US2011183959A1PendingUtilityA1
P38 kinase inhibiting agents
Est. expiryAug 12, 2025(expired)· nominal 20-yr term from priority
A61P 37/06A61P 37/02A61P 43/00A61P 31/18A61P 31/12A61P 33/06A61P 29/00A61P 25/04A61P 35/00A61P 31/04A61P 27/02A61P 25/00A61P 19/10A61P 17/02A61P 17/06C07D 471/04A61P 19/08A61P 21/00A61P 1/04A61P 19/06A61P 17/00A61P 11/00A61P 19/02A61P 19/00
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 - 7 . (canceled)
8 . A method of treating pain comprising a step of administering an effective amount of 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 heterocyloalkyl 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,
(C5) 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 .
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.
9 . A method of treating rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, or gouty arthritis comprising a step of administering an effective amount of 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 heterocyloalkyl 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:
(22) hydrogen,
(23) C 1 -C 6 alkyl,
(24) alkoxy,
(25) CHO,
(26) CONH 2 ,
(27) C(O) 2 R a ,
(28) C 0 -C 4 alkyl-OH,
(29) O—C 1 -C 4 alkyl,
(30) halogen,
(31) aryl,
(32) heteroaryl,
(33) heterocycloalkyl,
(34) COR a ,
(35) O—C 1 -C 4 alkyl-N—C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(36) heterocycloalkyl-C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(37) N(R a )(R a ),
(38) O—R a ,
(39) N—C(O)—N-heterocycloalkyl,
(40) O—C(O)—N-heterocycloalkyl,
(41) N—C 1 -C 4 alkyl-N—R a , and
(42) 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:
(20) halogen,
(21) C 1 -C 6 alkyl,
(22) CN,
(23) OR a ,
(24) alkoxy,
(25) cycloalkyl,
(26) C═R a (R a ),
(27) CON(R a )(R a ),
(28) aryl,
(29) N(R a )(R a ),
(30) heteroaryl,
(31) hydrogen,
(32) C 1 -C 4 —OH,
(33) heterocycloalkyl,
(34) CON-alkyl-CO 2 —R a ,
(35) CON-alkyl-CON(R a )(R a ),
(36) CON-alkyl-N(R a )(R a ),
(37) C(═O)R a , and
(38) 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:
(12) hydrogen,
(13) halogen,
(14) NH—C 1 -C 4 alkyl,
(15) C 1 -C 6 alkyl,
(16) C 1 -C 4 -alkyl-heteroaryl,
(17) C 1 -C 4 -alkyl-cycloalkyl,
(18) heteroaryl,
(19) C 1 -C 4 alkyl-heterocycloalkyl,
(20) heterocycloalkyl,
(21) C 0 -C 4 alkyl-NH 2 , and
(22) 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.
10 . A method of treating sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, osteoporosis, reperfusion injury, graft v. host rejection, allograft rejection, fever, myalgia due to infection, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDs related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, or viral infections comprising a step of administering an effective amount of 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 heterocyloalkyl 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:
(43) hydrogen,
(44) C 1 -C 6 alkyl,
(45) alkoxy,
(46) CHO,
(47) CONH 2 ,
(48) C(O) 2 R a ,
(49) C 0 -C 4 alkyl-OH,
(50) O—C 1 -C 4 alkyl,
(51) halogen,
(52) aryl,
(53) heteroaryl,
(54) heterocycloalkyl,
(55) COR a ,
(56) O—C 1 -C 4 alkyl-N—C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(57) heterocycloalkyl-C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(58) N(R a )(R a ),
(59) O—R a
(60) N—C(O)—N-heterocycloalkyl,
(61) O—C(O)—N-heterocycloalkyl,
(62) N—C 1 -C 4 alkyl-N—R a , and
(63) 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:
(39) halogen,
(40) C 1 -C 6 alkyl,
(41) CN,
(42) OR a ,
(43) alkoxy,
(44) cycloalkyl,
(45) C═R a (R a ),
(46) CON(R a )(R a ),
(47) aryl,
(48) N(R a )(R a ),
(49) heteroaryl,
(50) hydrogen,
(51) C 1 -C 4 —OH,
(52) heterocycloalkyl,
(53) CON-alkyl-CO 2 —R a ,
(54) CON-alkyl-CON(R a )(R a ),
(55) CON-alkyl-N(R a )(R a ),
(56) C(═O)R a , and
(57) 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:
(23) hydrogen,
(24) halogen,
(25) NH—C 1 -C 4 alkyl,
(26) C 1 -C 6 alkyl,
(27) C 1 -C 4 -alkyl-heteroaryl,
(28) C 1 -C 4 -alkyl-cycloalkyl,
(29) heteroaryl,
(30) C 1 -C 4 alkyl-heterocycloalkyl,
(31) heterocycloalkyl,
(32) C 0 -C 4 alkyl-NH 2 , and
(33) 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.
11 . A method of treating inflamed joints, eczema, psoriasis, inflammatory skin conditions, inflammatory eye conditions, or pyresis comprising a step of administering an effective amount of 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 heterocyloalkyl 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:
(64) hydrogen,
(65) C 1 -C 6 alkyl,
(66) alkoxy,
(67) CHO,
(68) CONH 2 ,
(69) C(O) 2 R a ,
(70) C 0 -C 4 alkyl-OH,
(71) O—C 1 -C 4 alkyl,
(72) halogen,
(73) aryl,
(74) heteroaryl,
(75) heterocycloalkyl,
(76) COR a
(77) O—C 1 -C 4 alkyl-N—C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(78) heterocycloalkyl-C(O)—C 0 -C 2 alkyl(R b R c )—NH 2 ,
(79) N(R a )(R a ),
(80) O—R a ,
(81) N—C(O)—N-heterocycloalkyl,
(82) O—C(O)—N-heterocycloalkyl,
(83) N—C 1 -C 4 alkyl-N—R a , and
(84) 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:
(58) halogen,
(59) C 1 -C 6 alkyl,
(60) CN,
(61) OR a ,
(62) alkoxy,
(63) cycloalkyl,
(64) C═R a (R a ),
(65) CON(R a )(R a ),
(66) aryl,
(67) N(R a )(R a ),
(68) heteroaryl,
(69) hydrogen,
(70) C 1 -C 4 —OH,
(71) heterocycloalkyl,
(72) CON-alkyl-CO 2 —R a ,
(73) CON-alkyl-CON(R a )(R a ),
(74) CON-alkyl-N(R a )(R a ),
(75) C(═O)R a , and
(76) 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:
(34) hydrogen,
(35) halogen,
(36) NH—C 1 -C 4 alkyl,
(37) C 1 -C 6 alkyl,
(38) C 1 -C 4 -alkyl-heteroaryl,
(39) C 1 -C 4 -alkyl-cycloalkyl,
(40) heteroaryl,
(41) C 1 -C 4 alkyl-heterocycloalkyl,
(42) heterocycloalkyl,
(43) C 0 -C 4 alkyl-NH 2 , and
(44) 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.
12 . The method of claim 8 , wherein the compound is 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.
13 . The method of claim 8 , wherein the compound is 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.
14 . The method of claim 8 , wherein the compound is 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.
15 . The method of claim 8 , wherein the compound is 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.
16 . The method of claim 8 , wherein the compound is represented by:
or a pharmaceutically acceptable salt thereof.
17 . The method of claim 16 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18 . A compound represented by:
or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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