Piperazine derivatives and methods of use
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Abstract
Selected compounds are effective for treatment of pain and diseases, such as inflammation mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving pain, inflammation, and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Citations
117 Claims
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1. A compound of Formula I
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117)
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2. Compound of claim 1 wherein q is 1-2;
- and wherein t is 1.
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3. Compound of claim 2 wherein q is 1.
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4. Compound of claim 1 wherein X is selected from NH and NRa;
- and wherein R1 is (C1-3)alkyl.
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5. Compound of claim 4 wherein X is NH.
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6. Compound of claim 1 wherein R is selected from 9-11 membered fused bicyclic carbocyclic or heterocyclic ring substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, —
- C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl.
- C(O)R8, —
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7. Compound of claim 6 wherein R is a partially unsaturated carbocyclic ring;
- substituted with a basic moiety, optionally substituted with chloro.
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8. Compound of claim 7 wherein R is 1,2,3,4-tetrahydronaphthyl;
- substituted with a basic moiety, optionally substituted with chloro.
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9. Compound of claim 7 wherein R is indanyl;
- substituted with a basic moiety, optionally substituted with chloro.
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10. The compound of claim 7 wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;
- substituted with a basic moiety, optionally substituted with chloro.
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11. The compound of claim 1 wherein R is partially unsaturated heterocyclyl;
- substituted with a basic moiety, optionally substituted with chloro.
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12. The compound of claim 11 wherein R is chroman;
- substituted with a basic moiety, optionally substituted with chloro.
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13. The compound of claim 11 wherein R is 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl;
- substituted with a basic moiety, optionally substituted with chloro.
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14. The compound of claim 11 wherein R is chroman-4-yl or 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl;
- substituted with a basic moiety, optionally substituted with chloro.
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15. Compound of claim 1 wherein R is selected from phenyl and 5-6 membered heteroaryl;
- wherein R is substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C1-C6)alkoxy, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl.
- wherein R is substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C1-C6)alkoxy, —
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16. Compound of claim 15 wherein R is phenyl substituted with a basic moiety selected from (C1-C6)alkylamino(C1-C6)alkyl, C1-4-alkylamino-C2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-6-alkenyl, and heterocyclyl-C1-C6)alkylamino(C2-C6)alkyl.
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17. Compound of claim 16 wherein R is selected from 3-((piperidin-1-ylethyl)aminomethyl)phenyl and 4-imidazolin-2-ylphenyl.
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18. Compound of claim 1 wherein R is phenyl-(C1-3)-alkyl substituted with a basic moiety.
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19. Compound of claim 18 wherein R is selected from 4-(imidazolin-2-yl)phenylmethyl, 4-(imidazolin-2-yl)phenylethyl and 4-(imidazolin-2-yl)phenylpropyl.
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20. Compound of claim 1 wherein R1 is H or methyl.
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21. Compound of claim 1 wherein R2 is selected from phenyl-(C2-4)-alkenyl, phenyl, naphthyl, 5-membered nitrogen containing heteroaryl, 5-membered sullfur containing heteroaryl, 6-membered nitrogen containing heteroaryl, 9-membered heterocyclyl, and 10-membered heterocyclyl.
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22. Compound of claim 21 wherein R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, naphtho[2,3-d]dioxolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 2-thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl, 3-pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;
wherein R2 is optionally substituted with one to five groups independently selected from halo, —
NH2, hydroxyl, cyano, C1-C6)alkylamino, oxo, C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C1-C6)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, C1-C4)alkylamino, (C1-C4)haloalkyl, oxo, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, di(C1-C4)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
.
- CH—
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23. Compound of claim 22 wherein R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl; and
wherein R2 is optionally substituted.
- CH—
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24. Compound of claim 1 wherein R2 is selected from 2,4,6-trimethylphenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl and 4-tert-butylphenyl.
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25. Compound of claim 1 wherein the basic substituent on R is selected from amino, cycloalkylamino(C1-C6)alkyl, cycloalkyl(C1-C6)alkylamino(C1-C6)alkyl, heterocyclylamino(C1-C6)alkyl, heterocyclyl(C1-C6)alkylamino(C1-C6)alkyl, arylamino(C1-C6)alkyl, aryl(C1-C6)alkylamino(C1-C6)alkyl, C1-6-alkylamino-C1-6-alkoxy, C1-6-alkylamino-C1-6-alkoxy-C1-6-alkoxy, amino(C1-C6)alkoxy, amino(C1-C6)alkyl, C1-C6)alkylamino(C1-C6)alkyl, C1-4-alkylamino-C2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-6-alkenyl, heterocyclyl-(C1-C6)alkylamino(C2-C6)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl;
- and wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, —
CF3, (C1-C6)alkylamino, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, C1-C6)alkyl, substituted C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C1-C6)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, C1-C6)alkylamino, (C1-C6)haloalkyl, oxo, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
;
and pharmaceutically acceptable derivatives thereof.
- and wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —
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26. The compound of claim 25 wherein the basic substituent on R is selected from amino, mono-C1-4-alkylamino-C1-4-alkyl, di-C1-4-alkylamino-C1-4-alkyl, mono-C1-4-alkylamino-C2-4-alkenyl, di-C1-4-alkylamino-C2-4-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8 membered nitrogen-containing heterocyclyl-C1-4-alkyl;
- and pharmaceutically acceptable derivatives thereof.
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27. The compound of claim 26 wherein the basic substituent on R is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1 ]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
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28. The compound of claim 1 wherein R3 and R3a together form oxo;
- wherein R4 and R4a are independently selected from H and C1-3 alkyl; and
wherein R5 and R5a are independently H.
- wherein R4 and R4a are independently selected from H and C1-3 alkyl; and
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29. The compound of claim 28 wherein R3 and R3a together form oxo;
- wherein R4 and R4a are independently selected from H and methyl; and
wherein R5 and R5a are independently H.
- wherein R4 and R4a are independently selected from H and methyl; and
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30. The compound of claim 1 wherein R8 and R8′
- independently are H or selected from lower alkyl, aryl and heteroaryl, each of which is optionally substituted with one, two or three groups independently selected from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono-alkylamino, dialkylamino, and trifluoromethyl.
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31. Compound of claim 1 wherein Rx is H, methyl or trifluoromethyl.
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32. Compound of claim 1 wherein Rx is H.
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107. The compound of claim 1 and/or pharmaceutically acceptable derivatives thereof selected from:
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2-((2R,S)-1-((5-chloro-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((1R,S)-1-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(2-methylpropyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-propyl-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((1R,S)-1-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-(((1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R,S)-1-((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-(1-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-5-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-5-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-(1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((2-methylpropyl)amino)-1-propynyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((2-methylpropyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-piperidinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-piperidinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((2-methylpropyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((1 S)-1-methyl-2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(((2-methylpropyl)amino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-pyrrolidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
3-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)benzamide;
methyl 3-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)benzoate;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
3-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)benzoic acid;
2-fluoro-4-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)benzoic acid;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-(((2-methylpropyl)amino)methyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-pyrrolidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-methyl-1-piperazinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((2-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3-chloro-4-fluorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chloro-2-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((2-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-3-oxo-1-(phenylsulfonyl)-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-3-oxo-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3-bromo-5-chloro-2-thienyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((5-chloro-2-thienyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((4-methyl-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((4-methyl-1-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-(((2,2-dimethylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((cyclobutylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(1-pyrrolidinyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S) 1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(4-morpholinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((phenylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
methyl (2E)-3-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)-2-propenoate;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(4-morpholinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-methyl-1-piperazinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((phenylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-phenylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(2-fluorophenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((cyclobutylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(1-pyrrolidinyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((3-methylbutyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1-naphthalenylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(2-(methyloxy)phenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-((1,1-dimethylethyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-((2,2-dimethylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(cyclobutylamino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-((phenylmethyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(4-morpholinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-pyrrolidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((2R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((2R)-6-(2-((2-(1-pyrrolidinyl)ethyl)amino)ethyl)-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((((1 S)-1-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(1-pyrrolidinyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(4-morpholinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-(pentafluoroethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-((1R,S)-1-(cyclopentylamino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide d—
2_;
N-((1R)-6-(hydroxymethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(3-cyanophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-(bis(2-methylpropyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-((cyclopentylmethyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-aminopropyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-aminopropyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-(bis(2-methylpropyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(((cyclopropylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(((1-methylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-((cyclobutylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(1-(((1,1-dimethylethyl)amino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(1-(((cyclopropylmethyl)amino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(1-((cyclobutylamino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(1-(1-azetidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(1-((4-fluoro-1-piperidinyl)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-(acetylamino)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-(hydroxymethyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-((cyclobutylamino)methyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(3-((cyclopentylamino)methyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(1-(((2,2-dimethylpropyl)amino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((3-methylbutyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((3,3-dimethylbutyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((cyclohexylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((2-(2-fluorophenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(aminomethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((3-methylbutyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((cyclohexylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-((cyclohexylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((cyclopropylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-((cyclopropylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(1-azepanylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((3R,S)-3-hydroxy-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((2-(methyloxy)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((1R)-6-(((2-hydroxyethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((4-methyl-1-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((tetrahydro-2H-pyran-4-ylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-(((cyclopropylmethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-methyl-1-piperazinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((tetrahydro-2H-pyran4-ylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((cyclopropylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((4-pyridinylmethyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((tetrahydro-2H-pyran-4-ylmethyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((4R)-1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-1-(2-naphthalenylsulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((4R)-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
N-((4R)-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-5,5-dimethyl-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
1,1-dimethylethyl 4-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate;
2-((2R,S)-1-((4-(1,1-dimethylethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((2,5-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-5-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-pyrrolidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1R-((3,5-dibromo-4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R)-1-((3,5-dibromo-4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2S)-1-((3,5-dibromo-4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
N-((1R)-6-(1-(cyclopropylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide; and
N-((1R)-6-(1-(cyclohexylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide.
-
-
108. A pharmaceutically acceptable salt of a compound according to claim 1.
-
109. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1.
-
110. A method of treating pain comprising administering an effective amount a compound according to claim 1.
-
111. A pharmaceutical composition for the treatment of disease conditions mediated by bradykinin, in a mammalian subject, which comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
-
112. A pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer'"'"'s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or angio edema, which comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
-
113. A method for the treatment of disease conditions mediated by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.
-
114. A method for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer'"'"'s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or angio edema, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.
-
115. A pharmaceutical formulation comprising a compound according to claim 1, a pharmaceutically acceptable carrier and, optionally, one or more other pharmacologically active ingredients.
-
116. A method of treating, preventing, or ameliorating a disease or condition associated with B1 activity comprising administering to a human or animal subject a therapeutically effective amount of a compound according to claim 1.
-
117. The method according to claim 116 wherein the disease or condition is selected from the group of inflammation, inflammatory pain, acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, inflammatory bowel disorders, asthma, and allergic rhinitis.
-
2. Compound of claim 1 wherein q is 1-2;
-
33. A compound of Formula II
- View Dependent Claims (34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62)
-
34. Compound of claim 33 wherein X is selected from NH and NRa;
- and wherein Ra is (C1-3)alkyl.
-
35. Compound of claim 34 wherein X is NH.
-
36. Compound of claim 33 wherein R is selected from 9-11 membered fused bicyclic carbocyclic or heterocyclic ring substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, —
- C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl.
- C(O)R8, —
-
37. Compound of claim 36 wherein R is a partially unsaturated carbocyclic ring;
- substituted with a basic moiety, optionally substituted with chloro.
-
38. Compound of claim 37 wherein R is 1,2,3,4-tetrahydronaphthyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
39. Compound of claim 37 wherein R is indanyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
40. The compound of claim 37 wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;
- substituted with a basic moiety, optionally substituted with chloro.
-
41. The compound of claim 33 wherein R is partially unsaturated heterocyclyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
42. The compound of claim 41 wherein R is chroman;
- substituted with a basic moiety, optionally substituted with chloro.
-
43. The compound of claim 41 wherein R is 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
44. The compound of claim 41 wherein R is chroman-4-yl or 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl;
- substituted with a basic moiety, optionally substituted with chloro.
-
45. Compound of claim 33 wherein R is selected from phenyl and 5-6 membered heteroaryl;
- wherein R is substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C1-C6)alkoxy, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl.
- wherein R is substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C1-C6)alkoxy, —
-
46. Compound of claim 45 wherein R is phenyl substituted with a basic moiety selected from (C1-C6)alkylamino(C1-C6)alkyl, C14-alkylamino-C2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-6-alkenyl, and heterocyclyl-C1-C6)alkylamino(C2-C6)alkyl.
-
47. Compound of claim 46 wherein R is selected from 3-((piperidin-1-ylethyl)aminomethyl)phenyl and 4-(imidazolin-2-yl)phenyl.
-
48. Compound of claim 33 wherein R is phenyl-(C1-3)-alkyl substituted with a basic moiety.
-
49. Compound of claim 48 wherein R is selected from 4-(imidazolin-2-yl)phenylmethyl, 4-(imidazolin-2-yl)phenylethyl and 4-(imidazolin-2-yl)phenylpropyl.
-
50. Compound of claim 33 wherein R1 is H or methyl.
-
51. Compound of claim 33 wherein R2 is selected from phenyl-(C2-4)-alkenyl, phenyl, naphthyl, 5-membered nitrogen containing heteroaryl, 5-membered sullfur containing heteroaryl, 6-membered nitrogen containing heteroaryl, 9-membered heterocyclyl, and 10-membered heterocyclyl.
-
52. Compound of claim 51 wherein R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, naphtho[2.3-d]dioxolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;
wherein R2 is optionally substituted with one to five groups independently selected from halo, —
NH2, hydroxyl, cyano, (C1-C6)alkylamino, oxo, C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C1-C6)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, (C1-C4)alkylamino, (C1-C4)haloalkyl, oxo, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, di(C1-C4)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
.
- CH—
-
53. Compound of claim 52 wherein R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl; and
wherein R2 is optionally substituted.
- CH—
-
54. Compound of claim 33 wherein R2 is selected from 2,4,6-trimethylphenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl and 4-tert-butylphenyl.
-
55. Compound of claim 33 wherein the basic substituent on R is selected from amino, cycloalkylamino(C1-C6)alkyl, cycloalkyl(C1-C6)alkylamino(C1-C6)alkyl, heterocyclylamino(C1-C6)alkyl, heterocyclyl(C1-C6)alkylamino(C1-C6)alkyl, arylamino(C1-C6)alkyl, aryl(C1-C6)alkylamino(C1-C6)alkyl, C1-6-alkylamino-C1-6-alkoxy, C1-6-alkylamino-C1-6-alkoxy-C1-6-alkoxy, amino(C1-C6)alkoxy, amino(C1-C6)alkyl, C1-C6)alkylamino(C1-C6)alkyl, C1-4-alkylamino-C2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-6-alkenyl, heterocyclyl-(C1-C6)alkylamino(C2-C6)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl;
- and wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, —
CF3, (C1-C6)alkylamino, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C1-C6)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, C1-C6)alkylamino, (C1-C6)haloalkyl, oxo, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
;
and pharmaceutically acceptable derivatives thereof.
- and wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —
-
56. The compound of claim 55 wherein the basic substituent on R is selected from amino, mono-C1-4-alkylamino-C1-4-alkyl, di-C1-4-alkylamino-C1-4-alkyl, mono-C1-4-alkylamino-C2-4-alkenyl, di-C1-4-alkylamino-C2-4-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8 membered nitrogen-containing heterocyclyl-C1-4-alkyl;
and pharmaceutically acceptable derivatives thereof.
-
57. The compound of claim 56 wherein the basic substituent on R is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
-
58. The compound of claim 33 wherein R3 and R3a together form oxo;
- wherein R4 and R4a are independently selected from H, and C1-3 alkyl;
wherein R5 and R5a are independently H.
- wherein R4 and R4a are independently selected from H, and C1-3 alkyl;
-
59. The compound of claim 58 wherein R3 and R3a together form oxo;
- wherein R4 and R4a are independently selected from H and methyl;
wherein R5 and R5a are independently H.
- wherein R4 and R4a are independently selected from H and methyl;
-
60. Compound of claim 33 wherein R8 and R8′
- independently are H or selected from lower alkyl, aryl and heteroaryl, each of which is optionally substituted with one, two or three groups independently selected from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono-alkylamino, dialkylamino, and trifluoromethyl.
-
61. Compound of claim 33 wherein Rx is selected from H, methyl and trifluoromethyl.
-
62. Compound of claim 61 wherein Rx is H.
-
34. Compound of claim 33 wherein X is selected from NH and NRa;
-
63. A compound of Formula III
- View Dependent Claims (64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76)
-
64. The compound of claim 63 wherein R is a partially unsaturated carbocyclic ring;
- substituted with a basic moiety, optionally substituted with chloro.
-
65. The compound of claim 64 wherein R is 1,2,3,4-tetrahydronaphthyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
66. The compound of claim 64 wherein R is indanyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
67. The compound of claim 64 wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;
- substituted with a basic moiety, optionally substituted with chloro.
-
68. The compound of claim 63 wherein R is partially unsaturated heterocyclyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
69. The compound of claim 68 wherein R is chroman;
- substituted with a basic moiety, optionally substituted with chloro.
-
70. The compound of claim 68 wherein R is 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
71. The compound of claim 68 wherein R is chroman-4-yl or 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl;
- substituted with a basic moiety, optionally substituted with chloro.
-
72. The compound of claim 63 wherein each R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, naphtho[2.3d]dioxolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;
wherein R2 is optionally substituted with one to five groups independently selected from halo, —
NH2, hydroxyl, cyano, —
CF3, (C1-C6)alkylamino, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl;
wherein each substituted (C1-C6)alkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl and substituted saturated or partially saturated heterocyclyl is substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, (C1-C6)alkylamino, halo(C1-C6)alkyl, oxo, (C1-C6)alkoxy, C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
;
wherein R1 is selected from H and C1-2-alkyl;
wherein the basic substituent on R is selected from amino, cycloalkylamino(C1-C6)alkyl, cycloalkyl(C1-C6)alkylamino(C1-C6)alkyl, heterocyclylamino(C1-C6)alkyl, heterocyclyl(C1-C6)alkylamino(C1-C6)alkyl, arylamino(C1-C6)alkyl, aryl(C1-C6)alkylamino(C1-C6)alkyl, C1-6-alkylamino-C1-6-alkoxy, C1-6-alkylamino-C1-6-alkoxy-C1-6-alkoxy, amino(C1-C6)alkoxy, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, C1-4-alkylamino-C2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-6-alkenyl, heterocyclyl-(C1-C6)alkylamino(C2-C6)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl; and
wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, —
CF3, (C1-C6)alkylamino, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted C1-C6)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, (C1-C4)alkylamino, (C1-C4)haloalkyl, oxo, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, di(C1-C4)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
;
and pharmaceutically acceptable derivatives thereof.
- CH—
-
73. The compound of claim 72 wherein R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl;
wherein each R2 is said optionally substituted;
wherein R1 is H; and
wherein the basic substituent on R is selected from amino, mono-C1-4-alkylamino-C1-4-alkyl, di-C1-4-alkylamino-C1-4-alkyl, mono-C1-4-alkylamino-C2-4-alkenyl, di-C1-4-alkylamino-C2-4-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8 membered nitrogen-containing heterocyclyl-C1-4-alkyl;
and pharmaceutically acceptable derivatives thereof.
- CH—
-
74. The compound of claim 63 wherein R1 is H.
-
75. The compound of claim 63 wherein the basic substituent on R is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
-
76. The compound of claim 63 and/or pharmaceutically acceptable derivatives thereof selected from
2-[3-Oxo-1-(2,4,6-trimethylbenzenesulfonyl)-piperizin-2(R,S)-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide; -
N-((1R)-6-(((1,1-Dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
2-[3-Oxo-1-(toluene-4-sulfonyl)piperizin-2-yl]-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide;
N-7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2-yl]-acetamide;
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(4-methoxy-benzenesulfonyl)-piperazin-2-yl]-acetamide;
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(4-chloro-benzenesulfonyl)-piperazin-2-yl]-acetamide;
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(3-trifluoromethyl-benzenesulfonyl)-piperazin-2-yl]-acetamide; and
N-((4R)-2,2-dimethyl-7-(2-piperidinyl)-3,4dihydro-2H-chromen-4-yl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide.
-
-
64. The compound of claim 63 wherein R is a partially unsaturated carbocyclic ring;
-
77. A compound of Formula IV
- View Dependent Claims (78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88)
-
78. The compound of claim 77 wherein R9 and R11 are H;
- and wherein R10 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
-
79. The compound of claim 77 wherein R10 and R11 are H;
- and wherein R9 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
-
80. The compound of claim 77 wherein R9 and R10 are H;
- and wherein R11 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
-
81. The compound of claim 77 wherein the C ring is selected from
-
82. The compound of claim 81 wherein the C ring is
-
83. The compound of claim 77 wherein R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, naphtho[2.3-d]dioxol-6-yl, 1-benzofur-2-yl, 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzothiadiazol-4-yl, 1,3-benzothiazol-2-yl, 1H-pyrazol-4-yl, thien-2-yl, 5-isoxazolthien-2-yl, benzothien-2-yl, thieno[3,2-c]pyridin-2-yl, 2-naphthyl, phenyl, 3-pyridyl, tetrahydroisoquinolyl, 8-quinolyl and 5-isoquinolyl;
wherein R2 is selected from phenyl-CH═
CH—
, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl;
wherein each R2 is optionally substituted with one to five groups independently selected from halo, —
NH2, hydroxyl, cyano, —
CF3, (C1-C6)alkylamino, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl;
wherein each substituted C1-C6)alkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl and substituted saturated or partially saturated heterocyclyl is substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, (C1-C6)alkylamino, C1-C6)haloalkyl, oxo, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
.
- CH—
-
84. The compound of claim 77 wherein R2 is selected from 2-naphthyl, 1-naphthyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,4,6-trichlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-biphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-methylphenyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl.
-
85. The compound of claim 77 wherein R1 is H or methyl.
-
86. The compound of claim 77 wherein R2 is 2-naphthyl.
-
87. The compound of claim 77 wherein R2 is 3,4-dichlorophenyl.
-
88. The compound of claim 77 wherein R2 is 3-trifluoromethylphenyl.
-
78. The compound of claim 77 wherein R9 and R11 are H;
-
89. A compound of Formula V
- View Dependent Claims (90, 91, 92)
-
90. The compound of claim 89 wherein R7 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
-
91. The compound of claim 89 wherein R7 is at position 7.
-
92. The compound of claim 89 wherein R2 is 2-naphthyl, 3,4-dichlorophenyl or 3-trifluoromethylphenyl.
-
90. The compound of claim 89 wherein R7 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
-
93. A compound of Formula VI
- View Dependent Claims (94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106)
-
94. The compound of claim 93 wherein R is a partially unsaturated carbocyclic ring;
- substituted with a basic moiety, optionally substituted with chloro.
-
95. The compound of claim 94 wherein R is 1,2,3,4-tetrahydronaphthyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
96. The compound of claim 94 wherein R is indanyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
97. The compound of claim 94 wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;
- substituted with a basic moiety, optionally substituted with chloro.
-
98. The compound of claim 93 wherein R is partially unsaturated heterocyclyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
99. The compound of claim 98 wherein R is chroman;
- substituted with a basic moiety, optionally substituted with chloro.
-
100. The compound of claim 98 wherein R is 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl;
- substituted with a basic moiety, optionally substituted with chloro.
-
101. The compound of claim 98 wherein R is chroman-4-yl or 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl;
- substituted with a basic moiety, optionally substituted with chloro.
-
102. The compound of claim 93 wherein each R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, naphtho[2.3-d]dioxolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;
wherein R2 is optionally substituted with one to five groups independently selected from halo, —
NH2, hydroxyl, cyano, —
CF3, (C1-C6)alkylamino, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl;
wherein each substituted (C1-C6)alkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl and substituted saturated or partially saturated heterocyclyl is substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, (C1-C6)alkylamino, halo(C1-C6)alkyl, oxo, (C1-C6)alkoxy, C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
;
wherein R1 is selected from H and C1-2-alkyl;
wherein the basic substituent on R is selected from amino, cycloalkylamino(C1-C6)alkyl, cycloalkyl(C1-C6)alkylamino(C1-C6)alkyl, heterocyclylamino(C1-C6)alkyl, heterocyclyl(C1-C6)alkylamino(C1-C6)alkyl, arylamino(C1-C6)alkyl, aryl(C1-C6)alkylamino(C1-C6)alkyl, C1-6-alkylamino-C1-6-alkoxy, C1-6-alkylamino-C1-6-alkoxy-C1-6-alkoxy, amino(C1-C6)alkoxy, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, C1-4-alkylamino-C2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-6-alkenyl, heterocyclyl-C1-C6)alkylamino(C2-C6)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl; and
wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, —
CF3, (C1-C6)alkylamino, oxo, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, —
NR8C(O)R8′
, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C1-C6)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —
NH2, hydroxyl, cyano, (C1-C4)alkylamino, (C1-C4)haloalkyl, oxo, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, di(C1-C4)alkylamino, —
C(O)R8, —
COOR8, —
C(O)NR8R8′
, and —
NR8C(O)R8′
;
and pharmaceutically acceptable derivatives thereof.
- CH—
-
103. The compound of claim 102 wherein R2 is selected from phenyl-CH═
- CH—
, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl;
wherein each R2 is said optionally substituted;
wherein Ra is H; and
wherein the basic substituent on R is selected from amino, mono-C1-4-alkylamino-C1-4-alkyl, di-C1-4-alkylamino-C1-4-alkyl, mono-C1-4-alkylamino-C2-4-alkenyl, di-C(1-4-alkylamino-C2-4-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8 membered nitrogen-containing heterocyclyl-C1-4-alkyl;
and pharmaceutically acceptable derivatives thereof.
- CH—
-
104. The compound of claim 93 wherein R1 is H.
-
105. The compound of claim 93 wherein the basic substituent on R is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.
-
106. The compound of claim 93 and/or pharmaceutically acceptable derivatives thereof selected from 2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperazinyl)-N-(1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
-
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[5,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)-yl]-acetamide N-((1R,S)-6-(((1, 1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-5,5-dimethyl -1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
2-[5,5-Dimethyl-3-oxo-1-(toluene-4-sulfonyl)-piperizin-2(R,S)-yl]-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-1(R)-yl)-acetamide; and
N-((4R)-6-Chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperazinyl)acetamide.
-
-
94. The compound of claim 93 wherein R is a partially unsaturated carbocyclic ring;
Specification
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Current AssigneeAmgen Inc.
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Original AssigneeAmgen Inc.
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InventorsZhu, Jiawang, Harried, Scott, Liu, Qingyian, Li, Aiwen, Yang, Kevin, Nguyen, Thomas, Han, Nianhe, Yuan, Chester Chenguang, Chen, Jian J., Fotsch, Christopher H., Biswas, Kaustav, D'Amico, Derin C., Qian, Wenyuan, Peterkin, Tanya, Nomak, Rana, Chau, Jennifer N., Nishimura, Nobuku, Riahi, Babak, Askew, Ben C.
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/227.500
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CPC Class CodesA61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 1/18 for pancreatic disorders, e...A61P 11/00 Drugs for disorders of the ...A61P 11/02 Nasal agents, e.g. deconges...A61P 11/06 AntiasthmaticsA61P 13/02 of urine or of the urinary ...A61P 13/10 of the bladderA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/04 AntipruriticsA61P 17/06 AntipsoriaticsA61P 17/16 Emollients or protectives, ...A61P 19/02 for joint disorders, e.g. a...A61P 21/00 Drugs for disorders of the ...A61P 25/00 Drugs for disorders of the ...A61P 25/04 Centrally acting analgesics...A61P 25/06 Antimigraine agentsA61P 25/08 Antiepileptics; Anticonvuls...A61P 25/28 : for treating neurodegenerat...A61P 25/32 : Alcohol-abuseA61P 27/02 : Ophthalmic agentsA61P 27/06 : Antiglaucoma agents or mioticsA61P 27/16 : OtologicalsA61P 29/00 : Non-central analgesic, anti...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/04 : Antibacterial agentsA61P 31/12 : AntiviralsA61P 31/18 : for HIVA61P 31/22 : for herpes virusesA61P 35/00 : Antineoplastic agentsA61P 35/04 : specific for metastasisA61P 37/08 : Antiallergic agents antiast...A61P 39/02 : AntidotesA61P 41/00 : Drugs used in surgical meth...A61P 43/00 : Drugs for specific purposes...A61P 7/10 : Antioedematous agents; Diur...A61P 9/00 : Drugs for disorders of the ...A61P 9/10 : for treating ischaemic or a...A61P 9/14 : Vasoprotectives; Antihaemor...C07D 241/08 : with oxygen atoms directly ...C07D 243/08 : not condensed with other ringsC07D 245/02 : not condensed with other ringsC07D 401/12 : linked by a chain containin...C07D 403/12 : linked by a chain containin...C07D 405/12 : linked by a chain containin...C07D 405/14 : containing three or more he...C07D 409/12 : linked by a chain containin...C07D 409/14 : containing three or more he...C07D 413/14 : containing three or more he...