P38 kinase inhibiting agents
View Patent ↗Compounds described by the chemical formula (I) or pharmaceutically acceptable salts thereof: are inhibitors of p38 and are useful in the treatment of inflammation such as in the treatment of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
1. A compound represented by chemical formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
X is a single covalent bond is selected from the group consisting of:
(1) O,
(2) C 1 -C 4 alkylene,
(3) S(O) n ,
(4) C 2 -C 6 alkenylene,
(5) C(O),
(6) CHR a ,
(7)
(8) NR a ,
(9) arylene, and
(10) heteroarylene,
said arylene and heteroarylene are each optionally substituted with one or more substituents selected from R 5 and R 6 ;
R a is selected from the group consisting of:
(1) hydrogen,
(2) C 1 -C 6 alkyl,
(3) C 1 -C 6 alkoxy,
(4) CONH 2 ,
(5) C(O) 2 R 4 ,
(6) C 0 -C 4 alkyl-OH,
(7) O—C 1 -C 4 alkyl,
(8) halogen,
(9) aryl,
(10) heteroaryl,
(11) heterocycloalkyl,
(12) COR 4 ,
(13) N(R 4 )(R 4 ),
(14) O—R 4 ,
(15) N—C 1 -C 4 alkyl-O—R 4 ;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R 5 and R 6 ;
R c and R d are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and O—C 1 -C 6 alkyl, or R c and R d can join together with the carbon atom to which they are attached to form a ring selected from the group consisting of cycloalkyl and heterocycloalkyl;
R 1 , R 2 and R 3 are each independently selected from the group consisting of:
(1) hydrogen,
(2) C 1 -C 6 alkoxy,
(3) C 3 -C 6 cycloalkyl,
(4) heteroaryl,
(5) CN,
(6) halogen,
(7) C 1 -C 6 alkyl,
(8) C 2 -C 6 alkene,
(9)
(10) C(O)—R 4 ,
(11) aryl,
(12) OR 4 ,
(13) CON(R 4 ) 2 ,
(14) N(R 4 ) 2 ,
(15) C 1 -C 4 —OH,
(16) heterocycloalkyl,
(17) C(O) 2 —R 4
said aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are each optionally substituted with one or more substituents selected from R 5 and R 6 ;
R 4 is selected from the group consisting of:
(1) aryl,
(2) hydrogen,
(3) halogen,
(4) heteroaryl,
(5) C 1 -C 6 alkyl-aryl,
(6) C 3 -C 6 cycloalkyl,
(7) C 1 -C 6 alkyl,
(8) C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl,
(9) C 1 -C 6 alkyl-heteroaryl,
(10)
(11) C(O)—R 5 ,
(12) NH—C 1 -C 4 alkyl,
(13) NH-aryl,
(14) C 1 -C 4 alkyl-heterocycloalkyl,
(15) heterocycloalkyl,
(16) C 0 -C 4 alkyl-NH 2 , and
(17) C 0 -C 4 alkyl-OH;
said heteroaryl, aryl, heterocycloalkyl and cycloalkyl are each optionally substituted with one or more substituents selected from R 5 and R 6 ;
R 5 and R 6 are each independently selected from:
(1) hydrogen,
(2) halogen,
(3) C 1 -C 6 alkoxy,
(4) aryl,
(5) C 3 -C 6 cycloalkyl,
(6) C 1 -C 6 alkyl, and
(7) heteroaryl,
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R 7 , or R 5 and R 6 , together with the nitrogen atom to which they are attached, can join to form a 5- to 7-membered heteroaryl or heterocycloalkyl
R 7 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) aryl,
(4) C 3 -C 6 cycloalkyl,
(5) NH—C 1 -C 4 alkyl,
(6) C 1 -C 6 alkyl,
(7) heteroaryl,
(8) C 1 -C 4 alkyl-heterocycloalkyl,
(9) heterocycloalkyl,
(10) C 0 -C 4 alkyl-NH 2 , and
(11) C 0 -C 4 alkyl-OH;
m is 0, 1, 2, or 3; and
n is 0, 1, or 2.
2. The compound according to claim 1 represented by the chemical Formula Ib, or a pharmaceutically acceptable salt thereof:
wherein all variables are as defined in Formula I.
3. The compound according to claim 1 represented by the chemical Formula Ic, or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , and R 4 are as defined in Formula I, and X is selected from CH 2 and O.
4. The compound according to claim 1 represented by the chemical Formula Id, or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 5 and R 6 are as defined in Formula I, and X is selected from CH 2 and O.
5. The compound according to claim 1 represented by the chemical Formula Ie, or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 5 and R 6 are as defined in Formula I, and X is selected from CH 2 and O.
6. The compound according to claim 5 wherein R 1 , R 2 R 3 are each independently selected from the group consisting of:
(1) hydrogen,
(2) C 1 -C 6 alkoxy,
(3) heteroaryl,
(4) halogen,
(5) aryl
(6) CN,
(7) C 1 -C 6 alkyl,
(8) C 2 -C 6 alkene,
(9)
(10) C(O) 2 —R 4 ,
said heteroaryl and aryl is optionally substituted with one or more substituents selected from selected from R 5 and R 6 .
7. The compound according to claim 6 wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of:
(1) hydrogen,
(2) C 1 -C 6 alkoxy,
(3) heteroaryl,
(4) halogen,
(5) C 2 -C 6 alkene,
(6)
(7) C(O) 2 —R 4 ,
said heteroaryl is optionally substituted with one or more substituents selected from selected from R 5 and R 6 .
8. The compound according to claim 7 wherein R 4 is selected from the group consisting of:
(1) aryl,
(2) C 1 -C 6 alkyl-aryl,
(3) C 3 -C 6 cycloalkyl,
(4) C 1 -C 6 alkyl,
(5) C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl,
(6)
(7) C(O)—R 5 ,
said aryl and cycloalkyl are each optionally substituted with one or more substituents selected from R 5 and R 6 .
9. The compound according to claim 6 wherein
R 5 and R 6 are each independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C 1 -C 6 alkoxy,
(4) C 3 -C 6 cycloalkyl,
(5)
(6) C 1 -C 6 alkyl;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R 7 , or R 5 and R 6 , together with the nitrogen atom to which they are attached, can join to form a 5- to 7-membered heteroaryl or heterocycloalkyl.
10. The compound according to claim 1 , represented by
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising an inert carrier and a compound according to claim 1 .