Substituted pyrimidinones

A compound of the formula

• or a pharmaceutically acceptable salt thereof, wherein
• L and M are independently selected from —O—, —CH2—, —S—, —NR—, —N(R)—N(R)—, C(═O)—, —SO2—;
• R5 is
• wherein
• X1, X2, Xa, Xb, Xc, Xd, and Xe at are independently selected from —C(O)NR6R7, —(C1-C4 alkyl)-C(O)NR6R7, —NR6R7, hydroxy(C1-C4)alkyl, C1-C4 dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, C3-C7 cycloalkyl, R6R7N—(C1-C6 alkyl)-, —CO2—(C1-C6)alkyl, —N(R)C(O)NR6R7, —N(R)C(O)—(C1-C6)alkoxy, CO2R—(C1-C6 alkyl)-, or —SO2NR6R7;
• wherein the heteroaryl and heterocycloalkyl groups are optionally substituted with —NR6R7, —C(O)NR6R7, R6R7N—(C1-C6 alkyl)-, C1-C6 alkyl, C1-C6 alkoxy, or halogen;
• or
• R5 is heteroaryl or heteroarylalkyl, wherein the heteroaryl and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 groups that are independently —C(O)NR6R7, —(C1-C4 alkyl)-C(O)NR6R7, —NR6R7, hydroxy(C1-C4)alkyl, C1-C4 dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, R6R7N—(C1-C6 alkyl)-, —CO2—(C1-C6)alkyl, —N(R)C(O)NR6R7, or —N(R)C(O)—(C1-C6)alkoxy;
• wherein
• R6 and R7 are independently at each occurrence H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, OH, C1-C6 hydroxyalkyl, C1-C4 dihydroxyalkyl, C1-C6 thiohydroxyalkyl, —(C1-C4)alkyl-CO2-alkyl, pyridyl C1-C6 alkyl, C1-C6 alkanoyl, benzyl, phenyl C1-C6 alkoxy, or phenyl C1-C6 alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, piperidinyl C1-C6 alkyl, morpholinyl C1-C6 alkyl, piperazinyl C1-C6 alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), —O—C1-C4 alkanoyl, C1-C4 alkyl, CF3, or OCF3;
• or
• R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, hydroxy, hydroxy C1-C4 alkyl, C1-C4 dihydroxyalkyl, or halogen;
• R at each occurrence is independently H or C1-C6 alkyl;
• and
• Y, Y1, Y2, Y3, and Y4 are independently selected from H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, and carboxyl.

A method of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a compound of the formula:

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is H, halogen, NO2, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl, arylalkynyl, —CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, carboxyl, or arylalkanoyl,
• wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is 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 CO2R;
• wherein the alkyl portion of the alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, or C3-C7 cycloalkyl;
• R2 is H, OH, halogen, —OSO2—(C1-C6) alkyl, —OSO2-aryl, arylalkoxy, aryloxy, arylthio, arylthioalkoxy, arylalkynyl, alkoxy, aryloxy(C1-C6)alkyl, alkyl, alkynyl, —OC(O)NH(CH2)naryl, —OC(O)N(alkyl)(CH2)naryl, alkoxyalkoxy, dialkylamino, alkyl, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkenyl, heterocycloalkyl, heterocycloalkylalkyl, alkoxyalkoxy, NR8R9, dialkylamino, or CO2R, wherein
• n is 0, 1, 2, 3, 4, 5 or 6;
• each of which groups is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, —(C1-C6)alkyl-N(R)—CO2R30, haloalkyl, heteroaryl, heteroarylalkyl, —NR6R7, R6R7N—(C1-C6 alkyl)-, —C(O)NR6R7, —(C1-C4 alkyl)-C(O)NR6R7, —(C1-C4 alkyl)-NRC(O)NR16R17, haloalkoxy, alkyl, CN, alkoxy, alkoxycarbonyl, phenyl, —SO2-phenyl wherein the phenyl and —SO2-phenyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen or NO2, or —OC(O)NR6R7, wherein
• R16 and R17 are independently H or C1-C6 alkyl;
• or
• R16, R17 and the nitrogen to which they are attached form a morpholinyl ring;
• R6 and R7 are independently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, alkoxycarbonyl, —SO2-alkyl, OH, alkoxy, alkoxyalkyl, arylalkoxycarbonyl, —(C1-C4)alkyl-CO2-alkyl, heteroarylalkyl, or arylalkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 2 groups that are independently, halogen, OH, SH, heterocycloalkyl, heterocycloalkylalkyl, C3-C7 cycloalkyl, alkoxy, NH2, NH(alkyl), N(alkyl)(alkyl), —O-alkanoyl, alkyl, haloalkyl, carboxaldehyde, or haloalkoxy;
• or
• R6, R7, and the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently C1-C4 alkyl, alkoxycarbonyl, C1-C4 alkoxy, hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen;
• R at each occurrence is independently hydrogen or C1-C6 alkyl optionally substituted with optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C3-C6 cycloalkyl;
• R30 is C1-C6 alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C3-C6 cycloalkyl;
• each R8 is independently hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl, wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl;
• each R9 is hydrogen, alkyl, alkanoyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkanoyl, —SO2-phenyl, and aryl wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl;
• R4 is hydrogen or R4 is alkyl unsubstituted or substituted with one or two groups that are independently CO2R, —CO2—(C1-C6)alkyl, —C(O)NR6R7, —(C1-C4 alkyl)-C(O)NR6R7, —N(R30)C(O)NR16R17, —N(R30)C(O)—(C1-C6)alkoxy, or —NR6R7, arylalkoxy, arylalkyl, heteroaryl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, R6R7N—(C1-C6 alkyl)-, —NR6R7, alkoxy, carboxaldehyde, CO2R, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl portion of arylalkoxy and arylalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, —CO2—(C1-C6)alkyl, —CONR6R7, —NR6R7, R6R7N—(C1-C6)alkyl-, nitro, haloalkyl, or haloalkoxy;
• and
• R5 is H, aryl, arylalkyl, arylthioalkyl, alkyl optionally substituted with 1, 2, or 3 groups that are independently arylalkoxycarbonyl, —NR8R9, halogen, —C(O)NR8R9, alkoxycarbonyl, C3-C7 cycloalkyl, or alkanoyl, alkoxy, alkoxyalkyl optionally substituted with one trimethylsilyl group, amino, alkoxycarbonyl, hydroxyalkyl, dihydroxyalkyl, alkynyl, —SO2-alkyl, alkoxy optionally substituted with one trimethylsilyl group, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -alkyl-S-aryl, -alkyl-SO2-aryl, heteroarylalkyl, heterocycloalkyl, heteroaryl, or alkenyl optionally substituted with alkoxycarbonyl, wherein
• each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO2R, CN, OH, hydroxyalkyl, dihydroxyalkyl, amidinooxime, —NR6R7, —NR8R9, R6R7N—(C1-C6 alkyl)-, carboxaldehyde, SO2alkyl, —SO2H, —SO2NR6R7, alkanoyl wherein the alkyl portion is optionally substituted with OH, halogen or alkoxy, —C(O)NR6R7, —(C1-C4 alkyl)-C(O)NR6R7, amidino, haloalkyl, —(C1-C4 alkyl)-NR15C(O)NR16R17, —(C1-C4 alkyl)-NR15C(O)R18, —O—CH2—O, —O—CH2CH2—O—, or haloalkoxy;
• wherein
• R15 is H or C1-C6 alkyl;
• R18 is C1-C6 alkyl optionally substituted with —O—(C2-C6 alkanoyl, C1-C6 hydroxyalkyl, C1-C6 dihydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl;
• amino C1-C6 alkyl, mono or dialkylamino C1-C6 alkyl.