Benzothiophene compound, preparation method therefor and use thereof
A compound represented by formula (I) or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotope labeled compound, a metabolite or a prodrug thereof, a pharmaceutical composition and a pill container comprising same, a preparation method therefor, and the use thereof in the preparation of drugs for preventing or treating STING-mediated related diseases.
1. A compound of formula (I):
wherein
both X 1 and X 3 are —O—;
X 2 is C 1-6 alkylene, wherein the C 1-6 alkylene, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
L 1 is —(C(R 8 ) 2 ) p —;
L 2 is —C(O)—;
L 3 is —(C(R 9 ) 2 ) q —;
A 1 is —C(O)—OR a ;
R 1 and R 4 are H;
R 2 and R 3 are the same or different, and are each independently selected from the group consisting of H, halogen, cyano, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NR a R b , —C(O)—NR a R b , —NR a —C(O)—R a , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, hydroxy and C 1-6 alkoxy;
R 5 is selected from the group consisting of H, C 1-6 alkyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —NR a R b , —CO 2 R a and —S(O) 2 R a ;
R 6 is OR a or —C(O) 2 R 7 ;
R 7 is selected from the group consisting of H and C 1-6 alkyl;
R 8 is each independently selected from the group consisting of H and C 1-6 alkyl;
R 9 is each independently selected from the group consisting of H and C 1-6 alkyl;
R a and R b are each independently selected from the group consisting of H and C 1-6 alkyl wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen and C 1-6 alkyl;
m and n are each independently selected from the group consisting of 0, 1, 2 and 3; and
p and q are each independently selected from the group consisting of 1, 2, and 3,
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
2. The compound according to claim 1 , wherein
X 2 is unsubstituted C 1-4 alkylene;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
3. The compound according to claim 1 , wherein
L 1 is —(CH 2 ) 2 —,
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
4. The compound according to claim 1 , wherein
L 3 is —CH 2 , —(CH 2 ) 2 — or —(CH 2 ) 3 —,
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
5. The compound according to claim 1 , wherein
A 1 is selected from the group consisting of —C(O)—OH and —C(O)—O—(CH 2 CH 3 ),
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
6. The compound according to claim 1 , wherein
R 2 and R 3 are the same or different, and are each independently selected from the group consisting of H, halogen and —OR a ;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
7. The compound according to claim 1 , wherein
R 5 is selected from the group consisting of H, C 1-6 alkyl, and C 3-6 cycloalkyl;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
8. The compound according to claim 1 , wherein
R 6 is selected from the group consisting of —O(C 1-6 alkyl), —C(O) 2 H and —C(O) 2 —(C 1-6 alkyl);
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
9. The compound according to claim 1 , wherein
m and n are each independently selected from the group consisting of 0 and 1;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
10. The compound according to claim 1 , wherein the compound has a structure of formula (III):
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
11. The compound according to claim 10 , wherein the compound has a structure of formula (III-1):
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
12. The compound according to claim 10 , wherein the compound has a structure of formula (IV):
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
13. The compound according to claim 2 , wherein
X 2 is propylene;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
14. The compound according to claim 6 , wherein
R 2 and R 3 are the same or different, and are each independently selected from the group consisting of —OH and —O(C 1-6 alkyl), wherein the C 1-6 alkyl in the —O(C 1-6 alkyl) is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C 1-6 alkyl;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
15. The compound according to claim 14 , wherein
R 2 and R 3 are the same or different, and are each independently selected from the group consisting of methoxy, 2-hydroxy-2-methylpropoxy and 3-hydroxy-3-methylbutoxy;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
16. The compound according to claim 7 , wherein
R 5 is C 1-6 alkyl;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
17. The compound according to claim 16 , wherein
R 5 is methyl;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
18. The compound according to claim 8 , wherein
R 6 is selected from the group consisting of methoxy, —C(O) 2 H and —C(O) 2 —(CH 2 CH 3 );
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
19. The compound according to claim 9 , wherein
both m and n are 1;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
20. The compound according to claim 1 , wherein the compound has a structure selected from the group consisting of:
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
21. A pharmaceutical composition, comprising a prophylactically or therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof, and one or more pharmaceutically acceptable carriers.
22. A pharmaceutical composition, comprising a prophylactically or therapeutically effective amount of the compound according to claim 10 , or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof, and one or more pharmaceutically acceptable carriers.
23. A pharmaceutical composition, comprising a prophylactically or therapeutically effective amount of the compound according to claim 20 , or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof, and one or more pharmaceutically acceptable carriers.
24. A kit, comprising the compound according to claim 1 , or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
25. A method for preparing the compound according to claim 10 , comprising the following steps:
wherein
L 3 , R 2 , R 3 , R 5 , R 6 , X 2 , m and n are as defined in claim 14 ;
R a is C 1-6 alkyl; and
LG represents a leaving group, wherein the leaving group includes, but is not limited to, a halogen atom, methanesulfonyloxy, p-toluenesulfonyloxy, and the like.
26. A method for preparing the compound according to claim 11 , comprising the following steps:
wherein
L 3 , R 2 , R 3 , R 5 , R 6 , X 2 , m and n are as defined in claim 11 ; and
R a is C 1-6 alkyl.
27. A method for the prophylaxis or treatment of a STING-mediated disease, comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, or an isotope-labeled compound thereof.
28. The method of claim 27 , wherein the compound is administered via an oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal route.
29. The method of claim 27 , wherein the STING-mediated disease is a tumor.