INHIBITION OF P38 KINASE ACTIVITY USING SUBSTITUTED HETEROCYCLIC UREAS

1 .- 42 . (canceled)

43 . A method for the treatment of a disease mediated by p38, comprising administering a compound of formula I

wherein

B is of the formula:

wherein

Y is —O—, —S—, —CH 2 — or —SCH 2 —,

Q is phenyl substituted or unsubstituted by halogen, up to per-halosubstitution,

Q 1 is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halo substitution,

each X is independently —R 6 , —OR 6 and —NHR 7 , wherein

R 6 is hydrogen, C 1 -C 10 -alkyl or C 3 -C 10 -cycloalkyl and

R 7 is hydrogen, C 3 -C 10 -alkyl, C 3 -C 6 -cycloalkyl and C 6 -C 10 -aryl,

wherein R 6 and R 7 can be substituted by halogen up to per-halosubstitution,

each Z is independently —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —C(O)—NR 5 , —NO 2 , —OR 5 , —SR 5 , —NR 5 R 5′ , —NR 5 C(O)OR 5′ , —NR 5 C(O)R 5′ , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, substituted C 1 -C 10 alkyl, substituted C 3 -C 10 cycloalkyl, substituted C 7 -C 24 alkaryl and substituted C 4 -C 23 alkheteroaryl;

wherein if Z is a substituted group, it is substituted by the one or more of —CN, —CO 2 R 5 , —C(O)NR 5 R 5′ , —OR 5 , —SR 5 , —NO 2 , —NR 5 R 5′ , —NR 5 C(O)R 5′ and

—NR 5 C(O)OR 5′ ,

n is 0-3,

n1 is 0 to 3 and

s is 0 or 1;

and

A is a heteroaryl moiety selected from the group consisting of

wherein

R 1 is selected from the group consisting of C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl, up to per-halosubstituted C 1 -C 10 alkyl and up to per-halosubstituted C 3 -C 10 cycloalkyl;

R 2 is selected from the group consisting of H, —C(O)R 4 , —CO 2 R 4 , —C(O)NR 3 R 3′ , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, substituted C 1 -C 10 alkyl, substituted C 3 -C 10 cycloalkyl, substituted C 7 -C 24 alkaryl and substituted C 4 -C 23 alkheteroaryl,

where R 2 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 4 , —C(O)—NR 3 R 3′ , —NO 2 , —SR 4 , and halogen up to per-halosubstitution,

wherein R 3 and R 3′ are independently selected from the group consisting of H, —OR 4 , —SR 4 , —NR 4 R 4′ , —C(O)R 4 , —CO 2 R 4 , —C(O)NR 4 R 4′ , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per-halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14 aryl and up to per-halosubstituted C 3 -C 13 heteroaryl; and

wherein R 4 and R 4′ are independently selected from the group consisting of H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl; C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per-halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14 aryl and up to per-halosubstituted C 3 -C 13 heteroaryl,

wherein the disease mediated by p38, is rheumatoid arthritis, osteoporosis, osteoarthritis, asthma, septic shock, inflammatory bowel disease, or the result of host-versus-graft reactions.

44 . A method as in claim 43 wherein each H Z is independently selected from the group consisting of —R 6 , —OR 6 and —NHR 7 , wherein

R 6 is hydrogen, C 1 -C 10 -alkyl or C 3 -C 10 -cycloalkyl and

R 7 is selected from the group consisting of hydrogen, C 3 -C 10 -alkyl, C 3 -C 6 -cycloalkyl and C 6 -C 10 -aryl,

wherein R 6 and R 7 can be substituted by halogen or up to per-halosubstitution.

45 . A method as in claim 43 , comprising administering a compound of the formula

wherein R 1 and R 2 and B are as defined in claim 43 .

46 . A method as in claim 45 , wherein B is 2,3-dichlorophenyl or of the formula

wherein X is CF 3 , and Z is —OH, —Cl or NHC(O)—C p H 2p+1 , where p=2-4, and s=1, n=0 or 1 and n1=0 or 1.

47 . A method as in claim 45 comprising administering a compound selected from the group consisting of:

N-(3-tert-Butyl-5-pyrazolyl)-N′-(4-(2,3-dichlorophenyl)urea;

N-(3-tert-Butyl-5-pyrazolyl)-N′-(3-(4-pyridinyl)thiophenyl)urea;

N-(3-tert-Butyl-5-pyrazolyl)-N′-(4-(4-pyridinyl)methylphenyl)urea;

N-(3-tert-Butyl-5-pyrazolyl)-N′-(4-(4-pyridinyl)oxyphenyl)urea;

N-(3-tert-Butyl-5-pyrazolyl)-N′-(4-(4-pyridinyl)thiophenyl)urea;

N-(3-tert-Butyl-5-pyrazolyl)-N′-(4-(4-pyridinyl)methylphenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(2,3-dichlorophenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(4-(4-hydroxy-phenyl)thiophenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(4-(4-ethylaminocarbonyl-phenyl)oxyphenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(4-(4-isobutylaminocarbonyl-phenyl)thiophenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(4-(4-pyridinyl)thiophenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(3-(4-pyridinyl)thiophenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(4-(4-pyridinyl)thio-3-(trifluoro-methyl)phenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(4-(4-pyridinyl)oxyphenyl)urea;

N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N′-(44(4-pyridinyl)methylthio)-phenyl)urea;

N-(1-(2,2,2-Trifluoroethyl)-3-tert-butyl-5-pyrazolyl)-N′-(2,3-dichloro-phenyl)urea;

N-(1-(2-Hydroxyethyl)-3-tert-butyl-5-pyrazolyl)-N′-(2,3-dichlorophenyl)urea;

N-(1-Ethoxycarbonylmethyl-3-tert-butyl-5-pyrazolyl)-N′-(2,3-dichloro-phenyl)urea;

N-(1-(2-Cyanoethyl)-3-tert-butyl-5-pyrazolyl)-N′-(2,3-dichlorophenyl)urea;

N-(1-(3-Hydroxyphenyl)methyl-3-tert-butyl-5-pyrazolyl)-N′-(2,3-dichloro-phenyl)urea;

N-(1-Cyclohexyl-3-tert-butyl-5-pyrazolyl)-N′-(4-(4-pyridinyl)methyl-phenyl)urea;

and pharmaceutically acceptable salts thereof.

48 . A method as in claim 45 , wherein R 1 is t-butyl.

49 . A method as in claim 43 comprising administering a compound of the formula

wherein R 1 and B are as defined in claim 43 .

50 . A method as in claim 49 , wherein B is 2,3-dichlorophenyl or of the formula

wherein X is CF 3 , Z is OH, CH 3 , —O—C p H 2p+1 , wherein n=2-6 or —C(O)—NH—CH 3 , s=1, n=0 or 1 and n1=0 or 1.

51 . A method as in claim 43 comprising administering a compound selected from the group consisting of:

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-hydroxyphenyl)oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-isopropoxyphenyl)oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-isobutoxyphenyl)oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-pentyloxyphenyl)oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-methylaminocarbonylphenyl)-oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(3-(4-pyridinyl)thiophenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(3-(4-pyridinyl)oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-pyridinyl)oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-pyridinyl)thiophenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-pyridinyl)methylphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(4-pyridinyl)thio-3-(trifluoromethyl)-phenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(3-(3-methyl-4-pyridinyl)thiophenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(3-(3-methyl-4-pyridinyl)oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(3-methyl-4-pyridinyl)oxyphenyl)urea;

N-(5-tert-Butyl-3-isoxazolyl)-N′-(4-(3-methyl-4-pyridinyl)thiophenyl)urea;

and pharmaceutically acceptable salts thereof.

52 . A method as in claim 49 , wherein R 1 is t-Butyl.

53 . A method as in claim 43 comprising administering a compound of the formula wherein R 1 and B are as defined in claim 43 .

54 . A method as in claim 53 , wherein R 1 is t-butyl.

55 . A method as in claim 43 comprising administering a compound selected from the group consisting of:

N-(3-Isopropyl-5-isoxazolyl)-N′-(3-(4-pyridinyl)thiophenyl)urea;

N-(3-tert-Butyl-5-isoxazolyl)-N′-(2,3-dichlorophenyl)urea;

N-(3-tert-Butyl-5-isoxazolyl)-N′-(4-(4-methoxyphenyl)aminophenyl)urea;

N-(3-tert-Butyl-5-isoxazolyl)-N′-(4-(4-methoxyphenyl)oxyphenyl)urea;

N-(3-tert-Butyl-5-isoxazolyl)-N′-(4-(4-pyridinyl)oxyphenyl)urea;

N-(3-tert-Butyl-5-isoxazolyl)-N′-(4-(4-pyridinyl)thiophenyl)urea;

N-(3-tert-Butyl-5-isoxazolyl)-N′-(4-(4-pyridinyl)methylphenyl)urea;

N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N′-(4-(4-pyridinyl)methyl-phenyl)urea;

N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N′-(3-(4-pyridinyl)thiophenyl)urea;

N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N′-(4-(2-benzothiazolyl)-oxyphenyl)urea;

N-(3-(1-Methyl-1-ethylpropyl)-5-isoxazolyl)-N′-(4-(4-pyridinyl)oxy-phenyl)urea;

N-(3-(1-Methyl-1-ethylpropyl)-5-isoxazolyl)-N′-(4-(4-pyridinyl)methyl-phenyl)urea;

and pharmaceutically acceptable salts thereof.

56 . A compound of one of the formulae

wherein R 6 is —O—CH 2 -phenyl, —NH—C(O)—O-t-butyl, —O-n-pentyl, —O-n-butyl, —C(O)—N(CH 3 ) 2 , —O—CH 2 CH(CH 3 ) 2 or —O-n-propyl;

wherein R 1 is —CH 2 -t-butyl;

wherein R 2 is —CH 2 CF 3 , —C 2 H 4 —OH, —CH 2 -(3-HOC 6 H 4 ), —CH 2 C(O)NHCH 3 , —CH 2 C(O)OC 2 H 5 , —C 2 H 4 CN, or

and pharmaceutically acceptable salts thereof.

57 . A pharmaceutical composition comprising a compound according to claim 56 or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier.