P38 kinase inhibiting agents
View Patent ↗Compounds described by the chemical formula (I) or pharmaceutically acceptable salts thereof: (I) 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:
or a pharmaceutically acceptable salt thereof, wherein:
X and Y are each independently selected from —CR 4 — and —N—;
R 1 is selected from:
(1) hydrogen,
(2) halogen,
(3) OH, and
(4) alkoxy;
R 2 is selected from:
(1) NR a ,
(2) aryl,
(3) heteroaryl,
(4) heterocycloalkyl, and
(5) OR a ;
said heteroaryl, aryl and heterocycloalkyl are each optionally substituted with one or more substituents selected from R 6 , R 7 and R 8 ;
R 3 is selected from:
(1) aryl,
(2) benzyl,
(3) heteroaryl, and
(4) heterocycloalkyl;
said heteroaryl, aryl and heterocycloalkyl are each optionally substituted with one or more substituents selected from R 6 , R 7 and R 8 ;
R 4 is selected from:
(1) hydrogen,
(2) C 1 -C 6 alkyl,
(3) alkoxy,
(4) CHO,
(5) CONH 2 ,
(6) C(O) 2 R a ,
(7) C 0 -C 4 alkyl-OH,
(8) O—C 1 -C 4 alkyl,
(9) halogen,
(10) aryl,
(11) heteroaryl,
(12) heterocycloalkyl,
(13) COR a ,
(14) O—C—C4alkyl-N—C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(15) heterocycloalkyl-C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(16) N(R a )(R a ),
(17) O—R a
(18) N—C(O)—N-heterocycloalkyl,
(19) O—C(O)—N-heterocycloalkyl,
(20) N—C 1 -C 4 alkyl-N—R a , and
(21) N—C 1 -C 4 alkyl-O—R a ;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R 6 , R 7 and R 8 ;
R 6 , R 7 and R 8 are each independently selected from:
(1) halogen,
(2) C 1 -C 6 alkyl,
(3) CN,
(4) OR a ,
(5) alkoxy,
(6) cycloalkyl,
(7) C═R a (R a ),
(8) CON(R a )(R a ),
(9) aryl,
(10) N(R a )(R a ),
(11) heteroaryl,
(12) hydrogen,
(13) C 1 -C 4 —OH,
(14) heterocycloalkyl,
(15) CON-alkyl-CO 2 —R a ,
(16) CON-alkyl-CON(R a )(R a ),
(17) CON-alkyl-N(R a )(R a ),
(18) C(═O)R a , and
(19) C(O) 2 R a ;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R a ;
R a is selected from:
(1) hydrogen,
(2) halogen,
(3) NH—C 1 -C 4 alkyl,
(4) C 1 -C 6 alkyl,
(5) C 1 -C 4 -alkyl-heteroaryl,
(6) C 1 -C 4 -alkyl-cycloalkyl,
(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;
R b and R c are each independently selected from hydrogen and alkyl, or R b and R c can join together to form a cycloalkyl.
2. A compound according to claim 1 represented by chemical Formula Ia, or a pharmaceutically acceptable salt thereof:
or a pharmaceutically acceptable salt thereof, wherein:
X and Y are each independently selected from —CR 4 — and —N—;
R 4 is selected from:
(1) hydrogen,
(2) C 1 -C 6 alkyl,
(3) alkoxy,
(4) CHO,
(5) CONH 2 ,
(6) C(O) 2 R a ,
(7) C 0 -C 4 alkyl-OH,
(8) O—C 1 -C 4 alkyl,
(9) halogen,
(10) aryl,
(11) heteroaryl,
(12) heterocycloalkyl,
(13) COR a ,
(14) O—C 1 -C 4 alkyl-N—C(O)—C 0 -C 2 alkyl(R b R c )—NH 2
(15) heterocycloalkyl-C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(16) N(R a )(R a ),
(17) O—R a ,
(18) N—C(O)—N-heterocycloalkyl,
(19) O—C(O)—N-heterocycloalkyl,
(20) N—C 1 -C 4 alkyl-N—R a , and
(21) N—C 1 -C 4 alkyl-O—R a ;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R 6 , R 7 and R 8 ;
R 6 , R 7 and R 8 are each independently selected from:
(1) halogen,
(2) C 1 -C 6 alkyl,
(3) CN,
(4) OR a ,
(5) alkoxy.
(6) cycloalkyl,
(7) C═R a (R a ),
(8) CON(R a )(R a ),
(9) aryl,
(10) N(R a )(R a ),
(11) heteroaryl,
(12) hydrogen,
(13) C 1 -C 4 —OH,
(14) heterocycloalkyl,
(15) CON-alkyl-CO 2 —R a ,
(16) CON-alkyl-CON(R a )(R a ),
(17) CON-alkyl-N(R a )(R a ),
(18) C(═O)R a , and
(19) C(O) 2 R a ;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R a ; and
R a is selected from:
(1) hydrogen,
(2) halogen,
(3) NH—C 1 -C 4 alkyl,
(4) C 1 -C 6 alkyl,
(5) C 1 -C 4 -alkyl-heteroaryl,
(6) C 1 -C 4 -alkyl-cycloalkyl,
(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;
R b and R c are each independently selected from hydrogen and alkyl, or R b and R c can join together to form a cycloalkyl.
3. A compound according to claim 1 represented by the chemical Formula Ib, or a pharmaceutically acceptable salt thereof:
or a pharmaceutically acceptable salt thereof, wherein:
R 6 , R 7 and R 8 are each independently selected from:
(1) halogen,
(2) C 1 -C 6 alkyl,
(3) CN,
(4) OR a ,
(5) CON(R a )(R a ),
(6) aryl,
(7) heteroaryl,
(8) C═R a (R a ),
(9) hydrogen,
(10) C 1 -C 4 —OH,
(11) C(═O)R a , and
(12) C(O) 2 R a ;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R a ; and
R a is selected from:
(1) hydrogen,
(2) halogen,
(3) NH—C 1 -C 4 alkyl,
(4) C 1 -C 6 alkyl,
(5) C 1 -C 4 -alkyl-heteroaryl,
(6) C 1 -C 4 -alkyl-cycloalkyl,
(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.
4. A compound represented by the chemical Formula Ic, or a pharmaceutically acceptable salt thereof:
or a pharmaceutically acceptable salt thereof, wherein:
X is —CR 4 —;
R 4 is selected from:
(1) hydrogen,
(2) C 1 -C 6 alkyl,
(3) alkoxy,
(4) CONH 2 ,
(5) C(O) 2 R a ,
(6) C 0 -C 4 alkyl-OH,
(7) O—C 1 -C 4 alkyl,
(8) aryl,
(9) heteroaryl,
(10) heterocycloalkyl,
(11) COR a ,
(12) O—C 1 -C 4 alkyl-N—C(O)—C 0 -C 2 alkyl(R b R c )—NH 2
(13) heterocycloalkyl-C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(14) N(R a )(R a ),
(15) O—R a ,
(16) N—C(O)—N-heterocycloalkyl,
(17) O—C(O)—N-heterocycloalkyl,
(18) N—C 1 -C 4 alkyl-N—R a and
(19) N—C 1 -C 4 alkyl-O—R a ;
said aryl and heteroaryl are each optionally substituted with one or more substituents selected from R 6 , R 7 and R 8 ;
R 6 , R 7 and R 8 are each independently selected from:
(1) halogen,
(2) C 1 -C 6 alkyl,
(3) CN,
(4) OR a ,
(5) aryl,
(6) C═R a (R a ),
(7) heteroaryl,
(8) hydrogen,
(9) C 1 -C 4 —OH, and
(10) C(═O)R a ;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R a ;
R a is selected from:
(1) hydrogen,
(2) halogen,
(3) NH—C 1 -C 4 alkyl,
(4) C 1 -C 6 alkyl,
(5) C 1 -C 4 -alkyl-heteroaryl,
(6) C 1 -C 4 -alkyl-cycloalkyl,
(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;
R b and R c are each independently selected from hydrogen and alkyl, or R b and R c can join together to form a cycloalkyl.
5. A compound represented by the chemical Formula Id, or a pharmaceutically acceptable salt thereof:
or a pharmaceutically acceptable salt thereof, wherein:
R 6 , R 7 and R 8 are each independently selected from:
(1) halogen,
(2) C 1 -C 6 alkyl,
(3) CN,
(4) OR a ,
(5) CON(R a )(R a ),
(6) aryl,
(7) heteroaryl,
(8) hydrogen,
(9) C 1 -C 4 —OH,
(10) C(═O)R a , and
(11) C(O) 2 R a ;
said heteroaryl and aryl are each optionally substituted with one or more substituents selected from R a ;
R a is selected from:
(1) hydrogen,
(2) halogen,
(3) NH—C 1 -C 4 alkyl,
(4) C 1 -C 6 alkyl,
(5) C 1 -C 4 -alkyl-heteroaryl,
(6) C 1 -C 4 -alkyl-cycloalkyl,
(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.
6. The compound according to claim 1 , represented by
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 1 .