Diaryl Substituted Pyridinones

• US 20070088033A1
• Filed: 09/13/2006
• Published: 04/19/2007
• Est. Priority Date: 02/14/2002
• Status: Abandoned Application

• Current Assignee: Aruna Sambandam, Balekudru Devadas, Brian Hickory, Edgardo Alvira, Heather Madsen, Huey Shieh, Ian Scott, Jeff Hitchcock, John Walker, Kevin Jerome, Kevin Mcgee, Laura Marruto, Li Xing, Michele Promo, Paul Rucker, Radhika Blevis-Bal, Rajesh Devraj, Richard Durley, Shaun Selness, Shuang Liu, Terri Boehm, Thomas Owen, Win Naing
• Original Assignee: Aruna Sambandam, Balekudru Devadas, Brian Hickory, Edgardo Alvira, Heather Madsen, Huey Shieh, Ian Scott, Jeff Hitchcock, John Walker, Kevin Jerome, Kevin Mcgee, Laura Marruto, Li Xing, Michele Promo, Paul Rucker, Radhika Blevis-Bal, Rajesh Devraj, Richard Durley, Shaun Selness, Shuang Liu, Terri Boehm, Thomas Owen, Win Naing
• Inventors: Liu, Shuang, Walker, John, Sambandam, Aruna, Xing, Li, Owen, Thomas, Devraj, Rajesh, Devadas, Balekudru, Alvira, Edgardo, Selness, Shaun, Hitchcock, Jeff, Naing, Win, Scott, Ian, Madsen, Heather, Durley, Richard, Marruto, Laura, Jerome, Kevin, Hickory, Brian, McGee, Kevin, Shieh, Huey, Boehm, Terri, Blevis-Bal, Radhika, Rucker, Paul, Promo, Michele
• Application Number:
  US11/531,492
• Publication Number:
  US 20070088033A1
• Time in Patent Office: Days
• US Class Current: 514/241
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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.

Claims

2. A compound or salt of the formula:

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, wherein

n 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.

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.

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-C,)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.

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, wherein

the phenyl, naphthyl, and aryl portions of arylalkoxycarbonyl₁, 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.

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, CF_3, 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-C,)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, wherein

n 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;

or R₄ 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 (C-C_{1 -4})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.

9. A compound or salt according to claim 8 wherein

R₁ is halogen, (Cl-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, (C_{1 -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)alkoxy₁ (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.

10. A compound or salt according to claim 9 wherein

R₁ is bromo, phenyl(C_{1 -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(C_{1 -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.

24. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound or salt according to claim 2.

11. A compound of the formula

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(C_{1 -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.

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, wherein

n is 1, 2, 3, or 4.

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, 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.

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)alky, 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, wherein n 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(CI-C₆)thioalkyl, pyrrolyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (C₁-C₅)alkyl, halogen, (C₁-C₆)alkoxy, benzyloxy, (C₁-C₆)thioalkoxy, alkoxycarbonyl, CO₂H, CN, amidinooxime, amidino, CF₃, or OCF₃.

25. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound or salt according to claim 11.

18. A compound of the formula

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, wherein

n 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, wherein

R₆ 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.

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)_n,phenyl, 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, 4, 5, or 6;

or

R₂, 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.

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, wherein

n 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, 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, 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.

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)_n,phenyl, OC(O)N(alkyl) (CH₂)_nphenyl, or dialkylamino, wherein

n 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.

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.

27. A compound of the formula:

28. A compound or salt according to claim 27 wherein

R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenyl(C₁-C₆)alkoxy, phenyl(C-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.

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, 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, heteroarylalkyl, NR₆R₇alkyl, —

OC(O)NR₆R₇, 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, haloalkyl, or haloalkoxy.

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 R₅ is benzyl or methyl, R, is not hydrogen.

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, 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, heteroarylalkyl, NR₆R₇alkyl, —

OC(O)NR₆R₇, 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, 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, phenyethyl, 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.

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, -QO2 (C₃-C₅ alkyl), benzyloxy, and amidinooxime.

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(1Hl)-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(11H)-one;

4-(benzyloxy)_n-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(11H)-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)benzyl]pyridin-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(21)-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.

38. A compound of the formula

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 )phenyl, 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, 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, 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.

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 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.

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, 21 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, wherein

each 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(C_{1 -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, benzyloxy, thioalkoxy, —

CO₂CH₃, —

CO₂CH₂CH₃, OH, CO₂H, CN, —

CO₂(C₃-C₅ alkyl), phenylalkoxycarbonyl, amidinooxime, amidino, CF₃, CF₂CF₃, C₁CH₂, or OCF₃;

provided that when R₂ is OH, R₄ is methyl and R₅ is phenyl, R₁ is not acetyl.

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, 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;

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.

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, —

C₂(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.

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.

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.