Bemis, Guy W.; Salituro, Francesco Gerald; Duffy, John Patrick;

Inhibitors of p38

The present invention relates to inhibitors of p38, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.

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We claim:

1. A compound of the formula: ##STR38## wherein: each of Q.sub.1 and Q.sub.2 are independently selected from phenyl or pyridyl;

wherein:

Q.sub.1 is substituted with 1 to 4 substituents, independently selected from halo; C.sub.1 -C.sub.3 alkyl; C.sub.1 -C.sub.3 alkyl substituted with NR', OR', CO.sub.2 R' or CONR'.sub.2 ; O--(C.sub.1 -C.sub.3)-alkyl; O--(C.sub.1 -C.sub.3)-alkyl substituted with NR', OR', CO.sub.2 R' or CONR'.sub.2 ; NR'.sub.2 ; OCF.sub.3 ; CF.sub.3 ; NO.sub.2 ; CO.sub.2 R'; CONR'; SR'; SCF.sub.3 ; or CN; and

Q.sub.2 is optionally substituted with up to 4 substituents, independently selected from halo; C.sub.1 -C.sub.3 alkyl; C.sub.1 -C.sub.3 alkyl substituted with NR', OR', CO.sub.2 R' or CONR'.sub.2 ; O--(C.sub.1 -C.sub.3)-alkyl; O--(C.sub.1 -C.sub.3)-alkyl substituted with NR', OR', CO.sub.2 R' or CONR'.sub.2 ; NR'.sub.2 ; OCF.sub.3 ; CF.sub.3 ; NO.sub.2 ; CO.sub.2 R'; CONR'; SR'; SCF.sub.3 ; or CN;

wherein R' is selected from hydrogen, (C.sub.1 -C.sub.3)-alkyl or (C.sub.2 -C.sub.3)-alkenyl or alkynyl;

X is selected from --S--, --O--, --S(O.sub.2)--, --S(O)--, --S(O.sub.2)--N(R)--, --N (R) --S(O.sub.2)--, --N(R)--C(O)O--, --O--C(O)--N(R)--, --C(O)--, --C(O)O--, --O--C(O)--, --C(O)--N(R)--, --N(R) --C(O)--, --N(R)--, or --C(R.sub.2)--;

each R is independently selected from hydrogen, --R.sup.2, --NR.sup.2.sub.2, --OR.sup.2, SR.sup.2, --C(O)--NR.sup.2.sub.2 or --C(O)--OR.sup.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.sup.2 is selected from hydrogen, (C.sub.1 -C.sub.3)-alkyl, O--(C.sub.2 -C.sub.3)-alkyl, (C.sub.1 -C.sub.3)-alkenyl or O--C(C.sub.2 -C.sub.3)-alkenyl, each optionally substituted with W;

W is selected from --N(R').sub.2, --OR', --SR', --S(O)R', --S(O.sub.2)R', C(O)OR', ##STR39## or any 5 to 7-membered heterocyclic ring comprising up to 3 heteroatoms independently selected from N, O or S, wherein said heterocyclic ring is optionally substituted with up to 3 substituents independently selected from halo, C.sub.1 -C.sub.3 alkyl, O--(C.sub.1 -C.sub.3)-alkyl, NR'.sub.2, OCF.sub.3, CF.sub.3, NO.sub.2, CO.sub.2 R', CONR' or CN;

Y is C;

A is N;

n is 1 and

R.sub.1 is selected from hydrogen, (C.sub.1 -C.sub.3)-alkyl, OH, or O--(C.sub.1 -C.sub.3)-alkyl.

2. The compound according to claim 1, wherein Q.sub.1 is selected from phenyl or pyridyl containing 1 to 3 substituents independently selected from chloro, fluoro, bromo, --CH.sub.3, --OCH.sub.3, --OH, --CF.sub.3, --OCF.sub.3, --O(CH.sub.2).sub.2 CH.sub.3 or NH.sub.2, and wherein at least one of said substituents is in the ortho position and said substituents are independently selected from chloro, fluoro, bromo, --CH.sub.3, --OCH.sub.3, --OH, --CF.sub.3, --OCF.sub.3, --O(CH.sub.2).sub.2 CH.sub.3 or NH.sub.2.

3. The compound according to claim 2, wherein Q.sub.1 contains at least two substituents, both of which are in the ortho position.

4. The compound according to claim 2, wherein Q.sub.1 is selected from: ##STR40##

5. The compound according to claim 3, wherein Q.sub.1 is selected from 2,6-difluorophenyl or 2,6-dichlorophenyl.

6. The compound according to claim 1, wherein Q.sub.2 is selected from phenyl or pyridyl and wherein Q.sub.2 optionally contains up to 3 substituents, each of which is independently selected from chloro, fluoro, methyl, --OCH.sub.3, --OH, --NH.sub.2, --CF.sub.3, --OCF.sub.3, --SCH.sub.3, --OCH.sub.3, --C(O)OH and --CH.sub.2 CH.sub.2 OH.

7. The compound according to claim 6, wherein, Q.sub.2 is selected from: or unsubstituted phenyl.

8. The compund according to claim 7, wherein Q.sub.2 is selected from phenyl or 4-fluorophenyl.

9. The compound according to claim 1, wherein X is selected from --S--, --O--, --S(O.sub.2)--, --S(0)--, --NR--, --C(R.sub.2)-- or --C(O)--.

10. The compound according to claim 9, wherein X is S.

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

12. The compound according to claim 11, having formula: ##STR41## and being selected from the compounds indicated in the table below:

    ______________________________________
    Cmpd# Q.sub.1      Q.sub.2    R.sub.a
                                         R.sub.b
    ______________________________________
    2     4-fluorophenyl
                       phenyl     hydrogen
                                         hydrogen
    3     2,4-dichlorophenyl
                       phenyl     hydrogen
                                         hydrogen
    5     2,4-dichlorophenyl
                       4-methylphenyl
                                  hydrogen
                                         hydrogen
    6     2,6-dichlorophenyl
                       phenyl     hydrogen
                                         hydrogen
    7     2-chlorophenyl
                       phenyl     hydrogen
                                         hydrogen
    8     2-methylphenyl
                       phenyl     hydrogen
                                         hydrogen
    9     3,4-dichlorophenyl
                       phenyl     hydrogen
                                         hydrogen
    10    4-methoxyphenyl
                       phenyl     hydrogen
                                         hydrogen
    11    2-methoxyphenyl
                       phenyl     hydrogen
                                         hydrogen
    12    2,6-dichlorophenyl
                       4-fluorophenyl
                                  hydrogen
                                         hydrogen
    13    2,6-dichlorophenyl
                       phenyl     methyl methyl
    14    2,6-dichlorophenyl
                       4-methylphenyl
                                  hydrogen
                                         hydrogen
    15    2,6-dichlorophenyl
                       3-methlyphenyl
                                  hydrogen
                                         hydrogen
    16    2,6-dichlorophenyl
                       3,4-       hydrogen
                                         hydrogen.
                       dichlorophenyl
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