3-aminocarbonyl, 6-phenyl substituted pyridine-1-oxides as p38 kinase inhibitors

1. A compound of formula (I):

wherein

R 1 is selected from hydrogen, C 1-6 alkyl optionally substituted by up to three groups independently selected from C 1-6 alkoxy, halogen and hydroxy, C 2-6 alkenyl, C 3-7 cycloalkyl optionally substituted by one or more C 1-6 alkyl groups, phenyl optionally substituted by up to three groups independently selected from R 5 and R 6 , and heteroaryl optionally substituted by up to three groups independently selected from R 5 and R 6 ,

R 2 is selected from hydrogen, C 1-6 alkyl and —(CH 2 ) q —C 3-7 cycloalkyl optionally substituted by one or more C 1-6 alkyl groups,

or (CH 2 ) m R 1 and R 2 , together with the nitrogen atom to which they are bound, form a four- to six-membered heterocyclic ring optionally substituted by up to three C 1-6 alkyl groups;

R 3 is chloro or methyl;

R 4 is the group —NH—CO—R 7 or —CO—NH—(CH 2 ) q —R 8 ;

R 5 is selected from C 1-6 alkyl, C 1-6 alkoxy, —(CH 2 ) q —C 3-7 cycloalkyl optionally substituted by one or more C 1-6 alkyl groups, —CONR 9 R 10 , —NHCOR 10 , —SO 2 NHR 9 , —(CH 2 ) s NHSO 2 R 10 , halogen, CN, OH, —(CH 2 ) s NR 11 R 12 , and trifluoromethyl;

R 6 is selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, trifluoromethyl and —(CH 2 ) s NR 11 R 12 ;

R 7 is selected from hydrogen, C 1-6 alkyl, —(CH 2 ) q —C 3-7 cycloalkyl optionally substituted by one or more C 1-6 alkyl groups, trifluoromethyl, —(CH 2 ) r heteroaryl optionally substituted by R 13 and/or R 14 , and —(CH 2 ) r phenyl optionally substituted by R 13 and/or R 14 ;

R 8 is selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl optionally substituted by one or more C 1-6 alkyl groups, CONHR 9 , phenyl optionally substituted by R 13 and/or R 14 , and heteroaryl optionally substituted by R 13 and/or R 14 ;

R 9 and R 10 are each independently selected from hydrogen and C 1-6 alkyl,

or R 9 and R 10 , together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N—R 15 , wherein the ring may be substituted by up to two C 1-6 alkyl groups;

R 11 is selected from hydrogen, C 1-6 alkyl and —(CH 2 ) q —C 3-7 cycloalkyl optionally substituted by one or more C 1-6 alkyl groups,

R 12 is selected from hydrogen and C 1-6 alkyl,

or R 11 and R 12 , together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N—R 15 ;

R 13 is selected from C 1-6 alkyl, C 1-6 alkoxy, —(CH 2 ) q —C 3-7 cycloalkyl optionally substituted by one or more C 1-6 alkyl groups, —CONR 9 R 10 , —NHCOR 10 , halogen, CN, —(CH 2 ) s NR 11 R 12 , trifluoromethyl, phenyl optionally substituted by one or more R 14 groups and heteroaryl optionally substituted by one or more R 14 groups;

R 14 is selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, trifluoromethyl and —NR 11 R 12 ;

R 15 is selected from hydrogen and methyl;

X and Y are each independently selected from hydrogen, methyl and halogen;

m is selected from 0, 1, 2, 3 and 4, wherein each carbon atom of the resulting carbon chain may be optionally substituted with up to two groups selected independently from C 1-6 alkyl and halogen;

q is selected from 0, 1 and 2;

r is selected from 0 and 1; and

s is selected from 0, 1, 2 and 3;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein R 1 is selected from C 1-6 alkyl optionally substituted by up to three groups independently selected from C 1-6 alkoxy, halogen and hydroxy, and phenyl optionally substituted by up to three groups independently selected from R 5 and R 6 .

3. A compound according to claim 1 wherein R 2 is hydrogen.

4. A compound according to claim 1 wherein R 3 is methyl.

5. A compound according to claim 1 wherein X is fluorine.

6. A compound according to claim 1 wherein R 4 is —CO—NH—(CH 2 ) q —R 8 .

7. A compound according to claim 1 wherein R 8 is C 3-6 cycloalkyl optionally substituted by one or more C 1-6 alkyl groups.

8. A compound according to claim 1 selected from:

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(15)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(15)-1,2-dimethylpropyl]-3-pyridinecarboxamide 1-oxide; and

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(3,4-dimethylphenyl)methyl]-3-pyridinecarboxamide 1-oxide;

or pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 which is 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide 1-oxide; or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 2 wherein R 1 is 1-methylethyl, n-propyl, 2-methylpropyl, t-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl or 1,2,2-trimethylpropyl optionally substituted by methoxy.

11. A compound according to claim 1 wherein m is 0 or 1.

12. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable excipients, diluents and/or carriers.

13. A process for preparing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof which comprises reacting compound of formula (II)

in which R 1 , R 2 , R 3 , R 4 , X, Y and m are as defined in claim 1 , with an oxidising agent.