Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof
Compounds that inhibit mitogen-activated protein kinases (MAPKs) are disclosed. Some inhibitor compounds specifically target a single MAPK such as MAPK13, while others target multiple MAPKs such as MAPK13 and MAPK12. The compounds can be used therapeutically for a variety of diseases, including cancer and respiratory diseases. Methods of synthesis of the compounds are also disclosed.
1. A compound of Formula I
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is hydrogen or —NH(CO)R 2 ;
R 2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, OR 3 and NR 4 R 4 ;
R 3 is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl;
each R 4 is independently selected from the group consisting of H, alkyl, cycloalkyl and cycloalkylalkyl;
J 1 is —CH 2 — and is substituted at position 4 on the pyridine;
G 1 is thiazole wherein L 1 is CH, L 2 is N and L 3 is S;
Z 1 and Z 2 are each NH;
G 2 is pyrazole, isoxazole, or phenyl;
E 1 is CH or CR 1 when G 2 is phenyl, or E 1 is NR 1 when G 2 is pyrazole, or E 1 is N or O when G 2 is isoxazole;
wherein R 1 is selected from the group consisting of H, C 1-8 alkyl, cycloalkyl, cycloalkylalkyl, and halogen;
E 2 is N when G 2 is pyrazole, E 2 is N or O when G 2 is isoxazole, or E 2 is CH—CH when G 2 is phenyl;
E 3 is C when G 2 is pyrazole, isoxazole, or phenyl;
E 4 is CH when G 2 is pyrazole, isoxazole, or phenyl; and
M 1 is selected from the group consisting of C and Si;
wherein if M 1 is Si, each of M 2 and M 3 is methyl, R 6 is methyl, and X is absent;
wherein if M 1 is C, each of M 2 and M 3 is selected from the group consisting of CH 3 and CH 2 , R 6 is selected from the group consisting of H and C 1-8 alkyl, and X is selected from the group consisting of CH 2 , O and S, or is absent;
wherein if M 1 is C and X is CH 2 , O or S, then M 1 , M 2 , M 3 and X together form a 4-member ring.
2. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the compound is
3. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the compound is
4. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the compound is
R 2 is cycloalkyl.
5. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 4 , wherein R 2 is cyclopropyl.
6. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the compound is