Coumarin-like cyclic compound as MEK inhibitor and use thereof
Disclosed are a class of coumarin-like cyclic compounds as MEK inhibitors and pharmaceutical compositions comprising the compounds, and the use of same in the preparation of a drug for treating MEK-related diseases. Particularly disclosed are compounds as shown in formula (I) and pharmaceutically acceptable salts thereof or tautomers thereof.
1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof or a tautomer thereof:
wherein,
n is selected form 0, 1 or 2;
r is selected from 0, 1, 2 or 3;
m is selected from 0 or 1; when m is 0, then
is H;
ring A is selected from phenyl or 5-6 membered heteroaryl;
L is selected from a single bond, —S(═O)—, —S(═O) 2 —, —C(═O)—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—S(═O) 2 —, —NH—S(═O)— and —NH—C(═O)—NH—, wherein the —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—S(═O) 2 —, —NH—S(═O)— and —NH—C(═O)—NH— are each optionally substituted by 1, 2 or 3 R;
R 1 is selected from H, NH 2 , C 1-6 alkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl and C 1-3 heteroalkyl, wherein the NH 2 , C 1-6 alkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl and C 1-3 heteroalkyl are each optionally substituted by 1, 2 or 3 R;
R 2 is selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 5-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 5-6 membered heterocycloalkyl are each optionally substituted by 1, 2 or 3 R;
R 3 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl and phenyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl and phenyl are each optionally substituted by 1, 2 or 3 R;
R 4 and R 5 are independently selected from H, F, Cl, Br, I, NH 2 , OH, C 1-6 alkyl and C 1-3 alkoxy, wherein the C 1-6 alkyl and C 1-3 alkoxy are each optionally substituted by 1, 2 or 3 R;
R 6 and R 7 are independently selected from H, F, Cl, Br, I, CH 3 , Et, CH 3 —O— and CH 3 —CH 2 —O—;
R is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 heteroalkyl, wherein the NH 2 , C 1-3 alkyl and C 1-3 heteroalkyl are each optionally substituted by 1, 2 or 3 R′;
R′ is selected from F, Cl, Br, I, NH 2 or C 1-3 alkyl;
each of the “hetero” in the 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, and C 1-3 heteroalkyl is independently selected from —NH—, N, —O—, —S(═O) 2 —, —S(═O) 2 —NH—, —NH—S(═O) 2 —NH—, —C(═O)—NH—, —S(═O)—, —C(═O)—, —S(═O)—NH— and —O—C(═O)—NH—;
in any of the above cases, the number of the heteroatom or heteroatomic group is independently selected from 1, 2, 3 or 4.
2. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein R′ is selected from F, Cl, Br, I, NH 2 or CH 3 .
3. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein R is selected from F, Cl, Br, I, OH, NH 2 , methyl, ethyl, C 1-3 alkyl-S(═O) 2 —NH—, C 1-3 alkyl-S(═O) 2 —, C 1-3 alkyl-C(═O)—NH— and C 1-3 alkyl-O—, wherein the NH 2 , methyl, ethyl, C 1-3 alkyl-S(═O) 2 —NH—, C 1-3 alkyl-S(═O) 2 —, C 1-3 alkyl-C(═O)—NH— and C 1-3 alkyl-O— are each optionally substituted by 1, 2 or 3 R′.
4. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 3 , wherein R is selected from F, Cl, Br, I, OH, NH 2 , CH 3 ,
wherein the NH 2 , CH 3 ,
are each optionally substituted by 1, 2 or 3 R′.
5. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 4 , wherein R is selected from F, Cl, Br, I, OH, NH 2 , CH 3 ,
6. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein ring A is selected from phenyl, pyridyl or pyrazinyl.
7. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 6 , wherein ring A is selected from
8. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein L is selected from a single bond, —NH—, —N(CH 3 )—,
9. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein R 1 is selected from H, NH 2 , methyl, ethyl, isobutyl, oxetanyl, morpholinyl, cyclopropyl and CH 3 —O—, wherein the NH 2 , methyl, ethyl, isobutyl, oxetanyl, morpholinyl, cyclopropyl and CH 3 —O— are each optionally substituted by 1, 2 or 3 R.
10. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein R 1 is selected from H, NH 2 , Me, Et,
wherein the NH 2 , Me, Et,
are each optionally substituted by 1, 2 or 3 R.
11. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 10 , wherein R 1 is selected from H, NH 2 , CH 3 , CF 3 , Et,
12. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein R 2 is selected from H, methyl, ethyl, propyl, cyclopropyl and tetrahydropyranyl, wherein the methyl, ethyl, propyl, cyclopropyl and tetrahydropyranyl are each optionally substituted by 1, 2 or 3 R.
13. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 12 , wherein R 2 is selected from H, CH 3 ,
wherein the CH 3 ,
are each optionally substituted by 1, 2 or 3 R.
14. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 13 , wherein R 2 is selected from H, CH 3 ,
15. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein R 3 is selected from H, F, Cl, Br, I, CH 3 , CF 3 or CH 3 —O—.
16. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein R 4 and R 5 are independently selected from H, F, Cl, Br, I, CH 3 , CH 3 CH 2 — and CH 3 —O—.
17. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein the structural unit
is selected from H, CH 3 , NH 2 ,
18. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein the structural unit
is selected from
19. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , which is selected from
wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L, r and n are as defined in claim 1 .
20. A compound, a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein the compound is selected from
21. The compound according to claim 20 , which is selected from
22. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 1 , wherein the salt is selected from hydrochloride or formate.
23. The compound, the pharmaceutically acceptable salt thereof or the tautomer thereof according to claim 22 , wherein the hydrochloride is selected from
24. A pharmaceutical composition comprising a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.