OA13332A - Pyrimidin-4-one derivatives and their use as P38 kinase modulators. - Google Patents

Pyrimidin-4-one derivatives and their use as P38 kinase modulators. Download PDF

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OA13332A
OA13332A OA1200600180A OA1200600180A OA13332A OA 13332 A OA13332 A OA 13332A OA 1200600180 A OA1200600180 A OA 1200600180A OA 1200600180 A OA1200600180 A OA 1200600180A OA 13332 A OA13332 A OA 13332A
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alkyl
oxy
methyl
difluorobenzyl
bromo
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OA1200600180A
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Balenkundru Devadas
Richard Durley
Brian Hickory
Heather Madsen
Katherine Palmquist
Shaun Selness
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Pharmacia Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Claims (17)

  1. 013332 346 What is claimed is:
    or a pharmaceutically acceptable sait thereof, wherein L and M are independently selected from -O-, -CH2-, -S-, -N(R)-N(R)-, C(=O)-, - SO2-;
    Xi, X2, Xa, Xb, Xc, Xd, and Xe at are independently selected from -C(O)NReR7, -(C1-C4 alkyl)-C(O)NRiR7, -NReRï, hydroxy(Ci-C4)alkyl, C1-C4 dihydroxyalkyl, H,halogen, haloalkyl, alkyl, haloalkoxy, heteroaiyl, heterocycloalkyl, C3-C7 cycloalkyl,R«R7N-(Ci-C6 alkyl)-, -CO2-(CrC6)alkyl, -N(R)C(O)NReR7, -N(R)C(O)-(CI-Ce)alkoxy,CO2R-(Ci-C6 alkyl)-, or -SO2NReR7, wherein the heteroaryl and heterocycloalkyl groupsare optionally substituted with -NRéR7, -C(O)NR<R7, R«R7N-(Ci-C6 alkyl)-, Ci-Ce alkyl,Ci-Cô alkoxy, or halogen; or R5 is heteroaryl or heteroarylalkyl, wherein the heteroaryl and heteroaryl groupsare optionally substituted with 1,2, 3, or 4 groups that are independently -C(O)NRîR7, -(C1-C4 alkyl)-C(O)NReR7, -NReR?, hydroxy(Ci-C4)alkyl, C1-C4 dihydroxyalkyl, H, OH,halogen, haloalkyl, alkyl, haloalkoxy, ReR7N-(Ci-C6 alkyl)-, -CO2-(Ci-Ce)alkyl,-N(R)C(O)NReR7, or -N(R)C(O)-(Ci-C6)alkoxy; wherein Re and R7 are independently at each occurrence H, Ci-Cô alkyl, Ci-Ce alkoxy, Ci-C6 alkoxy Ci-C6 alkyl, Cj-Cé alkoxycarbonyl, OH, Ci-Ce hydroxyalkyl, C1-C4 013332 347 dihydroxyalkyl, Ci-Cé thiohydroxyalkyl, -(Ci-C4)alkyl-CO2-alkyl, pyridyl C]-Cc alkyl,Ci-Cê alkanoyl, benzyl, phenyl C1-C6 alkoxy, or phenyl Ci-Cé alkanoyl, wherein each ofthe above is unsubstituted or substituted with 1, 2, or 3 groups that are independently,halogen, C3-Ce cycloalkyl, Ci-Cé alkoxy, piperidinyl Cj-Cg alkyl, morpholinyl Ci-Cgalkyl, piperazinyl Ci-C6 alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-C1-C4alkanoyl, C1-C4 alkyl, CF3, or OCF3; or Ré, R7, and the nitrogen to which they are attached form a morpholinyl,thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionallysubstituted with 1 or 2 groups that are independently C1-C4 alkyl, CÎ-C4 alkoxy, hydroxy,hydroxy C1-C4 alkyl, C1-C4 dihydroxyalkyl, or halogen; R at each occurrence is independently H or Ci-Cé alkyl; and Y, Yi, Y2, Y3, and Y4 are independently selected from H, halogen, alkyl,carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl, alkoxy,alkoxyalkyl, haloalkyl, and carboxyl.
  2. 2. The compound according to claim 1 of the formula
    or a pharmaceutically acceptable sait thereof.
  3. 3. The compound according to claim 8, wherein R5 is a heteroaryl or heteroarylalkyl group, where each heteroaryl is pyrazolyl, imidazolyl, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl,dihydroindolyl, dihydroisoindolyl, indolon-2-yl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, dihydroisoquinolinyl, or indolyl, each of which is optionallysubstituted with 1, 2, 3, or 4 groups that are independently -C(O)NRéR7, -(C1-C4 alkyl)-C(O)NRéR7, -NRéR?, hydroxy(Ci-C4)alkyl, C1-C4 dihydroxyalkyl, hydrogen, hydroxy, 013332 348 halogen, haloalkyl, alkyl, haloalkoxy, ReR7N-(Ci-Cg alkyl)-, -CO2-(Ci-C6)alkyl,-N(R)C(O)NReR7, or -N(R)C(O)-(Ci-Ce)alkoxy; wherein Re and R7 are independently at each occurrence H, Ci-Ce alkyl, Ci-Cé alkoxy, Ci-Câ alkoxy Ci-Cô alkyl, Ci-Ce alkoxycarbonyl, OH, Ci-Ce hydroxyalkyl, Ci-Câdihydroxyalkyl, Cj-Cî thiohydroxyalkyl, -(Ci-C4)alkyl-CO2-alkyl, pyridyl Cj-Cé alkyl,Ci-Cê alkanoyl, benzyl, phenyl Ci-Ce alkoxy, or phenyl Ci-Ce alkanoyl, wherein each ofthe above is unsubstituted or substituted with 1, 2, or 3 groùps that are independently,halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, piperidinyl Ci-Ce alkyl, morpholinyl Ci-Cealkyl, piperazinyl Ci-Ce alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-C1-C4alkanoyl, C1-C4 alkyl, CF3, or OCF.
  4. 4. The compound according to claim 3, wherein Y2, Y4, and Y are independently halogen; and Yi and Y3 are both hydrogen.
  5. 5. The compound according to claim 4, wherein Xi and X2 are independently H, methyl, -NR^R?, R6R7N-(Ci-C6 alkyl)-, -C(0)NRîR7, -(C1-C4 alkyl)-C(O)NReR7, Ci-C6 hydroxyalkyl, C1-C5 dihydroxyalkyl, or -(C1-C4 alkyl)-morpholinyl.
  6. 6. The compound according to claim 5, wherein R5 is pyridyl Ci-Cé alkyl, pyrimidinyl Ci-Câ alkyl, or pyrazinyl Ci-Câ alkyl, eachof which is optionally substituted with 1, 2, or 3 groups that are independentlyhydroxy(Ci-C4)alkyl, C1-C4 dihydroxyalkyl, OH, halogen, CF3, (Ci-C4)alkyl, OCF3,-NReR7, -(C1-C4 alkyI)-C(O)NR6R7, R^N-CCi-G alkyl)-, or -C(O)NRîR7.
  7. 7. A compound according to claim 2, wherein Xa Xe Xb ψ Xd Rs is or Xb' Xa Xd Xe Xc 013332 349
  8. 8. The compound according to claim 7, wherein Xa is hydrogen; two of Xb, Xc> and Xd are hydrogen and the other is -C(O)NRîR7, -(Ci-Cô alkyl)-C(O)NRôR7, -NRôRî, R6R7N-(Ci-C6 alkyl)- or -CO2-(Ci-Cô)alkyl; wherein Rô and R7 are independently at each occurrence H, Ci-Cô alkyl, Ci-Cô alkoxy, Ci-Ce alkoxy Ci-Cs alkyl, Ci-Cô alkoxycarbonyl, OH, Ci-Ci hydroxyalkyl, Ci-Cedihydroxyalkyl, -(Cj-C4)alkyl-CO2-alkyl, pyridyl Ci-C<s alkyl, Ci-C6 alkanoyl, benzyl,phenyl Ci-Cg alkoxy, or phenyl Ci-Ce alkanoyl, wherein each of the above isunsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, C3-C6cycloalkyl, Cj-Ce alkoxy, piperidinyl Ci-Cô alkyl, morpholinyl Ci-Cô alkyl, piperazinylCi-C6 alkyl, OH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-C1-C4 alkanoyl, C1-C4 alkyl, CF3,or OCF3; or Rô, R7, and the nitrogen to which they are attached form a morpholinyl,piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2groups that are independently C1-C4 alkyl, C1-C4 alkoxy, hydroxy, hydroxy C1-C4 alkyl,C1-C4 dihydroxyalkyl, or halogen; and Xe is hydrogen, methyl, C1-C2 alkoxy, or halogen.
  9. 9. The compound according to claim 8, wherein Xb is -C(O)NRôR7, -(Ci-C6 alkyl)-C(O)NRôR7, -NRôR7, or RôR-zN-ÎCî-Cs alkyl)-wherein Rî is hydrogen or C1-C4 alkyl; R7 is OH, Ci-Ci alkyl or C1-C5 alkanoyl, wherein the alkyl and alkanoyl groupssubstituted with 1, 2, or 3 groups that are independently NH2, NH(Ci-Cô alkyl), N(Ci-Cealkyl)(Ci-Ce alkyl), C3-C6 cycloalkyl, OH, or C1-C4 alkoxy.
  10. 10. The compound according to claim 7, wherein Xa is halogen or methyl; Xb is H, -NRôR7, RôR7N-(Ci-C6 alkyl)-, -C(O)NRôR7, or -CO2-(C,-C6)alkyl, 013332 350 Xo is -NR«R7, RîR7N-(Ci-C6 alkyl)-, -C(O)NR6R7, halogen, -CO2-(Ci-C«)alkyl,NH2, NH(C,-C6 alkyl), N(CrC6 alkyl)(Ci-C6 alkyl), -SO2NH2, -SO2NH(Ci-C6 alkyl), -SO2N(Ci-Ce alkyl)(Ci-Cô alkyl), or piperazinyl, wherein the piperazinyl group isoptionally substituted with 1 or 2 groups that are independently C1-C4 alkyl, C1-C4alkoxy, hydroxy, hydroxy C4-C4 alkyl, C1-C4 dihydroxyalkyl, or halogen; Xd is hydrogen; and Xe is H, methyl, NH2, NH(Ci-C6 alkyl) or N(Ci-C6 alkyl)(Ci-C6 alkyl).
  11. 11. The compound according to claim 7, wherein Xi, X2, Xa, Xb, Xc, Xa, and Xe are independently selected from H, OH, halogen,CF3, alkyl, OCF3, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl,piperidinyl, piperazinyl, or C3-C7 cycloalkyl, wherein each of the above is optionallysubstituted with -NRôR7, -C(O)NRîR7, -(C1-C4 alkyl)-C(O)NRôR7, R«R7N-(Ci-C6 alkyl)-,Ci-Cg alkyl, Ci-Ce alkoxy, or halogen.
  12. 12. The compound according to claim 7 selected from the group consisting of: 3-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-N,4-dimethylbenzamide; Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methylbenzoate; Methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methylbenzoate; 3-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methylbenzamide; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-l(6H)-yl]-4-methylbenzamide; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxyJ-6-oxopyrimidin-l(6H)-yl]-4- methylbenzamide; . (±) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methyl-N-{ 1 -[(methylamino)carbonyl]methyl}benzamide; 013332 351 (-) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methyl-N- {1 -[(methylamino)carbonyl]raethyl} benzamide; (+) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methyl-N- {1 -[(methylamino)carbonyl]methyl} benzamide; (-) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrîmidin-l(6H)-yl]-4-methylbenzamide; (+)3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4- methylbenzamide; (-) 3-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-N,4-dimethylbenzamide; (+) 3-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-rriethyl-6-oxopyrimidin-l(6H)-yl]-N,4-dimethylbenzamide; (-) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methyl-N-{ 1 -[aminocarbonyl]methyl} benzamide; (+) 3 -[5 -bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1 (6H)-yl]-4-methyl-N-{ 1 -[aminocarbonyl]methyl}benzamide; (±) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-N-[(2S)-2,3-dihydroxypropyl]-4-methylbenzamide; (-)3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]- N-[(2iS)-2,3-dihydiOxypropyl]-4-methylbenzamide; 013332 352 (+) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl] N-[(25)-2,3 -dihydroxypropyl]-4-methylbenzamide; (+) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]N-[(2A)-2,3-dihydroxypropyl]-4-methylbenzamide; (-) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l (6H)-ylj-N-[(2A)-2,3-dihydroxypropyl]-4-methylbenzamide; (+) 3-[5-bromo-4-[(2,4-dÎfluorobenzyl)oxy]-2-meîhyl-6-oxopyrimidin-l(6H)-yl]N-[(2/?)-2,3-dihydroxypropyl]-4-methylbenzamide; (+) N-[(l S)-l -(aminocarbonyl)ethyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methylbenzamide; (-) N-[(lS)-l-(aminocarbonyl)ethyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1 (6H)-yl]-4-methylbenzamide; (+) N-[(l S)-l -(aminocarbonyl)ethyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1 (6H)-yl]-4-methylbenzamide; (±) 3-(5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]N-[(l R)-2-hydroxy-1 -methylethyl]-4-methylbenzamide; (±) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidÎn-l(6H)-yl]N-[(l S)-2-hydroxy-l -methylethyl]-4-methylbenzamide; (±)3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyI-6-oxopyrimidin-l(6H)-yl]- N-[(2S)-2-hydroxypropyl]-4-methylbenzamide; 013332 353 (-)3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyriniidin'l(6H)-yl]- N-[(2S)-2-hydroxypropyl]'4-methylbenzamide; (+)3-[5-bromo-4-[(2)4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]- N-[(2S)-2-hydroxypropyl]-4-methylbenzamide; (±)3-[5-bromo-4-[(234-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]- N-[(2R)-2-hydroxypropyl]-4-methylbenzamide; (-)3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]- N-[(2R)-2-hydroxypropyl]-4-methylbenzainide; (+)3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]- N-[(2R)-2-hydroxypropyl]-4-methylbenzamide; (±) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-N-(2-hydroxyeîhyl)-4-methylbenzamide; (-) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyI-6-oxopyrimidin-l(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide; (+) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyriniidin-l (6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide; (±) N-[(l S)-l -(aminocarbonyl)propyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methylbenzamide; (-) N-[(lS)-l-(aminocarbonyl)propyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methylbenzamide; 013332 354 (+) N-[(l S)-l -(aminocarbonyl)propyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2- methyl-6-oxopyrimidin-1 (6H)-yl]-4-methylbenzamide; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl}-N-[l-(amin ocarbony l)methy 1] -4-methylbenzamide ; 3-[4-[(2,4"difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-4-methylbenzoate; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-4-methyl-N-{1 -[(methylamino)carbonyl]methyl} benzamide; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(2S)-2,3- dihydroxypropyl]-4-methylbenzamide; N-[(lS)-l-(aminocarbonyl)ethyl]-3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1 (6H)-yl]-4-methylbenzamide; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(lS)-2-hydroxy-1 -methylethyI]-4-methyibenzamide; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-(2- hydroxyethyl)-4-methylbenzamide; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(lR)-2-hydroxy-1 -methylethyl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[l- (aminocarbonyl)methyI]-N,4-dimethylbenzamide; 013332 355 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(2R)-2,3- dihydroxypropyl]-4-methylbenzamide; N-[(lR)-l-(aminocarbonyl)-2-hydroxyethyl]-3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1 (6H)-yl] -4-methylbenzamide; N-[(lR)-l-(aminocarbonyl)ethyI]-3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1 (6H)-yl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l (6H)-yl]-N-[(l S)-2-hydroxy-1-methylethyl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(lR)-2-hydroxy-1 -methylethyl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N,4- dimethylbenzamide; N-[ 1 -(ammocarbonyl)methyl]-3 -[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1 (6H)-yl]-4-methylbenzamide; N-[(lR)-l-(aminocarbonyl)ethyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6- oxopyrimidin-l(6H)-yl]-4-methylbenzamide; N-[(lS)-l-(aminocarbonyl)propyl]-3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1 (6H)-yl]-4-methylbenzamide; 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(2S)-2- hydroxypropyl]-4-methylbenzamide; 013332 356 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(2R)-2- hydroxypropyl]-4-methylbenzamide; 5-chloro-6-[(2,4-difluorobenzyl)oxy]-3-(5-{[(3S)-3-hydroxypyrrolidin-l-yl]carbonyl}-2-methylphenyl)pyrimidin-4(3H)-one; ' 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-(2- methoxyethyl)-4-methylbenzamide; 5-chloro-6-[(2,4-difIuorobenzyl)oxy]-3-(5 - {[(3 R)-3-hydroxypyrrolidin-1 -yljearbonyl} -2-methylphenyl)pyrimidin-4(3H)-one; 3-[4-[(2,4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-l(6H)-yl]-N-[(lR)-2-hydroxy-1 -meihylethyl]-4-methylbenzamide; methyl 3-[4-[(2,4-difluorobenzyl)oxy]-5-iodo-6-oxopyrimidin-l(6H)-yl]-4-methylbenzoate, methyl 3-[4-[(2î4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-l(6H)-yl]-4-methylbenzoate; 3-[4-[(2,4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-l(6H)-yl]-N-(2- hydroxyethyl)-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-(methylamino)-6-oxopyrimidin-l(6H) yl]-N,4-dimethylbenzamide; methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)o?Q']-2-(methylamino)-6-oxopyrimÎdin-l(6H)yl]-4-methylbenzoate; 013332 357 N-[l-(aminocarbonyl)methyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2- (methylamino)-6-oxopyrÎmidin-l(6H)-yl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-dï£luorobenzyl)oxy]-2-(methylainÎno)-6-oxopyrimidin-l(6H)- yl]-N-[(2S)-2,3-dihydroxypropyl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-4-methyl-N-{1 - [(methylamino)carbonyl]methyl} benzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(2S)-2,3- dihydroxypropyl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(2R)-2,3- dihydroxypropyl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-(2- hydroxyethyl)-4-methylbenzamide; N-[(lS)-l-(aminocarbonyI)ethyl]-3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimid in-1 (6H)-yl] -4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(2S)-2- hydroxypropyl]-4-methylbenzamide; 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-l(6H)-yl]-N-[(2R)-2- hydroxypropyl]-4-methylbenzamide; (±) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]- N-(2-hydroxyethyl)-4-methylbenzamide; 013332 358 (-) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]- N-(2-hydroxyethyl)-4-methylbenzamide; (+) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopynmidin-l(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide; (±) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4-methyl-N- {1 -[aminocarbonyl]methyl} benzamide; (-)3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4methyl-N- {1 -[aminocarbonyljmethyl} benzamide; (±) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-ylj-4-methyl-N- {1 -[(methylamino)carbonyl]methyl} benzamide; (±) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-ylj-4-methyl-N- {1 -[(methylamino)carbonyljmethyl} benzamide; ± 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-N[(2S)-2-hydroxypropyl]-4-methylbenzamide; ± 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-N[(2R)-2-hydroxypropyl]-4-methylbenzamide; 3- benzyl-6-(benzyloxy)-5-bromopyrimidin-4(3H)-one; 3 -benzyl-6-(benzyloxy)-pyrimidin-4(3H)-one; 4- {[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]methyl}-N-methylbenzamide; and methyl 4-{[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l (6H)-y 1 ]methyl} benzo ate; 013332 359 or their isomer and pharmaceutically acceptable sait thereof.
  13. 13. A pharmaceutical composition comprising a compound of claiml2, or apharmaceutically acceptable sait or tautomer thereof.
  14. 14. Use of a compound of Claim 12, or a pharmaceutically acceptable sait or tautomerthereof in the manufacture of a médicament for treating arthritis in a subject.
  15. 15. Use of a compound of Claim 12, or a pharmaceutically acceptable sait or tautomerthereof, in the manufacture of a médicament for treating rheumatoid arthritis in a subject.
  16. 16. Use of a compound of Claim 12, or a pharmaceutically acceptable sait or tautomerthereof in the manufacture of a médicament for treating asthma in a subject.
  17. 17. Use of a compound of Claim 12, or a pharmaceutically acceptable sait or tautomerthereof in the manufacture of a médicament for treating chronic obstructive pulmonarydisease (COPD) in a subject..
OA1200600180A 2006-06-02 2006-06-02 Pyrimidin-4-one derivatives and their use as P38 kinase modulators. OA13332A (en)

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