Inhibitors of p38

1. A method of treating inflammatory diseases selected from cerebral ischemia, reperfusion/ischemia in stroke, myocardial ischemia, renal ischemia, rheumatoid arthritis, or Crohn's disease in a patient, said method comprising administering to said patient a compound of the formula:

wherein each of Q 1 and Q 2 is independently selected from a phenyl, a 5–6 membered aromatic heterocyclic ring system, or a 8–10 membered bicyclic ring system selected from the group consisting of aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring;

the rings that make up Q 1 are substituted with 1 to 4 substituents, each of which is independently selected from halo; C 1 –C 3 alkyl optionally substituted with NR′ 2 , OR′, CO 2 R′ or CONR′ 2 ; O—(C 1 –C 3 ) -alkyl optionally substituted with NR′ 2 , OR′, CO 2 R′ or CONR′ 2 ; NR′ 2 ; OCF 3 ; CF 3 ; NO 2 ; CO 2 R′; CONHR′; SR′; S(O 2 )N(R′) 2 ; SCF 3 ; CN; N(R′)C(O)R 4 ; N(R′)C(O)OR 4 ; N(R′)C(O)C(O)R 4 ; N(R′)S(O 2 )R 4 ; N(R′)R 4 ; N(R 4 ) 2 ; OR 4 ; OC(O)R 4 ; OP(O) 3 H 2 ; N═C—N(R′) 2 ; 3,4-methylenedioxy; —NH—C(O)O—CH 2 -4-pyridine; —NH—C(O)CH 2 -morpholine; —NH—C(O)CH 2 -piperazine; or —NH—C(O)CH 2 -pyrrolidine;

the rings that make up Q 2 are optionally substituted with up to 4 substituents, each of which is independently selected from halo; C 1 –C 3 straight or branched alkyl optionally substituted with NR′ 2 , OR′, CO 2 R′, S(O 2 )N(R′) 2 , N═C—N(R′) 2 , R 3 , or CONR′ 2 ; O—(C 1 –C 3 )-alkyl optionally substituted with NR′ 2 , OR′, CO 2 R′, S(O 2 )N(R′) 2 , N═CH—N(R′) 2 , R 3 , or CONR′ 2 ; NR′ 2 ; OCF 3 ; CF 3 ; NO 2 ; CO 2 R′; CONHR′; R 3 ; OR 3 ; NHR 3 ; SR 3 ; C(O)R 3 ; C(O)N(R′)R 3 ; C(O)OR 3 ; SR′; S(O 2 )N(R′) 2 ; SCF 3 ; N═C—N(R′) 2 ; CN; —NH—C(═NH)—NH 2 ; or —CH 2 —NH—C(═NH)—NH 2 ;

Q 2 ′ is selected from phenyl or a 5–6 member aromatic heterocyclic ring optionally substituted with 1–3 substituents, each of which is independently selected from halogen; C 1 –C 3 alkyl optionally substituted with NR′ 2 , OR′, CO 2 R′, CONR′ 2 , or O—P(O 3 )H 2 ; O—(C 2 –C 3 )-alkyl optionally substituted with NR′ 2 , OR′, CO 2 R′, CONR′ 2 , or OP(O 3 )H 2 ; OCF 3 ; CF 3 ; OR 4 ; O—CO 2 R 4 ; O—P(O 3 )H 2 ; CO 2 R′; CONHR′; SR′; S(O 2 )N(R′) 2 ; SCF 3 ; CN; N(R′)C(O)R 4 ; N(R′)C(O)OR 4 ; N(R′)C(O)C(O)R 4 ; N(R′)S(O 2 )R 4 ; N(R′)R 4 ; N(R 4 ) 2 ; OR 4 ; OC(O)R 4 ; OP(O) 3 H 2 ; or N═CH—N(R′) 2 ; provided that Q 2 ′ is not phenyl optionally substituted 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;

R′ is selected from hydrogen; (C 1 –C 3 )-alkyl; (C 2 –C 3 )-alkenyl or alkynyl; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5–6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;

R 3 is selected from 5–8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring systems each optionally substituted with R′, R 4 , —C(O)R′, —C(O)R 4 , —C(O)OR 4 or —J; or an 8–10 membered bicyclic ring system selected from the group consisting of aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring each optionally substituted with R′, R 4 , —C(O)R′, —C(O)R 4 , —C(O)OR 4 or —J;

R 4 is (C 1 –C 4 )-straight or branched alkyl optionally substituted with N(R′) 2 , OR′, CO 2 R′, CON(R′) 2 , or SO 2 N(R 2 ) 2 ; or a 5–6 membered carbocyclic or heterocyclic ring system optionally substituted with N(R′) 2 , OR′, CO 2 R′, CON(R′) 2 , or SO 2 N(R 2 ) 2 ;

R 5 is selected from hydrogen; (C 1 –C 3 )-alkyl optionally substituted with R 3 ; (C 2 –C 3 )-alkenyl or alkynyl each optionally substituted with R 3 ; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5–6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;

W is selected from N(R 2 )SO 2 —N(R 2 ) 2 ; N(R 2 )SO 2 —N(R 2 )(R 3 ); N(R 2 )C(O)—OR 2 ; N(R 2 )C(O)—N(R 2 ) 2 ; N(R 2 )C(O)—N(R 2 )(R 3 ); N(R 2 )C(O)—R 2 ; N(R 2 ) 2 ; C(O)—R 2 ; CH(OH)—R 2 ; C(O)—N(R 2 ) 2 ; C(O)—OR 2 ; J; or (C 1 –C 4 ) straight or branched alkyl optionally substituted with N(R′) 2 , OR′, CO 2 R′, CON(R′) 2 , R 3 , SO 2 N(R 2 ) 2 , OC(O)R 2 , OC(O)R′, OC(O)N(R 2 ) 2 , —N(R 4 )(R 5 ), —C(O)N(R 5 )(R 2 ), —C(O)R 5 , —N(R 2 )C(O)N(R 2 )(R 5 ), —NHC(O)OR 5 , —OC(O)N(R 2 )(R 5 ), or —J; a 5–6 membered carbocyclic or heterocyclic ring system optionally substituted with N(R′) 2 , OR′, CO 2 R′, CON(R′) 2 , or SO 2 N(R 2 ) 2 ; or a 8–10 membered carbocyclic or heterocyclic ring system optionally substituted with N(R′) 2 , OR′, CO 2 R′, CON(R′) 2 , or SO 2 N(R 2 ) 2 ; provided that, unless U is W, W is not an R 3 substituted C 1 alkyl;

W′ is selected from N(R 2 )—SO 2 —Q 2 ; N(R 2 )—CO 2 —Q 2 ; N(R 2 )—C(O)—Q 2 ; N(R 2 )(Q 2 ); C(O)—Q 2 ; CO 2 —Q 2 ; C(O)N(R 2 )(Q 2 ); C(R 2 ) 2 Q 2 ;

each R is independently selected from hydrogen, —R 2 , —N(R 2 ) 2 , —OR 2 , SR 2 , —C(O)—N(R 2 ) 2 , —S(O 2 )—N(R 2 ) 2 , —C(O)—OR 2 or —C(O)R 2 wherein two adjacent R are optionally bound to one another and, together with each Y to which they are respectively bound, form a 4–8 membered carbocyclic or heterocyclic ring;

R 2 is selected from hydrogen, (C 1 –C 3 )-alkyl, or (C 2 –C 3 )-alkenyl; wherein each (C 1 –C 3 )-alkyl or (C 2 –C 3 )-alkenyl is optionally substituted with —N(R′) 2 , —OR′, SR′, —C(O)—N(R′) 2 , —S(O 2 )—N(R′) 2 , —C(O)—OR′, —NHSO 2 R 4 , —NHSO 2 R 3 , —C(O)N(R′)(R 3 ), —NHC(O)R 4 , —N(R′)(R 3 ), —N(R′)(R 4 ), —C(O)R 3 , —C(O)N(R′)(R 4 ), —N(R 4 ) 2 , —C(O)N═C(NH) 2 or R 3 ;

Y is C;

Z is CH, N, C(OCH 3 ), C(CH 3 ), C(NH 2 ), C(OH) or C(F);

U is selected from R or W;

V is selected from —C(O)NH 2 , —P(O)(NH 2 ) 2 , or —SO 2 NH 2 ;

J is a (C 1 –C 4 ) straight chain or branched alkyl substituted with 1–3 substituents selected from D, —T—C(O)R′, or —OPO 3 H 2 ;

D is selected from

T is O or NH; and

G is NH 2 or OH;

provided that in compounds of formula (Ia), when W is hydrogen, Z is CH or N, and V is —C(O)NH 2 , then U is not hydrogen; and

in compounds of formula (Ia), when W is hydrogen; Z is CH or N; V is —C(O)NH 2 ; and U is —R 2 , —N(R 2 ) 2 , —OR 2 , —SR 2 , —C(O)—N(R 2 ) 2 , —S(O 2 )—N(R 2 ) 2 , —C(O)—OR 2 or —C(O)R 2 ; then each of those R 2 is not hydrogen, (C 1 –C 3 )-alkyl, or (C 2 –C 3 )-alkenyl, or (C 1 –C 3 )-alkyl or (C 2 –C 3 )-alkenyl substituted with —N(R′) 2 , —OR′, —SR′, —C(O)—N(R′) 2 , —S(O 2 )—N(R′) 2 , —C(O)—OR′, or an unsubstituted 5–6 membered aromatic carbocyclic or heterocyclic ring system.

2. The method according to claim 1 , wherein said method is used to treat rheumatoid arthritis or Crohn's disease.

3. The method according to claim 1 , wherein said method is used to treat cerebral ischemia, ischemia/reperfusion in stroke, myocardial ischemia, or renal ischemia.

4. The method according to claim 1 , wherein Q 1 is selected from phenyl or pyridyl containing 1 to 3 substituents independently selected from chloro, fluoro, bromo, —CH 3 , —OCH 3 , —OH, —CF 3 , —OCF 3 , —O(CH 2 ) 2 CH 3 , NH 2 , 3,4-methylenedioxy, —N(CH 3 ) 2 , —NH—S(O) 2 -phenyl, —NH—C(O)O—CH 2 -4-pyridine, —NH—C(O)CH 2 -morpholine, —NH—C(O)CH 2 —N(CH 3 ) 2 , —NH—C(O)CH 2 -piperazine, —NH—C(O)CH 2 -pyrrolidine, —NH—C(O)C(O)-morpholine, —NH—C(O)C(O)-piperazine, —NH—C(O)C(O)-pyrrolidine, —O—C(O)CH 2 —N(CH 3 ) 2 , or —O—(CH 2 ) 2 —N(CH 3 ) 2 amd wherein at least one of said substituents is in the ortho position.

5. The method according to claim 4 , wherein Q 1 contains at least two substituents, both of which are in the ortho position.

6. The method according to claim 4 , wherein Q 1 is selected from:

7. The method according to claim 6 , wherein Q 1 is selected from 2-fluoro-6-trifluoromethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-chloro-4-hydroxyphenyl, 2-chloro-4-aminophenyl, 2,6-dichloro-4-aminophenyl, 2,6-dichloro-3-aminophenyl, 2,6-dimethyl-4-hydroxyphenyl, 2-methoxy-3,5-dichloro-4-pyridyl, 2-chloro-4,5 methylenedioxy phenyl, or 2-chloro-4-(N-2-morpholino-acetamido)phenyl.

8. The method according to claim 1 , wherein Q 2 is selected from phenyl, pyridyl or naphthyl and wherein Q 2 optionally contains up to 3 substituents, each of which is independently selected from chloro, fluoro, bromo, methyl, ethyl, isopropyl, —OCH 3 , —OH, —NH 2 , —CF 3 , —OCF 3 , —SCH 3 , —C(O)OH, —C(O)OCH 3 , —CH 2 NH 2 , —N(CH 3 ) 2 , —CH 2 -pyrrolidine, —CH 2 OH, —CH 2 —N(CH 3l ) 2 , —CH 2 -piperazine, —NH—C(═NH)—NH 2 , —CH 2 —NH—C(═NH)—NH 2 , and —CH 2 —NH-imidazoline.

9. The method according to claim 8 , wherein Q 2 is selected from:

unsubstituted 2-pyridyl or unsubstituted phenyl.

10. The method according to claim 9 , wherein Q 2 is selected from phenyl, 2-isopropylphenyl, 3,4-dimethylphenyl, 2-ethylphenyl, 3-fluorophenyl, 2-methylphenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 2-carbomethoxylphenyl, 2-carboxyphenyl, 2-methyl-4-chlorophenyl, 2-bromophenyl, 2-pyridyl, 2-methylenehydroxyphenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2-hydroxy-4-fluorophenyl or 2-methylenehydroxy-4-fluorophenyl, 1-naphthyl, 3-chloro-2-methylenehydroxy, 3-chloro-2-methyl, or 4-fluoro-2-methyl.

11. The method according to claim 1 , wherein each R and U attached to Y is independently selected from hydrogen or methyl.

12. The method according to claim 1 , wherein U, W or both U and W are a 0–4 atom chain terminating in an alcohol, amine, carboxylic acid, ester, amide or heterocycle.

13. The method according to claim 12 , wherein U, W or both U and W are selected from:

14. The method according to claim 13 , wherein U, W, or both U and W are selected from:

15. The method according to claim 1 , wherein the compound is selected from any one of the following compounds:

Cmpd

Number

Structure

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

126

127

128

129

130

132

133

134

135

136

137

140

141

142

143

144

146

147

148

149

150

151

152

153

154

155

156

157

158

160

161

162

163

164

165

166

167

16. The method according to claim 1 , wherein the compound is

and X is selected from H,

17. The method according to claim 1 , wherein the compound is

and X is selected from NH 2 or N(CH 3 ) 2 .

18. The method according to claim 1 , wherein the compound is

and X is selected from OH, NH 2 , or N(CH 3 ) 2 .

19. The method according to claim 1 , wherein the compound is

and X is selected from OH, NH 2 , or N(CH 3 ) 2 .

20. The method according to claim 1 , wherein the compound is

and X is selected from OH, NH 2 , N(CH 3 ) 2 ,

21. The method according to claim 1 , wherein the compound is

wherein X=H,

22. The method according to claim 1 , wherein the compound is

wherein X=

23. The method according to claim 1 , wherein the compound is

wherein X is

24. The method according to claim 1 , wherein the compound is selected from any one of