Diaryl substituted pyridinones
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Abstract
Disclosed are compounds Formula I
and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5 are defined herein. These compounds are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP Kinase and/or TNF activity. Pharmaceutical compositions containing the compounds, methods of preparing the compounds and methods of treatment using the compounds are also disclosed.
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Citations
56 Claims
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2. A compound or salt of the formula:
- View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 24)
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3. A compound or salt according to claim 2 wherein
R2 is arylalkoxy, aryloxy, OH, halogen, arylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, — - OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, or thiazolyl, thiophenyl, whereinn is 0, 1, 2, 3, 4, 5 or 6; and
the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, haloalkyl, or thiophenyl.
- OC(O)NH(CH2)nphenyl, —
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4. A compound or salt according to claim 2 wherein
R5 is phenyl(C1-C6)alkyl, (C1-C6)alkyl, phenyl, naphthyl, (C1-C6)alkoxy, piperidinyl (C1-C6)alkyl, pyrrolyl(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl, imidazolidinyl(C1-C6)alkyl, pyrazolyl(C1-C6)alkyl, imidazolyl(C1-C6)alkyl, tetrahydropyridinyl(C1-C6)alkyl, thiophenyl(C1-C6)alkyl, arylthio(C1-C6)alkyl, pyridyl, or pyridyl(C1-C6)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently (C1-C4)alkyl, fluoro, chloro, bromo, (C1-C4)alkoxy, phenyl(C1-C4)alkoxy, thio(C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, phenyl(C1-C4)alkoxycarbonyl, CO2H, CN, amidinooxime, NR6R7, NR6R7alkyl, — - C(O)NR6R7, amidino, CF3, —
CF2CF3, OCF3 or OCF2CF3.
- C(O)NR6R7, amidino, CF3, —
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5. A compound or salt according to claim 2 wherein
R1 is halogen, (C1-C6)alkanoyl, phenyl(C1-C6)alkanoyl, naphthyl(C1-C6)alkanoyl, naphthyl(C1-C6)alkyl, phenyl(C1-C6)alkyl, alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein the phenyl and naphthyl portions of the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or CO2H; the alkyl portion of the hydroxyalkyl, arylalkyl, alkanoyl, alkoxyalkyl and arylalkanoyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy.
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6. A compound or salt according to claim 2 wherein
R3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(C1-C6)alkyl, — - OC(O)NH(CH2)naryl, phenylalkoxy, —
OC(O)N(alkyl)(CH2)naryl, phenyloxy, naphthyloxy, phenylthio, thioalkoxy, arylthioalkoxy, (C2-C6)alkenyl, NR6R7 or alkyl, whereinthe phenyl, naphthyl, and aryl portions of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, —
OC(O)NH(CH2)naryl, arylthioalkoxy, arylalkoxy, and —
OC(O)N(alkyl)(CH2)naryl, are unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, or OCF3;
and wherein n is 0, 1, 2, 3, 4, 5, or 6.
- OC(O)NH(CH2)naryl, phenylalkoxy, —
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7. A compound or salt according to claim 2 wherein
R4 is H, (C1-C6)alkyl, phenylalkoxy, phenyl(C1-C6)alkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, (C1-C6)alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above groups is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, or OCF3. -
8. A compound or salt according to claim 2 wherein
R1 is halogen, (C1-C6)alkanoyl, phenyl(C1-C6)alkanoyl, naphthyl(C1-C6)alkanoyl, naphthyl(C1-C6)alkyl, phenyl(C1-C6)alkyl, alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein the phenyl and napthyl portions of the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or CO2H; -
the alkyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy. R2 is phenylalkoxy, aryloxy, OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, —
OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, or thiophenyl, whereinn is 0, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, halo(C1-C4)alkyl, thiophenyl;
R3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(C1-C6)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, arylthioalkoxy, (C2-C6)alkenyl, NR6R7 or alkyl, wherein the phenyl, naphthyl, and aryl portions of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, —
OC(O)NH(CH2)naryl, arylthioalkoxy, arylalkoxy, and —
OC(O)N(alkyl)(CH2)naryl, are unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, or OCF3,wherein n is 0, 1, 2, 3, 4, 5, or 6;
orR4 is H, (C1-C6)alkyl, phenylalkoxy, phenyl(C1-C6)alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, or OCF3. R5 is phenyl(C1-C6)alkyl, (C1-C6)alkyl, phenyl, naphthyl, pyridyl, (C1-C6)alkoxy, piperidinyl(C1-C6)alkyl, pyrrolyl(C1-C6)alkyl, imidazolidinyl(C1-C6)alkyl, pyrazolyl(C1-C6)alkyl, imidazolyl(C1-C6)alkyl, tetrahydropyridinyl(C1-C6)alkyl, thiophenyl(C1-C6)alkyl, phenylthio(C1-C6)alkyl, or pyridyl(C1-C6)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (C1-C4)alkyl, fluoro, chloro, bromo, (C1-C4)alkoxy, phenyl(C1-C4)alkoxy, thio(C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, phenyl(C1-C4)alkoxycarbonyl, CO2H, CN, amidinooxime, NR6R7, NR6R7alkyl, —
C(O)NR6R7, amidino, CF3, —
CF2CF3, OCF3 or OCF2CF3.
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9. A compound or salt according to claim 8 wherein
R1 is halogen, (C1-C4)alkanoyl, phenyl(C1-C4)alkanoyl, benzyl, phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or CO2H; -
the alkyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy, phenyloxy, OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, wherein n is 0, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, or 3, groups that are independently halogen, halo(C1-C4)alkyl, or thiophenyl;
R3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(C1-C6)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, (C2-C6)alkenyl, NR6R7 or alkyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy,(C1-C4)alkyl, CF3, or OCF3, R4 is H, (C1-C6)alkyl, phenylalkoxy, benzyl, phenethyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, (C1-C4)alkoxy, (C1-C4)alkyl, nitro, CF3, or OCF3. R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (C1-C6)alkyl, phenyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (C1-C4)alkyl, fluoro, chloro, bromo, (C1-C4)alkoxy, phenyl(C1-C4)alkoxy, thio(C1-C4)alkoxy, (C1-C4) alkoxycarbonyl, CO2H, CN, amidinooxime, NR6R7, amidino, CF3, or OCF3.
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10. A compound or salt according to claim 9 wherein
R1 is bromo, phenyl(C1-C4)alkanoyl, benzyl, phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or CO2H; -
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy, phenyloxy, OH, halogen, ro phenylthioalkoxy, wherein n is 0, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, or 3, groups that are independently halogen, halo(C1-C4)alkyl, or thiophenyl;
R3 is bromo, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(C1-C6)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, (C2-C6)alkenyl, NR6R7 or alkyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, (C1-C4)alkyl, CF3, or OCF3, R4 is H, (C1-C6)alkyl, phenylalkoxy, benzyl, or phenethyl, wherein the phenyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, (C1-C4)alkoxy, (C1-C4)alkyl, nitro, CF3, or OCF3. R5 is benzyl, phenethyl, phenpropyl, (C1-C6)alkyl, phenyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (C1-C4)alkyl, fluoro, chloro, bromo, (C1-C4)alkoxy, CO2H, CN, amidinooxime, amidino, CF3, or OCF3.
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24. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound or salt according to claim 2.
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3. A compound or salt according to claim 2 wherein
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11. A compound of the formula
- View Dependent Claims (12, 13, 14, 15, 16, 17, 25)
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12. A compound or salt according to claim 11 wherein
R1 is H, F, Cl, Br, (C1-C6)alkyl, carboxaldehyde, hydroxy(C1-C6)alkyl, phenyl(C1-C6)alkoxy, phenyl(C1-C6)alkyl, CN, or phenyl(C1-C6) alkanoyl wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO2H; wherein the alkyl portion of above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy.
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13. A compound or salt according to claim 11 wherein
R2 is H, phenylthio, — - OC(O)NH(CH2)naryl, phenylalkyl, —
OC(O)N(alkyl)(CH2)naryl, or phenylthio(C1-C6)alkoxy, whereinn is 1, 2, 3, or 4.
- OC(O)NH(CH2)naryl, phenylalkyl, —
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14. A compound or salt according to claim 11 wherein
R3 is halogen, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, — - OC(O)NH(CH2)nphenyl, phenylalkoxy, —
OC(O)N(alkyl)(CH2)nphenyl, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7 or alkyl, whereinthe phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, (C1-C4)alkoxy, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo(C1-C4)alkoxy, wherein n is 0, 1, 2, 3, or 4.
- OC(O)NH(CH2)nphenyl, phenylalkoxy, —
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15. A compound or salt according to claim 11 wherein
R4 is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of phenylalkoxy, phenylalkyl is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy. -
16. A compound or salt according to claim 11 wherein
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl, alkoxy, pyridyl (C1-C6)alkyl, phenyl(C1-C6)thioalkyl, pyrrolyl, pyrrolyl(C1-C6)alkyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (C1-C6)alkyl, halogen, (C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)thioalkoxy, alkoxycarbonyl, CO2H, CN, amidinooxime, amidino, CF3, or OCF3. -
17. A compound or salt according to claim 11 wherein
R1 is H, Cl, Br, (C1-C6)alkyl, carboxaldehyde, hydroxy(C1-C6)alkyl, wherein the alkyl portion of above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy R2 is H, phenylthio, — - OC(O)NH(CH2)naryl, phenylalkyl, —
OC(O)N(alkyl)(CH2)naryl, or phenylthio(C1-C6)alkoxy, whereinn is 1, 2, 3, or 4 R3 is bromo, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7 or alkyl, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, (C1-C4)alkoxy, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo(C1-C4)alkoxy, wherein n is 0, 1, 2, 3, or 4;
R4 is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or wherein the phenyl portion of phenylalkoxy, phenylalkyl is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy R5 is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl, phenyl(C1-C6)thioalkyl, pyrrolyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (C1-C6)alkyl, halogen, (C1-C6)alkoxy, benzyloxy, (C1-C6)thioalkoxy, alkoxycarbonyl, CO2H, CN, amidinooxime, amidino, CF3, or OCF3.
- OC(O)NH(CH2)naryl, phenylalkyl, —
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25. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound or salt according to claim 11.
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12. A compound or salt according to claim 11 wherein
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18. A compound of the formula
- View Dependent Claims (19, 20, 21, 22, 23, 26)
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19. A compound or salt according to claim 18 wherein
R1 is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy, phenylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or phenylalkanoyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO2H; -
wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, ethoxy or spirocyclopropyl;
R2 is phenylalkoxy, phenyloxy, OH, halogen, phenylthioalkoxy, alkoxy, —
OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, alkyl, alkoxyalkoxy, dialkylamino, or CO2H, whereinn is 0, 1, 2, 3, 4, 5 or 6;
the above aryl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, haloalkyl, pyridyl, thiophenyl, NR6R7, NR6R7alkyl, or —
OC(O)NR6R7, whereinR6 and R7 are independently at each occurrence H, alkyl, alkoxy, alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy.
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20. A compound or salt according to claim 18 wherein
R3 is halogen, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, — - OC(O)NH(CH2)nphenyl, phenylalkoxy, —
OC(O)N(alkyl)(CH2)nphenyl, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7 or alkyl, whereinthe phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, 4, 5, or 6;
orR2, R3 and the carbons to which they are attached form an phenyl, piperidinyl, pyrrolyl, pyrrolinyl or a pyridyl ring, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halogen, phenylalkyl, phenylalkoxy, CN, NO2, haloalkyl, or haloalkoxy;
R4 is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
R5 is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkyl pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl, pyrrolyl, piperidinyl, pyridyl, or thiophenylalkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl, CO2H, CN, amidinooxime, NR6R7, NR6R7alkyl, —
C(O)NR6R7, amidino, haloalkyl, or haloalkoxy.
- OC(O)NH(CH2)nphenyl, phenylalkoxy, —
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21. A compound or salt according to claim 18 wherein
R1 is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl, CN, alkanoyl, alkoxy, or phenylC(O)— - , phenylCH2C(O)—
, or phenylCH2CH2C(O),wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or CO2H;
wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, OH, halogen, phenylthioalkoxy, alkyl, alkoxy, —
OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, dialkylamino, or CO2H, whereinn is 0, 1, 2, 3, or 4;
the above aryl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, CF3, pyridyl, thiophenyl, NR6R7, or NR6R7alkyl, wherein R6 and R7 are independently at each occurrence H, alkyl, alkanoyl, benzyl, or phenylC(O)—
, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, or OCF3;
R3 is halogen, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, —
OC(O) NH(CH2)nphenyl, phenylalkoxy, —
OC(O)N(alkyl)(CH2)nphenyl, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7 or alkyl, whereinthe phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, or 4;
R4 is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
R5 is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkyl pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl, pyrrolyl, piperidinyl, pyridyl, or thiophenylalkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl, CO2H, CN, amidinooxime, NR6R7, NR6R7alkyl, —
C(O)NR6R7, amidino, haloalkyl, or haloalkoxy.
- , phenylCH2C(O)—
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22. A compound or salt according to claim 21 wherein
R1 is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, benzyl, phenethyl, CN, (C1-C6)alkanoyl, alkoxy, or phenylC(O)— - , or phenylCH2C(O)—
,wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or CO2H;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, OH, halogen, phenyl(C1-C4) thioalkoxy, —
OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, or dialkylamino, whereinn is 0, 1, 2, 3, or 4;
the above aryl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, CF3, NR6R7, or NR6R7alkyl, wherein R6 and R7 are independently at each occurrence H, (C1-C6)alkyl, acetyl, benzyl, or phenylC(O)—
, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, or OCF3;
R3 is halogen, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7 or alkyl, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3,or 4;
R4 is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
R5 is phenyl, phenyl(C1-C4)thioalkyl, pyridyl, or thiophenyl(C1-C4)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (C1-C4)alkyl, fluoro, chloro, bromo, (C1-C4)alkoxy, CN, amidinooxime, amidino, CF3, or OCF3.
- , or phenylCH2C(O)—
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23. A compound or salt according to claim 22 wherein
R5 is substituted with at least one group selected from fluoro, chloro, bromo, and methyl. -
26. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound or salt according to claim 18.
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19. A compound or salt according to claim 18 wherein
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27. A compound of the formula:
- View Dependent Claims (28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 49, 53)
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28. A compound or salt according to claim 27 wherein
R1 is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenyl(C1-C6)alkoxy, phenyl(C1-C6)alkyl, CN, phenyl(C2-C6 alkynyl), C2-C6 alkynyl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, or phenyl(C1-C6)alkanoyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO2H; wherein the alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, ethoxy or spirocyclopropyl.
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29. A compound or salt according to claim 27 wherein
R2 is phenyl(C1-C6)alkoxy, phenyloxy, phenylthioalkoxy, C1-C8 alkoxy, alkyl, alkoxyalkoxy, — - OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO2H, whereinn is 0, 1, 2, 3, 4, 5 or 6;
each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NR6R7alkyl, —
OC(O)NR6R7, whereinR6 and R7 are independently at each occurrence H, alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein the aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy.
- OC(O)NH(CH2)nphenyl, —
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30. A compound or salt according to claim 27 wherein
R4 is H, (C1-C6)alkyl, phenyl(C1-C6)alkoxy, phenyl(C1-C6)alkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy. -
31. A compound or salt according to claim 27 wherein
R5 is phenyl(C1-C6)alkyl, (C1-C6)alkyl, phenyl, alkoxy, heterocycloalkylalkyl, naphthyl(C1-C6)alkyl, heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl, CO2H, CN, amidinooxime, NR8R9, NR6R7alkyl, — - C(O)NR6R7, amidino, haloalkyl, or haloalkoxy;
wherein R8 is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl;
wherein R9 is alkyl, alkanoyl, arylalkyl and arylalkanoyl;
provided that when R2 is benzyloxy, and R6 is benzyl or methyl, R1 is not hydrogen.
- C(O)NR6R7, amidino, haloalkyl, or haloalkoxy;
-
32. A compound or salt according to claim 27 wherein
R1 is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenyl(C1-C6)alkoxy, phenyl(C1-C6)alkyl, CN, alkanoyl, alkoxy, ethynyl, alkoxyalkyl, haloalkyl, or phenyl(C1-C6)alkanoyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or CO2H; -
wherein the alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy;
R2 is phenyl(C1-C6)alkoxy, phenyloxy, phenylthioalkoxy, C1-C8 alkoxy, alkyl, alkoxyalkoxy, —
OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO2H, whereinn is 0, 1, 2, 3, 4, 5 or 6;
each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NR6R7alkyl, —
OC(O) NR6R7, whereinR6 and R7 are independently at each occurrence H, alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein the aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, OCF3;
R4 is H, (C1-C6)alkyl, phenyl(C1-C6)alkoxy, phenyl(C1-C6)alkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, OCF3; and
R5 is phenyl(C1-C6)alkyl, (C1-C6)alkyl, phenyl, alkoxy, piperidinylalkyl, thienylalkyl, naphthyl(C1-C6)alkyl, heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl, CO2H, CN, amidinooxime, NR8R9, NR6R7alkyl, —
C(O)NR6R7, amidino, CF3, or OCF3;
wherein R8 is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl;
wherein R9 is alkyl, alkanoyl, arylalkyl and arylalkanoyl;
provided that when R2 is benzyloxy, and R5 is benzyl or methyl, R1 is not hydrogen.
-
-
33. A compound or salt according to claim 32 wherein
R1 is H, halogen, alkyl, haloalkyl, carboxaldehyde, hydroxyalkyl, phenyl(C1-C6)alkoxy, benzyl, phenethyl, phenpropyl, CN, or phenyl(C1-C6)alkanoyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or CO2H; -
R2 is benzyloxy, phenyloxy, phenylthioalkoxy, C1-C8, —
OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO2H,wherein n is 0, 1, 2, 3, 4, 5 or 6;
each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl, or NR6R7alkyl, wherein R6 and R7 are independently at each occurrence H, alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein the aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, OCF3;
R4 is H, (C1-C6)alkyl, phenyl(C1-C6)alkoxy, phenyl(C1-C6)alkyl, hydroxyalkyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, OCF3; and
R5 is phenyl(C1-C6)alkyl, (C1-C6)alkyl, phenyl, piperidinylalkyl, thienylalkyl, heteroaryl, naphthyl(C1-C6)alkyl, heteroarylalkyl, or wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, —
CO2CH3, —
CO2CH2CH3, —
CO2(C3-C5 alkyl), CO2H, CN, amidinooxime, NR8R9, NR6R7alkyl, —
C(O)NR6R7, amidino, CF3, or OCF3;
wherein R8 is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl;
wherein R9 is alkyl, alkanoyl, arylalkyl and arylalkanoyl;
provided that when R2 is benzyloxy, and R5 is benzyl or methyl, R1 is not hydrogen.
-
-
34. A compound or salt according to claim 33 wherein
R1 is H, halogen, alkyl or carboxaldehyde; R2 is benzyloxy, phenyloxy, phenylthioalkoxy, or pyridyl;
wherein each of the above is unsubstituted or substituted with 1, 2, or 3, groups that are independently halogen, haloalkyl, or alkyl.
-
35. A compound or salt according to claim 33 wherein
R4 is H, (C1-C4)alkyl, phenyl(C1-C6)alkoxy, benzyl, phenylethyl, phenpropyl, hydroxy(C1-C6)alkyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, OCF3; - and
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (C1-C6)alkyl, phenyl, pyridyl, pyrimidyl, naphthyl (C1-C6)alkyl, thiophenyl(C1-C6)alkyl, or pyridyl(C1-C6)alkyl wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, —
CO2CH3, —
CO2CH2CH3, —
CO2(C3-C5 alkyl), CF3, OCF3, CO2H, CN, amidinooxime;
provided that when R2 is benzyloxy, and R5 is benzyl or methyl, R1 is not hydrogen.
- and
-
36. A compound or salt according to claim 33 wherein R1 is bromo, iodo, or H;
- and
R5 is benzyl, phenethyl, phenpropyl, phenyl, piperidinylalkyl, thienylalkyl, —
CH2-pyridyl, or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently C1-C4 alkyl, halogen, CF3, OCF3, —
CO2CH3, C1-C4 alkoxy, —
CO2CH3, —
CO2CH2CH3, —
CO2(C3-C5 alkyl), benzyloxy, and amidinooxime.
- and
-
37. A compound or salt according to claim 36 wherein R2 is benzyloxy, or phenethyloxy;
each of the above is unsubstituted or substituted with 1, 2, or 3, groups that are independently fluoro, chloro, bromo, CF3, or (C1-C4)alkyl.
-
49. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound or salt according to claim 27.
-
53. A compound according to claim 27 or claim 38, which is
1-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H)-one; -
3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-1-(4-fluorobenzyl)pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1(3-fluorobenzyl)pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;
4-bromo-2-(2,6-dichlorophenyl)-5-[(2,4-difluorobenzyl)oxy]pyridazin-3(2H)-one;
3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2 (1H) -one;
3-bromo-1-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;
1-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-fluorobenzyl)pyridin-2(1H)-one;
3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;
3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-1-(4-methylbenzyl)pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-1-(4-chlorobenzyl)pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-methoxybenzyl)pyridin-2(1H)-one;
4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoic acid;
4-(benzyloxy)-3-bromo-1-(2-fluorobenzyl)pyridin-2(1H)-one;
3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-1-[4-(methylthio)benzyllpyridin-2(1H)-one;
1-benzyl-4-(benzyloxy)-3-chloropyridin-2(1H)-one;
4-([4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}-N′
-hydroxybenzenecarboximidamide;
methyl 4-([4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate;
3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;
3-bromo-1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;
4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;
4-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-1-(4-bromobenzyl)pyridin-2(1H)-one;
4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;
1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one;
4-bromo-2-(2,6-dichlorophenyl)-5-{[2-(hydroxymethyl)benzyl]oxy}pyridazin-3(2H)-one;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;
3-bromo-1-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;
3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one;
or a pharmaceutically acceptable salt thereof.
-
-
28. A compound or salt according to claim 27 wherein
-
38. A compound of the formula
- View Dependent Claims (39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50)
-
39. A compound or salt according to claim 38 wherein
R1 is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy, phenylalkyl, CN, alkanoyl, phenyl, alkoxy, alkoxyalkyl, haloalkyl, or phenylalkanoyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, (C1-C4)alkyl, (C1-C4)alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO2H; wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy.
-
40. A compound or salt according to claim 38 wherein
R2 is phenylalkoxy, OH, phenyloxy, phenylthioalkoxy, alkoxy, — - OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, NR6R7, alkyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, phenyl(C1-C6 alkyl), triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO2H, whereinn is 0, 1, 2, 3, 4, 5 or 6;
each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, or NR6R7alkyl, wherein R6 and R7 at each occurrence are independently H, alkyl, alkoxy, alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy.
- OC(O)NH(CH2)nphenyl, —
-
41. A compound or salt according to claim 38 wherein
R4 is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy. -
42. A compound or salt according to claim 38 wherein
R5 is phenylalkyl, (C1-C6)alkyl, phenyl, naphthyl, alkoxy, piperidinyl, pyrolidinyl, imidazolidinyl, piperazinyl, tetrahydropyranyl, piperidinyl(C1-C6)alkyl, pyrolidinyl(C1-C6)alkyl, imidazolidinyl(C1-C6)alkyl, piperazinyl(C1-C6)alkyl, tetrahydropyranyl(C1-C6)alkyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyridyl(C1-C6)alkyl, pyrimidyl(C1-C6)alkyl, pyridazyl(C1-C6)alkyl, or pyrazinyl(C1-C6)alkyl wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl, OH, CO2H, CN, amidinooxime, NR8R9, NR6R7alkyl, — - C(O)NR6R7, amidino, haloalkyl, or haloalkoxy;
wherein R8 and Rg are independently hydrogen, alkyl, alkanoyl, phenylalkyl and phenylalkanoyl;
provided that when R2 is OH, R4 is methyl and R5 is phenyl, R1 is not acetyl.
- C(O)NR6R7, amidino, haloalkyl, or haloalkoxy;
-
43. A compound or salt according to claim 38 wherein
R1 is halogen, alkyl, phenyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy, phenylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, or phenylalkanoyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (C1-C4)alkyl, (C1-C4)alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO2H; -
wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy, R2 is phenylalkoxy, OH, phenyloxy, phenylthio(C1-C4)alkoxy, alkoxy, phenethyl, —
OC(O)NH(CH2)nphenyl, —
OC(O)N(alkyl)(CH2)nphenyl, alkyl, alkoxyalkoxy, NR6R7, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO2H,wherein n is 0, 1, 2, or 3;
each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, haloalkyl, haloalkoxy, alkyl, thiophenyl, or pyridyl;
R6 and R7 are independently at each occurrence H, alkyl, alkoxy, alkanoyl, benzyl, arylalkoxy, or arylalkanoyl, wherein the aryl portion of each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, or OCF3;
R4 is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
R5 is benzyl, phenethyl, (C1-C6)alkyl, phenyl, naphthyl, alkoxy, piperidinyl, pyrolidinyl, imidazolidinyl, piperazinyl, piperidinyl(C1-C6)alkyl, pyrolidinyl(C1-C6)alkyl, imidazolidinyl(C1-C6)alkyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyridyl(C1-C6)alkyl, pyrimidyl(C1-C6)alkyl, pyridazyl(C1-C6)alkyl, or pyrazinyl(C1-C6)alkyl wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl, OH, CO2H, CN, amidinooxime, NR8R9, NR6R7alkyl, —
C(O)NR6R7, amidino, haloalkyl, or haloalkoxy;
wherein R8 and R9 are independently hydrogen, alkyl, alkanoyl, phenylalkyl and phenylalkanoyl;
provided that when R2 is OH, R4 is methyl and R5 is phenyl, R1 is not acetyl.
-
-
44. A compound or salt according to claim 43 wherein
R1 is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy, phenyl, benzyl, phenethyl, phenpropyl, phenbutyl, CN, (C2-C6)alkanoyl, haloalkyl, or phenylCO— - , phenylCH2CO—
, phenylCH2CH2CO—
,wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (C1-C4)alkyl, (C1-C4)alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO2H;
wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy, R2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenylthio(C1-C4)alkoxy, NR6R7, (C1-C6)alkyl, phenethyl, —
OC(O)N(CH3)CH2phenyl, alkoxyalkoxy, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, piperidinyl, hexahydropyrimidinyl, benzimidazolyl, or thiophenyl, whereineach of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, CF3, OCF3, (C1-C4)alkyl, thiophenyl, or pyridyl;
R6 and R7 are independently at each occurrence H, alkyl, alkoxy, alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein the phenyl portion of each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, or OCF3;
R4 is H, alkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl, hydroxyalkyl, halo(C1-C4)alkyl, NR6R7alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3 or OCF3; and
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (C1-C6)alkyl, phenyl, piperidinyl, pyrolidinyl, imidazolidinyl, piperazinyl, piperidinyl(C1-C6)alkyl, pyrolidinyl(C1-C5)alkyl, imidazolidinyl(C1-C6)alkyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyridyl(C1-C6) alkyl, pyrimidyl(C1-C6)alkyl, pyridazyl(C1-C6)alkyl, or pyrazinyl(C1-C6)alkyl wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, —
CO2CH3, —
CO2CH2CH3, OH, CO2H, CN, —
CO2(C3-C5 alkyl), phenylalkoxycarbonyl, amidinooxime, amidino, CF3, CF2CF3, ClCH2, or OCF3;
provided that when R2 is OH, R4 is methyl and R5 is phenyl, R1 is not acetyl.
- , phenylCH2CO—
-
45. A compound or salt according to claim 44 wherein
R1 is halogen, alkyl, carboxaldehyde, hydroxy(C1-C4)alkyl, phenylalkoxy, benzyl, phenethyl, — - C(O)CH3, phenylCO—
, or phenylCH2CO—
,wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (C1-C4)alkyl, (C1-C4)alkoxy, nitro, CN, CF3, or OCF3;
wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, NR6R7, —
S-benzyl, or (C1-C6)alkyl, whereineach of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, CF3, OCF3, alkyl, thiophenyl, or pyridyl;
R6 and R7 are independently at each occurrence H, alkyl, alkanoyl, benzyl, benzyloxy, or phenylalkanoyl, wherein the phenyl portion of each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, or OCF3;
R4 is H, alkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, or hydroxyalkyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3 or OCF3; and
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (C1-C6)alkyl, phenyl, pyridyl, or pyridyl(C1-C4)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, halogen, (C1-C4)alkoxy, phenyl(C1-C4)alkoxy, thio(C1-C4)alkoxy, alkoxycarbonyl, OH, CO2H, CN, amidinooxime, amidino, CF3, or OCF3.
- C(O)CH3, phenylCO—
-
46. A compound or salt according to claim 45 wherein
R1 is halogen, alkyl, carboxaldehyde, or hydroxyalkyl; -
R2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenylthioalkoxy, or (C1-C6)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, CF3, OCF3, alkyl, thiophenyl, or pyridyl;
R4 is H, (C1-C4)alkyl, benzyloxy, phenethyloxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, (C1-C4)alkoxy, (C1-C4)alkyl, nitro, CF3 or OCF3 and R5 is benzyl, phenethyl, (C1-C6)alkyl, phenyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (C1-C4)alkyl, halogen, OH, CO2H, CN, (C1-C4)alkoxy, benzyloxy, —
CO2CH3, —
CO2CH2CH3, —
CO2(C3-C5 alkyl), amidino, thio(C1-C4)alkoxy, amidinooxime, CF3, or OCF3.
-
-
47. A compound or salt according to claim 46 wherein
R1 is bromo; - and
R5 is benzyl, phenethyl, phenpropyl, phenyl, or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, OH, halogen, alkoxy, and amidinooxime.
- and
-
48. A compound or salt according to claim 47 wherein
R2 is benzyloxy, or phenethyloxy, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, CF3, OCF3, or (C1-C4)alkyl. -
50. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound or salt according to claim 38.
-
39. A compound or salt according to claim 38 wherein
-
52-1. A method of treating a p38 kinase or TNF-alpha mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable carrier, adjuvant, solvent or excipient.
Specification
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Current AssigneePharmacia LLC (Pfizer Inc.)
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Original AssigneePharmacia Corporation Corporate Patent Department
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InventorsScott, Ian L., Liu, Shuang, Walker, John, Sambandam, Aruna, Xing, Li, Owen, Thomas, Promo, Michele A., Devraj, Rajesh, Rucker, Paul V., Jerome, Kevin D., Hickory, Brian S., Durley, Richard C., Devadas, Balekudru, Alvira, Edgardo, Madsen, Heather M., Shieh, Huey S., Boehm, Terri L., Marruto, Laura D., Selness, Shaun R., Hitchcock, Jeff, McGee, Kevin F., Naing, Win, Blevis-Bal, Radhika M.
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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 Current514/241
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CPC Class CodesA61P 1/02 Stomatological preparations...A61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 15/08 for gonadal disorders or fo...A61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 19/06 Antigout agents, e.g. antih...A61P 19/08 for bone diseases, e.g. rac...A61P 19/10 for osteoporosisA61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 25/02 for peripheral neuropathiesA61P 25/04 Centrally acting analgesics...A61P 25/14 for treating abnormal movem...A61P 25/16 Anti-Parkinson drugsView AllA61P 25/28 : for treating neurodegenerat...A61P 27/02 : Ophthalmic agentsA61P 27/06 : Antiglaucoma agents or mioticsA61P 29/00 : Non-central analgesic, anti...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/04 : Antibacterial agentsA61P 31/12 : AntiviralsA61P 31/16 : for influenza or rhinovirusesA61P 31/18 : for HIVA61P 31/22 : for herpes virusesA61P 33/02 : Antiprotozoals, e.g. for le...A61P 33/06 : AntimalarialsA61P 35/00 : Antineoplastic agentsA61P 35/02 : specific for leukemiaA61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 7/02 : Antithrombotic agents; Anti...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...A61P 9/12 : AntihypertensivesC07D 213/64 : attached in position 2 or 6C07D 213/69 : Two or more oxygen atomsC07D 213/70 : Sulfur atomsC07D 213/74 : Amino or imino radicals sub...C07D 213/75 : Amino or imino radicals, ac...C07D 213/79 : Acids; EstersC07D 213/84 : NitrilesC07D 213/85 : in position 3C07D 215/22 : attached in position 2 or 4C07D 401/04 : directly linked by a ring-m...C07D 401/06 : linked by a carbon chain co...C07D 401/10 : linked by a carbon chain co...C07D 401/12 : linked by a chain containin...C07D 401/14 : containing three or more he...C07D 405/04 : directly linked by a ring-m...C07D 405/06 : linked by a carbon chain co...C07D 405/12 : linked by a chain containin...C07D 405/14 : containing three or more he...C07D 409/06 : linked by a carbon chain co...C07D 409/14 : containing three or more he...C07D 413/10 : linked by a carbon chain co...
