27 . The compound of claim 1 wherein X and Y together are ——CH(R g )CH(R g )—, —CH(R g )CH(R g )CH(R g )—, —C(R g )═C(R g )CH(R g )—, —O—CH(R g )CH(R g )—, —S—CH(R g )CH(R g )—, —S(O)—CH(R g )CH(R g )—, —S(O) 2 —CH(R g )CH(R g )—, —NR f —CH(R g )CH(R g )—, or —CH(R g )CH(R g )C(═O)—; wherein each R g is independently hydrogen, C 1-7 alkyl, or together with an R g on an adjacent carbon atom forms a fused 4, 5, or 6, membered carbocyclic ring.
28 . The compound of claim 1 wherein X and Y together are ——CH(R g )CH(R g )—, —CH(R g )CH(R g )—, —O—CH(R g )CH(R g )—, —S—CH(R g )CH(R g )—; wherein each R g is independently hydrogen, C 1-7 alkyl, aryl, or (aryl)C 1-7 alkyl.
29 . The compound of claim 1 wherein X and Y together are ——CH 2 CH 2 CH 2 —, —CH 2 CH 2 C(CH 3 )H—, —CH 2 C(CH 3 )HCH 2 —, —C(CH 3 )HCH 2 CH 2 —, ——CH 2 CH 2 —, —CH 2 C(CH 3 )H—, —C(CH 3 )HC(CH 3 )H—, —CH(R g )CH(R g )—, —O—CH 2 CH 2 —, —O—C(CH 3 )HCH 2 —, or —S—CH 2 CH 2 —.
30 . The compound of claim 1 wherein X and Y together are ——CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH═CHCH 2 —, —O—CH 2 CH 2 —, —S—CH 2 CH 2 —, —S(O)—CH 2 CH 2 —, —S(O) 2 —CH 2 CH 2 —, —NR f CH 2 CH 2 —, —CH 2 C(═O)—, —CH 2 CH 2 C(═O)—, —CH 2 OC(═O)—, —OCH 2 C(═O)—.
31 . The compound of claims 1 wherein R 2 is hydrogen
32 . The compound of claim 1 which is:
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
2-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-methoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
(+)-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
(−)-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
(+)-5-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
(−)-5-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
(+)-4-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
(−)-4-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2-fluoro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2-methoxy-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
5-methyl-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
4,5-dimethyl-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2,3,4,5,8b,9,10,11,12,12a-decahydro-1H-azepino[4′,5′:4,5]pyrrolo[3,2,1-jk]carbazole;
6-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
6-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
2-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
2,2-dimethyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
4-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
4-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
5-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
6-(trifluoromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino [4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5,6-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5-chloro-6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
6-chloro-5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
5,6-dichloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
4,6-dichloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
1-chloro-2-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
1-chloro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
2-chloro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
2-fluoro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
2,3-dichloro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
6-propyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
6-(trifluoromethyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-ol;
4-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
10-benzoyl-4-phenoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline; or
4-phenoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
or a pharmaceutically acceptable salt thereof.
33 . The compound 1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole; or a pharmaceutically acceptable salt thereof.
34 . The compound of claim 1 which is:
4-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
6-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5,6-dibromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
4,6-dibromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
4-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
6-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
4-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
4-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
5-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
6-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole;
4-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
4-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
5-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
6-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
4,5-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
5,6-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4,6-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
4-chloro-5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-chloro-6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
5-chloro-6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
6-chloro-5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
5-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
6-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
4-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
5-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
6-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
4-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
5-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
6-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
4-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
5-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
6-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]thiazino[2,3,4-hi]indole;
1-fluoro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
3-fluoro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
1-bromo-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2-bromo-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi] indole;
3-bromo-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
3-chloro-1-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2-chloro-1-fluoro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
1-methoxy-4,5,8,9,10, 11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi] indole;
3-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
4-methyl-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
1-(trifluoromethyl)-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2-(trifluoromethyl)-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
3-(trifluoromethyl)-4,5, 8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
4-benzyloxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(3-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(2-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(3-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-bromo-2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
N-phenyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(4-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(3-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(2-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(4-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinolin-4-amine;
N-(3-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(4-bromo-2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-4-thione;
4-(phenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(3-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(2-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(3-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinoline;
4-(2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-bromo-2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-5-ol;
5-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-benzyloxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-phenoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(3-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(2-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(3-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-bromo-2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
N-phenyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
N-(4-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
N-(3-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5 ′:4,5]pyrrolo [3,2,1-ij]quinolin-5-amine;
N-(2-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5 ′:4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
N-(4-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinolin-5-amine;
N-(3-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinolin-5-amine;
N-(2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
N-(4-bromo-2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-5-thione;
5-(phenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinoline;
5-(3-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(2-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(3-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-bromo-2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(4-fluorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-fluorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-fluorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(4-chlorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-chlorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-chlorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(4-bromophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-bromophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-bromophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(4-methoxyphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-methoxyphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-methoxyphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(4-methylphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-methylphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1--[2-(2-methylphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(1-naphthyloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-naphthyloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-([1,1′-biphenyl]-4-yloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[ 4′,5′:4,5 ]pyrrolo[3,2,1-ij]quinoline;
1-[2-([1,1′-biphenyl]-3-yloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-([1,1′-biphenyl]-2-yloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-{ 2 -[4-(trifluoromethoxy)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-{2-[3-(trifluoromethoxy)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino ,[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-{2-[2-(trifluoromethoxy)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-{2-[4-(trifluoromethyl)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline;
1-{2-[3-(trifluoromethyl)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline; or 1-{2-[2-(trifluoromethyl)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline; or a pharmaceutically acceptable salt thereof.
35 . A pharmaceutical composition comprising a compound of claim 31 and a pharmaceutically acceptable excipient.
36 . A method for treating a disease or condition in a mammal wherein the 5-HT receptor is implicated and modulation of 5-HT function is desired comprising administering a therapeutically effective amount of a compound of claim 31 to the mammal.
37 . The method of claim 36 wherein the disease or condition is anxiety, obesity, depression, schizophrenia, a stress related disease, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the gastrointestinal or cardiovascular system, or sexual dysfunction.
38 . The method of claim 37 wherein the disease is anxiety, obesity, depression, or a stress related disease.
39 . A method for treating or preventing a disease or disorder of the central nervous system in a mammal comprising administering a therapeutically effective amount of a compound of claim 31 , or a pharmaceutically acceptable salt thereof to the mammal.
40 . The method of claim 39 wherein the disease or disorder of the central nervous system is obesity, depression, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, a stress related disease, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, gastrointestinal or cardiovascular system, neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine, headaches, cluster headaches, sexual dysfunction, addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioral disturbance, bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, generalized anxiety disorder, an inhalation disorder, an intoxication disorder, movement disorder, oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder, mood disorder, seasonal affective disorder, a sleep disorder, a specific development disorder, agitation disorder, selective serotonin reuptake inhibition syndrome, or a Tic disorder.
41 . A compound of formula I:
wherein,
each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b , wherein any C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, or C 1-7 alkanoyloxy of R 1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, —S(O) m R e , —S(O) m NR a R b , NR c R d or —C(═O)NR a R b ;
R 2 is a suitable protecting group;
X and Y together are a 2, 3, or 4 membered saturated or partially unsaturated chain comprising one or more carbon atoms and optionally comprising one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O) 2 —), or NR f in the chain; wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), NR q R r , —S(O) p R s , or —OR t , or with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl; or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring; or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain (e.g. —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —) forming a ring that is fused to the ring comprising X and Y;
each m is independently 0, 1, or 2;
n is 0, 1,2, or 3;
p is 0, 1, or 2;
each R a and R b is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R a and R b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R c and R d is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; or R c and R d together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R e is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
R f is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, or is a bond to a 2, 3, or 4 membered alkylene chain that forms a ring that is fused to the ring comprising X and Y;
each R q and R r is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R q and R r together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
R s is C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; and
R t is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
wherein any aryl or heteroaryl ring of R 1 , R 2 , X, Y, R a -R f , or R q -R t is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, phenyl, sulfonyl, NR j R k , or —C(═O)NR j R k ,; wherein each R j and R k is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, arylcarbonyl, or aryloxycarbonyl; or R j and R k together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
or a pharmaceutically acceptable salt thereof;
provided Y is not oxy, thio, sulfinyl, or NR f ; and
provided X and Y together are not a 2-membered unsaturated chain; and
provided no carbon of X and Y is bonded to more than one oxy, thio, sulfinyl, or NR f .
42 . The compound of claim 1 wherein R 2 is C 1-4 alkyl, C 1-4 alkanoyl, arylcarbonyl, (aryl)C 1-2 alkyl, C 1-4 alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or (aryl)methoxycarbonyl, wherein any aryl is optionaly substituted with 1, 2, or 3 substituents independently selected from C 1-4 alkyl and trifluoromethyl.
43 . The compound of claim 1 wherein R 2 is methyl, ethyl, propyl, isopropyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, orp-toluenesulfonyl.
44 . The compound of claim 1 which is: 10-benzoyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-chloro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-fluoro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2,3-dichloro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-propyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-(trifluoromethyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinolin-4-ol; or
10-benzoyl-4-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline.
45 . The compound of claim 1 which is: benzyl 5,6,8,9,11,12-hexahydro-4H, 1 OH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
benzyl 2-methyl-5,6,8,9,11,12-hexahydro-4H, 10H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
10-benzoyl-1-methoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′, 5′:4,5]pyrrolo-[3,2,1-ij]quinoline;
benzyl 2-fluoro-5,6,8,9,11,12-hexahydro-4H, 1 OH-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinoline-10-carboxylate;
benzyl 6-methyl-5,6,8,9,11,12-hexahydro-4H, 10H-azepino[4′,5 ′:4,5]pyrrolo [3,2,1-ij]quinoline-10-carboxylate;
benzyl 5-methyl-5,6,8,9,11,12-hexahydro-4H,10H--azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
benzyl 4-methyl-5,6,8,9,11,12-hexahydro-4H, 1 OH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
(+)-benzyl 6-methyl-5,6,8,9,11,12-hexahydro-4H, 10H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
(−)-benzyl 6-methyl-5,6,8,9,11,12-hexahydro-4H,1 OH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
(+)-benzyl 5-methyl-5,6,8,9,11,12-hexahydro-4H, 110H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
(−)-benzyl 5-methyl-5,6,8,9,11,12-hexahydro-4H, 10H-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinoline-10-carboxylate;
(+)-benzyl 4-methyl-5,6,8,9,11,12-hexahydro-4H, 10H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
(−)-benzyl 4-methyl-5,6,8,9,11,12-hexahydro-4H, 110H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
benzyl 2-methyl-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 2,2-dimethyl-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi] indole-9-carboxylate;
benzyl 4-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 4-chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 5-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 5-chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 5-methyl-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 6-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi] indole-9-carboxylate;
benzyl 6-chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 6-methyl-1,2,6b,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 6-(trifluoromethyl)-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino [2,3,4-hi]indole-9-carboxylate;
benzyl 5,6-difluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylatebenzyl;
benzyl 5-chloro-6-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 5-fluoro-6-chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 5,6-dichloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl 4,6-dichloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
7-benzoyl 4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
7-benzoyl 2-fluoro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
7-benzoyl 2-methoxy-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
benzyl-5-methyl-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]-7-carboxylate;
benzyl-4,5-dimethyl-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole-7-carboxylate;
benzyl-2,3,4,5,8b,9,10,11,12,12a-decahydro-1H-azepino[4′,5′:4,5]pyrrolo[3,2,1-jk]carbazole-7-carboxylate;
benzyl-1-chloro-2-fluoro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole-7-carboxylate;
benzyl-2-chloro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole-7-carboxylate;
benzyl-1-chloro-4,5,8,9, 10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole-7-carboxylate;
10-benzoyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo-[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-chloro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo-[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo-[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-fluoro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]-pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2,3-dichloro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-propyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo-[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-(trifluoromethyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo [3,2,1-ij]quinolin-4-ol; and
10-benzoyl-4-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline.
46 . A method for preparing a compound of formula (I) wherein R 2 is hydrogen comprising deprotecting a corresponding compound of formula (I) wherein R 2 is a protecting group.
47 . The method of claim 46 wherein the protecting group is benzyloxycarbonyl, or benzoyl.
48 . A method for treating a disease or condition in a mammal wherein the 5-HT receptor is implicated and modulation of 5-HT function is desired comprising administering to the mammal a therapeutically effective amount of a compound of formula I:
wherein,
each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b , wherein any C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, or C 1-7 alkanoyloxy of R 1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, —S(O) m R e , —S(O) m NR a R b , NR c R d , or —C(═O)NR a R b ;
R 2 is hydrogen;
X and Y together are a 2 or 3 membered saturated or partially unsaturated chain comprising one or more carbon atoms and one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O) 2 —), or NR f in the chain; wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), —NR q R r , —S(O) p R s , or —OR t , or with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl; or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring; or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain forming a ring that is fused to the ring comprising X and Y;
each m is independently 0, 1, or 2;
n is 0, 1,2, or 3;
p is 0, 1, or 2;
each R a and R b is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R a and R b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R c and R 1 is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; or R c and R d together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R e is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
R f is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, or is a bond to a 2, 3, or 4 membered alkylene chain that forms a ring that is fused to the ring comprising X and Y;
each R q and R r is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R q and R r together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
R s is C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; and
R t is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
wherein any aryl or heteroaryl ring of R 1 , R 2 , X, Y, R a -R f , or R q -R t is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, phenyl, sulfonyl, NR j R k , or —C(═O)NR j R k ,; wherein each R j and R k is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, arylcarbonyl, or aryloxycarbonyl; or R j and R k together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; and
wherein any heteroaryl is a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, C 1-4 alkyl, phenyl or benzyl, or a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom;
or a pharmaceutically acceptable salt thereof;
provided Y is not oxy, thio, sulfinyl, or NR f ; and
provided X and Y together are not a 2-membered unsaturated chain; and
provided no carbon of X and Y is bonded to more than one oxy, thio, sulfinyl, or NR f .
49 . The method of claim 48 wherein each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, Cl 7alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b .
50 . The method of claim 48 wherein each R 1 is independently C 1-7 alkyl, C 1-7 alkoxy, trifluoromethyl, or halo.
51 . The method of claim 48 wherein n is 1, 2, or 3.
52 . The method of claim 48 wherein X and Y together are —O—CH 2 CH 2 —, —S—CH 2 CH 2 —, —S(O)—CH 2 CH 2 —, —S(O) 2 —CH 2 CH 2 —, —NR f CH 2 CH 2 —, —CH 2 OC(═O)—, or —OCH 2 C(═O)—.
53 . The method of claim 48 wherein X and Y together are —O—CH 2 CH 2 —.
54 . The method of claim 48 wherein the compound is 1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole; or a pharmaceutically acceptable salt thereof.
55 . A method for treating or preventing a disease or disorder of the central nervous system in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I:
wherein,
each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b , wherein any C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, or C 1-7 alkanoyloxy of R 1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, —S(O) m R e , —S(O) m NR a R b , NR c R d , or —C(═O)NR a R b ;
R 2 is hydrogen;
X and Y together are a 2 or 3 membered saturated or partially unsaturated chain comprising one or more carbon atoms and one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O) 2 —), or NR f in the chain; wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), —NR q R r , —S(O) p R s , or —OR t , or with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl; or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring; or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain forming a ring that is fused to the ring comprising X and Y;
each m is independently 0, 1, or 2;
n is 0, 1,2, or 3;
p is 0, 1, or 2;
each R a and R b is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R a and R b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R c and R d is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; or R c and R d together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R e is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
R f is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, or is a bond to a 2, 3, or 4 membered alkylene chain that forms a ring that is fused to the ring comprising X and Y;
each R q and R r is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R q and R r together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
R s is C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; and
R t is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
wherein any aryl or heteroaryl ring of R 1 , R 2 , X, Y, R a -R f , or R q -R t is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, phenyl, sulfonyl, NR j R k , or —C(═O)NR j R k ,; wherein each R j and R k is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, arylcarbonyl, or aryloxycarbonyl; or R j and R k together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; and
wherein any heteroaryl is a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, C 1-4 alkyl, phenyl or benzyl, or a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom;
or a pharmaceutically acceptable salt thereof;
provided Y is not oxy, thio, sulfinyl, or NR f , and provided X and Y together are not a 2-membered unsaturated chain; and
provided no carbon of X and Y is bonded to more than one oxy, thio, sulfinyl, or NR f .
56 . The method of claim 55 wherein each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b .
57 . The method of claim 55 wherein each R 1 is independently C 1-7 alkyl, C 1-7 alkoxy, trifluoromethyl, or halo.
58 . The method of claim 55 wherein n is 1, 2, or 3.
59 . The method of claim 55 wherein X and Y together are —O—CH 2 CH 2 —, —S—CH 2 CH 2 —, —S(O)—CH 2 CH 2 —, —S(O) 2 —CH 2 CH 2 —, —NR f CH 2 CH 2 —, —CH 2 OC(═O)—, or —OCH 2 C(═O)—.
60 . The method of claim 55 wherein X and Y together are —O—CH 2 CH 2 —.
61 . The method of claim 55 wherein the compound is 1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole; or a pharmaceutically acceptable salt thereof.
62 . The method of claim 55 wherein the disease or disorder of the central nervous system is obesity, depression, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, a stress related disease, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, gastrointestinal or cardiovascular system, neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine, headaches, cluster headaches, sexual dysfunction, addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioral disturbance, bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, generalized anxiety disorder, an inhalation disorder, an intoxication disorder, movement disorder, oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder, mood disorder, seasonal affective disorder, a sleep disorder, a specific development disorder, agitation disorder, selective serotonin reuptake inhibition syndrome, or a Tic disorder.
63 . A method for modulating 5-HT receptor function in a mammal, comprising administering to the mammal an effective modulatory amount of a compound of formula I:
wherein,
each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , —S(O) m R e , or —C(═O)NR a R b , wherein any C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, or C 1-7 alkanoyloxy of R 1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, —S(O) m , R e , —S(O) m NR a R b , NR c R d , or —C(═O)NR a R b ;
R 2 is hydrogen;
X and Y together are a 2 or 3 membered saturated or partially unsaturated chain comprising one or more carbon atoms and one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O) 2 —), or NR f in the chain; wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), NR q R r , —S(O) p R s , or —OR t , or with one or two substituents independently selected from the group consisting of C 1-7 alkyl, (C 1-7 alkoxy)C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, and (aryl)oxyC 1-7 alkyl; or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring; or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain forming a ring that is fused to the ring comprising X and Y;
each m is independently 0, 1, or 2;
n is 0, 1,2, or 3;
p is 0, 1, or 2;
each R a and R b is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R a and R b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R c and R d is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; or R c and R d together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R e is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
R f is hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, (heteroaryl)C 1-7 alkyl, or is a bond to a 2, 3, or 4 membered alkylene chain that forms a ring that is fused to the ring comprising X and Y;
each R q and R r is independently hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; or R q and R r together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
R s is C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl; and
R t hydrogen, C 1-7 alkyl, aryl, (aryl)C 1-7 alkyl, heteroaryl, or (heteroaryl)C 1-7 alkyl;
wherein any aryl or heteroaryl ring of R 1 , R 2 , X, Y, R a -R f , or R q -R t is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, phenyl, sulfonyl, NR j R k , or —C(═O)NR j R k ,; wherein each R j and R k is independently hydrogen, C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, aryl, (aryl)C 1-7 alkyl, arylcarbonyl, or aryloxycarbonyl; or R j and R k together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; and
wherein any heteroaryl is a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, C 1-4 alkyl, phenyl or benzyl, or a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom;
or a pharmaceutically acceptable salt thereof;
provided Y is not oxy, thio, sulfinyl, or NR f , and
provided X and Y together are not a 2-membered unsaturated chain; and
provided no carbon of X and Y is bonded to more than one oxy, thio, sulfinyl, or NR f .
64 . The method of claim 63 wherein each R 1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, aryl, heteroaryl, —S(O) m NR a R b , NR c R d , S(O) m R e , or —C(═O)NR a R b .
65 . The method of claim 63 wherein each R 1 is independently C 1-7 alkyl, C 1-7 alkoxy, trifluoromethyl, or halo.
66 . The method of claim 63 wherein n is 1, 2, or 3.
67 . The method of claim 63 wherein X and Y together are —O—CH 2 CH 2 —, —S—CH 2 CH 2 —, —S(O)—CH 2 CH 2 —, —S(O) 2 —CH 2 CH 2 —, —NR f —CH 2 CH 2 —, —CH 2 OC(═O)—, or —OCH 2 C(═O)—.
68 . The method of claim 63 wherein X and Y together are —O—CH 2 CH 2 —.
69 . The method of claim 63 wherein the compound is 1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b] [1,4]oxazino[2,3,4-hi]indole; or a pharmaceutically acceptable salt thereof.Cited by (0)
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