US2019151324A1PendingUtilityA1
NON-CATALYTIC SUBSTRATE-SELECTIVE P38alpha-SPECIFIC MAPK INHIBITORS WITH ENDOTHELIAL-STABILIZING AND ANTI-INFLAMMATORY ACTIVITY, AND METHODS OF USE THEREOF
Est. expiryJun 23, 2036(~9.9 yrs left)· nominal 20-yr term from priority
C07D 213/81C07D 263/32C07D 413/12C07D 295/073A61K 31/18A61K 31/5375A61K 31/54A61P 29/00A61P 31/00A61P 35/00A61P 19/02A61K 31/495A61P 9/00A61P 1/00A61P 11/00A61P 11/06
62
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Claims
Abstract
Compounds that inhibit p38α MAPK protein, and methods of using the same, are provided for treating or preventing diseases such as cancer or inflammatory diseases.
Claims
exact text as granted — not AI-modified1 . (canceled)
2 . A p38-α MAPK inhibitor compound of Formula 1 or Formula 2, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
wherein in Formula 1 and Formula 2,
Q is —CH— or N;
each of R 1 , R 2 , R 3 , and R 4 is independently hydrogen or optionally substituted alkyl, alkoxy, aryl, or heteroaryl;
R 5 is —SO 2 —, —CH(OH)—, —O—, or —N(CH 3 )—;
each of R 10 and R 10′ is independently —OH, —NH 2 , or —SH;
L 1 is —CH 2 —, —C(CH 3 ) 2 — or —C(CH 2 CH 2 )—;
each of L 2 and L 3 is independently —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —;
each of L 4 , L 5 , and L 5′ is independently —NHCO—, —CONH—, —SO 2 NH—, —NHSO 2 —, or —CH═CH—;
each of L 6 and L 6′ is independently an optionally substituted C 1 -C 6 alkyl chain; and
Ar 1 is an optionally substituted aryl or heteroaryl ring.
3 . The p38α MAPK inhibitor compound of claim 2 , wherein the compound has any one of Formula 11, Formula 12, Formula 13, or Formula 14, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
wherein in Formula 11, Formula 12, Formula 13, and Formula 14,
Q is —CH— or N;
each of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 is independently hydrogen or optionally substituted alkyl, alkoxy, aryl, or heteroaryl;
R 5 is —SO 2 —, —CH(OH)—, —O—, or —N(CH 3 )—;
L 1 is —CH 2 —, —C(CH 3 ) 2 , or —C(CH 2 CH 2 )—;
each of L 2 and L 3 is independently —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —;
L 4 is —NHCO—, —CONH—, —SO 2 NH—, —NHSO 2 —, or —CH═CH—;
Ar 1 is an optionally substituted aryl or heteroaryl ring; and
X is a halogen.
4 . The p38α MAPK inhibitor compound of claim 2 , wherein the compound has any one of Formulas 1001 to 1256, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
wherein in Formulas 1001 to 1256,
Formula
R 3
R 4
R 5
R 9
L 1
L 4
Y
1001
H
H
—SO 2 —
H
—CH 2 —
—NHCO—
CH
1002
—OEt
H
—SO 2 —
H
—CH 2 —
—NHCO—
CH
1003
H
Ph
—SO 2 —
H
—CH 2 —
—NHCO—
CH
1004
—OEt
Ph
—SO 2 —
H
—CH 2 —
—NHCO—
CH
1005
H
H
—SO 2 —
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1006
—OEt
H
—SO 2 —
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1007
H
Ph
—SO 2 —
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1008
—OEt
Ph
—SO 2 —
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1009
H
H
—SO 2 —
4-oxazolyl
—CH 2 —
—NHCO—
CH
1010
—OEt
H
—SO 2 —
4-oxazolyl
—CH 2 —
—NHCO—
CH
1011
H
Ph
—SO 2 —
4-oxazolyl
—CH 2 —
—NHCO—
CH
1012
—OEt
Ph
—SO 2 —
4-oxazolyl
—CH 2 —
—NHCO—
CH
1013
H
H
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1014
—OEt
H
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1015
H
Ph
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1016
—OEt
Ph
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1017
H
H
—CH(OH)—
H
—CH 2 —
—NHCO—
CH
1018
—OEt
H
—CH(OH)—
H
—CH 2 —
—NHCO—
CH
1019
H
Ph
—CH(OH)—
H
—CH 2 —
—NHCO—
CH
1020
—OEt
Ph
—CH(OH)—
H
—CH 2 —
—NHCO—
CH
1021
H
H
—CH(OH)—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1022
—OEt
H
—CH(OH)—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1023
H
Ph
—CH(OH)—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1024
—OEt
Ph
—CH(OH)—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1025
H
H
—CH(OH)—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1026
—OEt
H
—CH(OH)—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1027
H
Ph
—CH(OH)—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1028
—OEt
Ph
—CH(OH)—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1029
H
H
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1030
—OEt
H
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1031
H
Ph
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1032
—OEt
Ph
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1033
H
H
—O—
H
—CH 2 —
—NHCO—
CH
1034
—OEt
H
—O—
H
—CH 2 —
—NHCO—
CH
1035
H
Ph
—O—
H
—CH 2 —
—NHCO—
CH
1036
—OEt
Ph
—O—
H
—CH 2 —
—NHCO—
CH
1037
H
H
—O—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1038
—OEt
H
—O—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1039
H
Ph
—O—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1040
—OEt
Ph
—O—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1041
H
H
—O—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1042
—OEt
H
—O—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1043
H
Ph
—O—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1044
—OEt
Ph
—O—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1045
H
H
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1046
—OEt
H
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1047
H
Ph
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1048
—OEt
Ph
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1049
H
H
—N(CH 3 )—
H
—CH 2 —
—NHCO—
CH
1050
—OEt
H
—N(CH 3 )—
H
—CH 2 —
—NHCO—
CH
1051
H
Ph
—N(CH 3 )—
H
—CH 2 —
—NHCO—
CH
1052
—OEt
Ph
—N(CH 3 )—
H
—CH 2 —
—NHCO—
CH
1053
H
H
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1054
—OEt
H
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1055
H
Ph
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1056
—OEt
Ph
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—NHCO—
CH
1057
H
H
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1058
—OEt
H
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1059
H
Ph
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1060
—OEt
Ph
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—NHCO—
CH
1061
H
H
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1062
—OEt
H
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1063
H
Ph
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1064
—OEt
Ph
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
CH
1065
H
H
—SO 2 —
H
—CH 2 —
—CH═CH—
CH
1066
—OEt
H
—SO 2 —
H
—CH 2 —
—CH═CH—
CH
1067
H
Ph
—SO 2 —
H
—CH 2 —
—CH═CH—
CH
1068
—OEt
Ph
—SO 2 —
H
—CH 2 —
—CH═CH—
CH
1069
H
H
—SO 2 —
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1070
—OEt
H
—SO 2 —
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1071
H
Ph
—SO 2 —
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1072
—OEt
Ph
—SO 2 —
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1073
H
H
—SO 2 —
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1074
—OEt
H
—SO 2 —
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1075
H
Ph
—SO 2 —
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1076
—OEt
Ph
—SO 2 —
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1077
H
H
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1078
—OEt
H
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1079
H
Ph
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1080
—OEt
Ph
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1081
H
H
—CH(OH)—
H
—CH 2 —
—CH═CH—
CH
1082
—OEt
H
—CH(OH)—
H
—CH 2 —
—CH═CH—
CH
1083
H
Ph
—CH(OH)—
H
—CH 2 —
—CH═CH—
CH
1084
—OEt
Ph
—CH(OH)—
H
—CH 2 —
—CH═CH—
CH
1085
H
H
—CH(OH)—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1086
—OEt
H
—CH(OH)—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1087
H
Ph
—CH(OH)—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1088
—OEt
Ph
—CH(OH)—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1089
H
H
—CH(OH)—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1090
—OEt
H
—CH(OH)—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1091
H
Ph
—CH(OH)—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1092
—OEt
Ph
—CH(OH)—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1093
H
H
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1094
—OEt
H
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1095
H
Ph
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1096
—OEt
Ph
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1097
H
H
—O—
H
—CH 2 —
—CH═CH—
CH
1098
—OEt
H
—O—
H
—CH 2 —
—CH═CH—
CH
1099
H
Ph
—O—
H
—CH 2 —
—CH═CH—
CH
1100
—OEt
Ph
—O—
H
—CH 2 —
—CH═CH—
CH
1101
H
H
—O—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1102
—OEt
H
—O—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1103
H
Ph
—O—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1104
—OEt
Ph
—O—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1105
H
H
—O—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1106
—OEt
H
—O—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1107
H
Ph
—O—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1108
—OEt
Ph
—O—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1109
H
H
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1110
—OEt
H
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1111
H
Ph
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1112
—OEt
Ph
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1113
H
H
—N(CH 3 )—
H
—CH 2 —
—CH═CH—
CH
1114
—OEt
H
—N(CH 3 )—
H
—CH 2 —
—CH═CH—
CH
1115
H
Ph
—N(CH 3 )—
H
—CH 2 —
—CH═CH—
CH
1116
—OEt
Ph
—N(CH 3 )—
H
—CH 2 —
—CH═CH—
CH
1117
H
H
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1118
—OEt
H
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1119
H
Ph
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1120
—OEt
Ph
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—CH═CH—
CH
1121
H
H
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1122
—OEt
H
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1123
H
Ph
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1124
—OEt
Ph
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—CH═CH—
CH
1125
H
H
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1126
—OEt
H
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1127
H
Ph
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1128
—OEt
Ph
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
CH
1129
H
H
—SO 2 —
H
—CH 2 —
—NHCO—
N
1130
—OEt
H
—SO 2 —
H
—CH 2 —
—NHCO—
N
1131
H
Ph
—SO 2 —
H
—CH 2 —
—NHCO—
N
1132
—OEt
Ph
—SO 2 —
H
—CH 2 —
—NHCO—
N
1133
H
H
—SO 2 —
H
—C(CH 2 CH 2 )—
—NHCO—
N
1134
—OEt
H
—SO 2 —
H
—C(CH 2 CH 2 )—
—NHCO—
N
1135
H
Ph
—SO 2 —
H
—C(CH 2 CH 2 )—
—NHCO—
N
1136
—OEt
Ph
—SO 2 —
H
—C(CH 2 CH 2 )—
—NHCO—
N
1137
H
H
—SO 2 —
4-oxazolyl
—CH 2 —
—NHCO—
N
1138
—OEt
H
—SO 2 —
4-oxazolyl
—CH 2 —
—NHCO—
N
1139
H
Ph
—SO 2 —
4-oxazolyl
—CH 2 —
—NHCO—
N
1140
—OEt
Ph
—SO 2 —
4-oxazolyl
—CH 2 —
—NHCO—
N
1141
H
H
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1142
—OEt
H
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1143
H
Ph
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1144
—OEt
Ph
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1145
H
H
—CH(OH)—
H
—CH 2 —
—NHCO—
N
1146
—OEt
H
—CH(OH)—
H
—CH 2 —
—NHCO—
N
1147
H
Ph
—CH(OH)—
H
—CH 2 —
—NHCO—
N
1148
—OEt
Ph
—CH(OH)—
H
—CH 2 —
—NHCO—
N
1149
H
H
—CH(OH)—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1150
—OEt
H
—CH(OH)—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1151
H
Ph
—CH(OH)—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1152
—OEt
Ph
—CH(OH)—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1153
H
H
—CH(OH)—
4-oxazolyl
—CH 2 —
—NHCO—
N
1154
—OEt
H
—CH(OH)—
4-oxazolyl
—CH 2 —
—NHCO—
N
1155
H
Ph
—CH(OH)—
4-oxazolyl
—CH 2 —
—NHCO—
N
1156
—OEt
Ph
—CH(OH)—
4-oxazolyl
—CH 2 —
—NHCO—
N
1157
H
H
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1158
—OEt
H
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1159
H
Ph
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1160
—OEt
Ph
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1161
H
H
—O—
H
—CH 2 —
—NHCO—
N
1162
—OEt
H
—O—
H
—CH 2 —
—NHCO—
N
1163
H
Ph
—O—
H
—CH 2 —
—NHCO—
N
1164
—OEt
Ph
—O—
H
—CH 2 —
—NHCO—
N
1165
H
H
—O—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1166
—OEt
H
—O—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1167
H
Ph
—O—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1168
—OEt
Ph
—O—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1169
H
H
—O—
4-oxazolyl
—CH 2 —
—NHCO—
N
1170
—OEt
H
—O—
4-oxazolyl
—CH 2 —
—NHCO—
N
1171
H
Ph
—O—
4-oxazolyl
—CH 2 —
—NHCO—
N
1172
—OEt
Ph
—O—
4-oxazolyl
—CH 2 —
—NHCO—
N
1173
H
H
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1174
—OEt
H
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1175
H
Ph
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1176
—OEt
Ph
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1177
H
H
—N(CH 3 )—
H
—CH 2 —
—NHCO—
N
1178
—OEt
H
—N(CH 3 )—
H
—CH 2 —
—NHCO—
N
1179
H
Ph
—N(CH 3 )—
H
—CH 2 —
—NHCO—
N
1180
—OEt
Ph
—N(CH 3 )—
H
—CH 2 —
—NHCO—
N
1181
H
H
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1182
—OEt
H
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1183
H
Ph
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1184
—OEt
Ph
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—NHCO—
N
1185
H
H
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—NHCO—
N
1186
—OEt
H
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—NHCO—
N
1187
H
Ph
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—NHCO—
N
1188
—OEt
Ph
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—NHCO—
N
1189
H
H
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1190
—OEt
H
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1191
H
Ph
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1192
—OEt
Ph
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—NHCO—
N
1193
H
H
—SO 2 —
H
—CH 2 —
—CH═CH—
N
1194
—OEt
H
—SO 2 —
H
—CH 2 —
—CH═CH—
N
1195
H
Ph
—SO 2 —
H
—CH 2 —
—CH═CH—
N
1196
—OEt
Ph
—SO 2 —
H
—CH 2 —
—CH═CH—
N
1197
H
H
—SO 2 —
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1198
—OEt
H
—SO 2 —
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1199
H
Ph
—SO 2 —
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1200
—OEt
Ph
—SO 2 —
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1201
H
H
—SO 2 —
4-oxazolyl
—CH 2 —
—CH═CH—
N
1202
—OEt
H
—SO 2 —
4-oxazolyl
—CH 2 —
—CH═CH—
N
1203
H
Ph
—SO 2 —
4-oxazolyl
—CH 2 —
—CH═CH—
N
1204
—OEt
Ph
—SO 2 —
4-oxazolyl
—CH 2 —
—CH═CH—
N
1205
H
H
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1206
—OEt
H
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1207
H
Ph
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1208
—OEt
Ph
—SO 2 —
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1209
H
H
—CH(OH)—
H
—CH 2 —
—CH═CH—
N
1210
—OEt
H
—CH(OH)—
H
—CH 2 —
—CH═CH—
N
1211
H
Ph
—CH(OH)—
H
—CH 2 —
—CH═CH—
N
1212
—OEt
Ph
—CH(OH)—
H
—CH 2 —
—CH═CH—
N
1213
H
H
—CH(OH)—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1214
—OEt
H
—CH(OH)—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1215
H
Ph
—CH(OH)—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1216
—OEt
Ph
—CH(OH)—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1217
H
H
—CH(OH)—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1218
—OEt
H
—CH(OH)—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1219
H
Ph
—CH(OH)—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1220
—OEt
Ph
—CH(OH)—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1221
H
H
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1222
—OEt
H
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1223
H
Ph
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1224
—OEt
Ph
—CH(OH)—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1225
H
H
—O—
H
—CH 2 —
—CH═CH—
N
1226
—OEt
H
—O—
H
—CH 2 —
—CH═CH—
N
1227
H
Ph
—O—
H
—CH 2 —
—CH═CH—
N
1228
—OEt
Ph
—O—
H
—CH 2 —
—CH═CH—
N
1229
H
H
—O—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1230
—OEt
H
—O—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1231
H
Ph
—O—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1232
—OEt
Ph
—O—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1233
H
H
—O—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1234
—OEt
H
—O—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1235
H
Ph
—O—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1236
—OEt
Ph
—O—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1237
H
H
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1238
—OEt
H
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1239
H
Ph
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1240
—OEt
Ph
—O—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1241
H
H
—N(CH 3 )—
H
—CH 2 —
—CH═CH—
N
1242
—OEt
H
—N(CH 3 )—
H
—CH 2 —
—CH═CH—
N
1243
H
Ph
—N(CH 3 )—
H
—CH 2 —
—CH═CH—
N
1244
—OEt
Ph
—N(CH 3 )—
H
—CH 2 —
—CH═CH—
N
1245
H
H
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1246
—OEt
H
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1247
H
Ph
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1248
—OEt
Ph
—N(CH 3 )—
H
—C(CH 2 CH 2 )—
—CH═CH—
N
1249
H
H
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1250
—OEt
H
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1251
H
Ph
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1252
—OEt
Ph
—N(CH 3 )—
4-oxazolyl
—CH 2 —
—CH═CH—
N
1253
H
H
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1254
—OEt
H
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1255
H
Ph
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
1256
—OEt
Ph
—N(CH 3 )—
4-oxazolyl
—C(CH 2 CH 2 )—
—CH═CH—
N
5 . The p38α MAPK inhibitor compound of claim 2 , wherein the compound has Formula 1033:
6 . (canceled)
7 . A pharmaceutical composition for the treatment or prevention of a disease alleviated by inhibiting p38α MAPK activity in a patient in need thereof, comprising:
a therapeutically effective amount of a p38α MAPK inhibitor compound of claim 2 , or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; and
a physiologically compatible carrier medium;
wherein the p38α MAPK inhibitor is a compound capable of binding to a pocket near the ED substrate-docking site of p38α MAPK and defined at least by residues R49, H107, L108, and K165 in p38α MAPK.
8 . The pharmaceutical composition of claim 7 , wherein the disease is cancer or an inflammatory disease.
9 . The pharmaceutical composition of claim 7 , wherein the disease is selected from the group consisting of rheumatoid arthritis, a cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI).
10 . The pharmaceutical composition of claim 8 , wherein the cancer is selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, throat cancer, uterine cancer, Wilm's tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia.
11 - 26 . (canceled)
27 . A method of treating or preventing a disease alleviated by inhibiting the p38α MAPK protein in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a p38α MAPK inhibitor, wherein the p38α MAPK inhibitor is a compound capable of binding to a pocket near the ED substrate-docking site of p38α MAPK, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
28 . The method of claim 27 , wherein the binding pocket is defined at least by residues R49, H107, L108, and K165 in p38α MAPK.
29 . The method of claim 27 , wherein the binding pocket is defined by residues R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 in p38α MAPK.
30 . The method of claim 27 , wherein the p38α MAPK inhibitor is a compound of Formula 1 or Formula 2, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
wherein in Formula 1 and Formula 2,
Q is —CH— or N;
each of R 1 , R 2 , R 3 , and R 4 is independently hydrogen or optionally substituted alkyl, alkoxy, aryl, or heteroaryl;
R 5 is —SO 2 —, —CH(OH)—, —O—, or —N(CH 3 )—;
each of R 10 and R 10′ is independently —OH, —NH 2 , or —SH;
L 1 is —CH 2 —, —C(CH 3 ) 2 — or —C(CH 2 CH 2 )—;
each of L 2 and L 3 is independently —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —;
each of L 4 , L 5 , and L 5′ is independently —NHCO—, —CONH—, —SO 2 NH—, —NHSO 2 —, or —CH═CH—;
each of L 6 and L 6′ is independently an optionally substituted C 1 -C 6 alkyl chain; and
Ar 1 is an optionally substituted aryl or heteroaryl ring.
31 . The method of claim 27 , wherein the p38α MAPK inhibitor is a compound of Formula 11, Formula 12, Formula 13, or Formula 14, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
wherein in Formula 11, Formula 12, Formula 13, and Formula 14,
Q is —CH— or N;
each of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 is independently hydrogen or optionally substituted alkyl, alkoxy, aryl, or heteroaryl;
R 5 is —SO 2 —, —CH(OH)—, —O—, or —N(CH 3 )—;
L 1 is —CH 2 —, —C(CH 3 ) 2 , or —C(CH 2 CH 2 )—;
each of L 2 and L 3 is independently —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —;
L 4 is —NHCO—, —CONH—, —SO 2 NH—, —NHSO 2 —, or —CH═CH—;
Ar 1 is an optionally substituted aryl or heteroaryl ring; and
X is a halogen.
32 . The method of claim 27 , wherein the p38α MAPK inhibitor is a compound of Formulas 1001 to 1256, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
33 . The method of claim 27 , wherein the p38α MAPK inhibitor is a compound of Formula UM101, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
34 . The method of claim 27 , wherein the p38α MAPK inhibitor is a compound of Formula UM60, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
35 . The method of claim 27 , wherein the p38α MAPK inhibitor is a p38α MAPK selective inhibitor.
36 - 37 . (canceled)
38 . The method of claim 27 , wherein the disease is cancer or an inflammatory disease.
39 . The method of claim 27 , wherein the disease is selected from the group consisting of rheumatoid arthritis, a cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, throat cancer, uterine cancer, Wilm's tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia.
40 . (canceled)
41 . The method of claim 27 , wherein the p38α MAPK inhibitor is a compound of Formula 1033, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:Join the waitlist — get patent alerts
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