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US 8,846,655 B2Granted
4-substituted-2-phenoxy-phenylamine delta opioid receptor modulators
AssigneeJanssen Pharmaceutica NV
InventorsSteven J. Coats, Haiyan Bian, Chaozhong Cai, Bart L. DeCorte, Li Liu, Mark J. Macielag, Scott L. Dax, Philip M. Pitis, Peter J. Connolly, Wei He
Life of this patent
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Abstract
Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: wherein R1, R2, R3, Ra, and Y are defined herein.
Claims24
A compound of Formula I
- wherein
- R1 is selected from the group consisting of
- i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, di(C1-4alkyl)aminocarbonyl, chloro, and fluoro;
- such that only one di(C1-4alkyl)aminocarbonyl is present;
- ii) naphthyl;
- iii) pyridinyl optionally substituted with one substituent selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano;
- iv) pyrimidin-5-yl;
- v) furanyl;
- vi) thienyl;
- vii) 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl;
- and
- viii) di(C1-2alkyl)aminocarbonyl;
- with the proviso that when R1 is 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, Y is a bond;
- Y is ethyl, vinyl, or a bond;
- or, Y is O when R1 is an optionally substituted phenyl;
- R2 is phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluoro, chloro, cyano, trifluoromethoxy, and hydroxy;
- or, R2 is phenyl substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alkoxycarbonyl, or carboxy substituent;
- R3 is selected from the group consisting of
- i) 3-amino-cyclohexyl;
- ii) 4-amino-cyclohexyl;
- iii) piperidin-3-yl;
- iv) piperidin-4-yl;
- v) pyrrolidin-2-ylmethyl wherein pyrrolidin-2-yl is optionally substituted at the 3- or 4- position with one to two fluoro substituents;
- vi) azetidin-3-ylmethyl;
- vii) 2-(N-methylamino)ethyl;
- viii) 3-hydroxy-2-amino-propyl;
- ix) piperidin-3-ylmethyl;
- x) 1-azabicyclo[2.2.2]octan-3-yl;
- and
- xi) 8-azabicyclo[3.2.1]octan-3-yl;
- or, R3 is taken with Ra and the nitrogen atom to which they are both attached to form piperazinyl optionally substituted with 4-C1-4alkyl;
- Ra is hydrogen, 2-(N-methylamino)ethyl, or C1-2alkyl optionally substituted with azetidin-3-yl;
- and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
30 more elements
A compound of Formula (I)
- wherein
- R1 is selected from the group consisting of
- i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy, di(C1-4alkyl)aminocarbonyl, and fluoro;
- such that only one di(C1-4alkyl)aminocarbonyl is present;
- ii) naphthyl;
- iii) pyridinyl optionally substituted with one substituent selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, and cyano;
- iv) pyrimidin-5-yl;
- v) furanyl;
- vi) thienyl;
- and
- vii) di(C1-2alkyl)aminocarbonyl;
- Y is vinyl or a bond;
- or, Y is 0 when R1 is an optionally substituted phenyl;
- R2 is phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluoro, chloro, and hydroxy;
- or, R2 is phenyl substituted with one aminocarbonyl or di(C1-4alkyl)aminocarbonyl substituent;
- R3 is selected from the group consisting of
- i) 3-amino-cyclohexyl;
- ii) 4-amino-cyclohexyl;
- iii) pyrrolidin-2-ylmethyl wherein pyrrolidin-2-yl is optionally substituted at the 3- or 4- position with one to two fluoro substituents;2-(N -methylamino)ethyl;piperidin-3-ylmethyl;
- and
- iv) 1-azabicyclo[2.2.2]octan-3-yl;
- or, R3 is taken with Ra and the nitrogen atom to which they are both attached to form piperazinyl;
- Ra is hydrogen or C1-2alkyl;
- and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
21 more elements
A compound of Formula (I)
- wherein
- R1 is selected from the group consisting of
- i) phenyl optionally substituted with one substituent selected from the group consisting of C1-4alkoxy, di(C1-4alkyl)aminocarbonyl, and fluoro;
- ii) pyridinyl optionally substituted with one substituent selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, and cyano;
- iii) pyrimidin-5-yl;
- and
- iv) di(C1-2alkyl)aminocarbonyl;
- Y is vinyl or a bond;
- R2 is phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, and hydroxy;
- or, R2 is phenyl substituted with one aminocarbonyl or di(C1-4alkyl)aminocarbonyl substituent;
- R3 is selected from the group consisting of
- i) 3-amino-cyclohexyl;
- ii) 4-amino-cyclohexyl;
- iii) pyrrolidin-2-ylmethyl wherein pyrrolidin-2-yl is optionally substituted at a carbon atom with one to two fluoro substituents;
- iv) 2-(N-methylamino)ethyl;
- v) piperidin-3-ylmethyl;
- and
- vi) 1-azabicyclo[2.2.2]octan-3-yl;
- or, R3 is taken with Ra and the nitrogen atom to which they are both attached to form piperazinyl;
- Ra is hydrogen;
- and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
18 more elements
A compound of Formula (I)
- wherein
- R1 is selected from the group consisting of
- i) phenyl optionally substituted with one methoxy substituent;
- ii) pyridinyl optionally substituted with one substituent selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, and cyano;
- iii) pyrimidin-5-yl;
- and
- iv) di(C1-2alkyl)aminocarbonyl;
- Y is vinyl or a bond;
- R2 is phenyl optionally substituted with one substituent independently selected from the group consisting of methoxy, hydroxy, aminocarbonyl, and C1-4alkylcarbonylamino;
- R3 is selected from the group consisting of
- i) 3-amino-cyclohexyl;
- ii) 4-amino-cyclohexyl;
- iii) pyrrolidin-2-ylmethyl wherein pyrrolidin-2-yl is optionally substituted at a carbon atom with one fluoro substituent;
- and
- or, R3 is taken with Ra and the nitrogen atom to which they are both attached to form piperazinyl;
- Ra is hydrogen;
- and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
14 more elements
A compound of Formula (I)
- selected from the group consisting of
- a compound wherein R1 is 2-(N,N-diethylaminocarbonyl), Y is (E)-vinyl, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 2-(N,N-diethylaminocarbonyl), Y is ethyl, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 2-(4-methoxy-phenyl), Y is ethyl, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 2-(3-methoxy-phenyl), Y is ethyl, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 2-phenyl, Y is ethyl, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 2-(4-fluoro-phenyl), Y is ethyl, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 2-(3-fluoro-phenyl), Y is ethyl, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 2-[3-(N,N-diethylaminocarbonyl)phenyl], Y is ethyl, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is N,N-diethylaminocarbonyl, Y is a bond, R2 is phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is N,N-diethylaminocarbonyl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is N,N-diethylaminocarbonyl, Y is a bond, R2 is 2-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-cyano-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 3-cyano-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 3-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-fluoro-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-trifluoromethoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 2,6-dichloro-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is 2-(N-methylamino)ethyl, and Ra is H;
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-methoxycarbonyl-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 3-methoxycarbonyl-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 2,4-dichloro-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is piperidin-4-yl, and Ra is H;
- a compound wherein R1 is 5-cyano-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is 4-fluoro-pyrrolidin-2-ylmethyl, and Ra is H;
- (2S,4R)
- a compound wherein R1 is 5-fluoro-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is 4-fluoro-pyrrolidin-2-ylmethyl, and Ra is H;
- (2S,4R)
- a compound wherein R1 is 5-methylthio-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is 4-fluoro-pyrrolidin-2-ylmethyl, and Ra is H;
- (2S,4R)
- a compound wherein R1 is 5-methoxy-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is 4-fluoro-pyrrolidin-2-ylmethyl, and Ra is H;
- (2S,4R)
- a compound wherein R1 is 5-methyl-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is 4-fluoro-pyrrolidin-2-ylmethyl, and Ra is H;
- (2S,4R)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-aminocarbonyl-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 3-aminocarbonyl-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-carboxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 3-carboxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-(N,N-diethylaminocarbonyl)phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 3-(N,N-diethylaminocarbonyl)phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is naphthalen-2-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is naphthalen-l-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is pyridin-4-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is furan-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is thiophen-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S) a compound wherein R1 is pyrimidin-5-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 5-fluoro-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 5-cyano-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is pyridin-3-yl, Y is a bond, R2 is 4-hydroxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is taken with Ra and the nitrogen atom to which they are both attached to form piperazin-1-yl;
- a compound wherein R1 is phenyl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is taken with Ra and the nitrogen atom to which they are both attached to form 4-methyl-piperazin-1-yl;
- a compound wherein R1 is 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is ethyl;
- (2S)
- a compound wherein R1 is 5-fluoro-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is ethyl;
- (2S)
- a compound wherein R1 is pyrimidin-5-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is ethyl;
- (2S)
- a compound wherein R1 is 5-cyano-pyridin-3-yl, Y is a bond, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is ethyl;
- (2S)
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is pyrrolidin-2-ylmethyl, and Ra is H;
- (2S)
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is piperidin-3-yl, and Ra is H;
- racemic;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is 3-hydroxy-2(R)-amino-propyl, and Ra is H;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is piperidin-4-yl, and Ra is H;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is 8-azabicyclo[3.2.1]octan-3-yl, and Ra is H;
- mixture of endo/exo isomers;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is azetidin-3-yl-methyl, and Ra is H;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is azetidin-3-yl-methyl, and Ra is azetidin-3-yl-methyl;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is 1-azabicyclo[2.2.2]octan-3-yl, and Ra is H;
- mixture of endo/exo isomers;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is piperidin-3-ylmethyl, and Ra is H;
- racemic;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is 3-amino-cyclohexyl, and Ra is H;
- mixture of 4 isomers;
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is 2-(N-methylamino)ethyl, and Ra is H;
- and
- a compound wherein R1 is 4-methoxy-phenyl, Y is 0, R2 is 4-methoxy-phenyl, R3 is 2-(N-methylamino)ethyl, and Ra is 2-(N-methylamino)ethyl;
- and pharmaceutically acceptable salts thereof.
117 more elements
Dependencies are inferred from the claim text.