| 摘要 |
The invention is directed to inhibition of p38-a kinase using compounds of the formula and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein Ar is an aryl group substituted with 0-5 non-interfering substituents, wherein two adjacent noninterfering substituents can form a fused aromatic or nonaromatic ring; L1 and L2 are linkers; X is an aliphatic monocyclic or aliphatic polycyclic moiety optionally comprising one or more hetero ring atoms wherein the cyclic moiety may be optionally substituted with one or more noninterfering substituents and where said optional substituents may constitute a ring fused to X; n is 0-3; each R1 is hydrogen or a noninterfering substituent; represents a single or double bond; one Z2 is CA or CR2A; the other Z2 is CR3, CR32, NR4 or N; and each R2, R3 and R4 is independently hydrogen or a noninterfering substituent; Z3 is NR5 or O; where R5 is hydrogen or a noninterfering substituent; A is -Wi-COXjY, where Y is COR6 or an isostere thereof, each of W and X is a spacer of 2-6 Å; each of i and j is independently 0 or 1; and R6 is a noninterfering substituent; and wherein the smallest number of covalent bonds in the compound separating the atom of Ar linked to L2 and the atom of the alpha ring linked to L1 is at least 5, each said bond having a bond length of 1.2 to 2.0 angstroms; and/or the distance in space between the atom of Ar linked to L2 and the atom of the alpha ring linked to L1 is 4.5-24 angstroms; and with the proviso that the portion of the compound represented by L2-X-L1 is not: where L2 and L1 are linkers; Z1 is CR or N wherein R is hydrogen or a non-interfering substituent; each R1 is independently a non-interfering substituent; and each of l and k is 0-3; and m is 0-4.
|
