Aza-benzothiophene compounds as STING agonists
Compounds of general formula (I), and their pharmaceutically acceptable salts, wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , R 9 , A, X 1 , X 2 , and X 3 are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are compositions comprising such compounds, processes for the synthesis of such compounds, and to uses of such compounds, including administration of such compounds to induce immune response, to induce STING-dependent type I interferon production, and/or to treat a cell proliferation disorder, such as cancer.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
each A-R 1 is selected independently from the group consisting of C—R 1 and N, and
is selected from the group consisting of
each R 1 is selected independently from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
R 2 is selected from the group consisting of halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 3 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
optionally R 3 and an adjacent A-R 1 may be taken together with the atoms to which they are attached form a fused 5- or 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ) wherein said heterocyclic ring is optionally substituted with or more members of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
each R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, wherein said C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl are optionally substituted with OH, O(C 1 -C 3 alkyl), and O(C 1 -C 3 haloalkyl);
X 1 is selected from the group consisting of CH 2 and C(O);
X 2 is (C(R 8 ) 2 ) (1-3) ;
each R 8 is independently selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring;
optionally 2 R 8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3- to 6-membered spirocycle;
X 3 is selected from the group consisting of COOR 6 ,
C(O)SR 6 , C(S)OR 6 , SO 2 R 6 , and C(O)N(R 9 ) 2 ; and
each R 9 is independently selected from the group consisting of H, COOR 6 , and SO 2 R 6 .
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is selected independently from the group consisting of H, F, Cl, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is selected independently from the group consisting of H and F.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of halogen, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, C 2 -C 3 alkenyl, and N(R 6 ) 2 .
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of Br, Cl, CH═CH 2 , OCH 3 , and N(R 6 ) 2 .
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, C 2 -C 3 alkenyl, and N(R 6 ) 2 .
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of Br, Cl, CH 3 , CH 2 CH 3 , CH═CH 2 , OCH 3 , and N(R 6 ) 2 .
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of,
each R 1 is selected independently from the group consisting of H, F, Cl, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl;
R 2 is selected from the group consisting of halogen, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, C 2 -C 3 alkenyl, and N(R 6 ) 2 ;
R 3 is selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, C 2 -C 3 alkenyl, and N(R 6 ) 2 ;
X 1 -X 2 -X 3 is selected from the group consisting of C(O)—CH 2 CHR 8 —COOR 6 , C(O)—CH 2 CHR 8 —SO 2 R 6 , and C(O)—CH 2 CHR 8 —C(O)N(R 9 ) 2 ;
each R 6 is independently selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and
each R 8 is selected from the group consisting of H, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by OH, C 1 -C 3 alkyl substituted by OC 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of,
each R 1 is selected from the group consisting of H and F;
R 2 is selected from the group consisting of Br, Cl, CH═CH 2 , OCH 3 , and N(R 6 ) 2 ;
R 3 is selected from the group consisting of Br, Cl, CH 3 , CH 2 CH 3 , CH═CH 2 , OCH 3 , and N(R 6 ) 2 ;
X 1 -X 2 -X 3 is C(O)—CH 2 CHR 8 —COOH;
each R 6 is independently selected from the group consisting of H and CH 3 ;
R 8 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 OCH 3 , and cyclopropyl.
11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of,
R 2 is selected from the group consisting of Br, Cl, CH═CH 2 , OCH 3 , and N(R 6 ) 2 ;
R 3 is selected from the group consisting of Br, Cl, CH 3 , CH 2 CH 3 , CH═CH 2 , OCH 3 , and N(R 6 ) 2 ;
X 1 -X 2 -X 3 is C(O)—CH 2 CHR 8 —COOH;
each R 6 is independently selected from the group consisting of H and CH 3 ;
R 8 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 OCH 3 , and cyclopropyl.
12. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition, said pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method of inducing an immune response in a patient in need of therapy, said method comprising:
administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the patient.
15. A method of inducing an immune response in a patient in need of therapy, said method comprising:
administering a therapeutically effective amount of a pharmaceutical composition according to claim 13 to the patient.
16. A method of inducing STING-dependent type I interferon production in a patient in need of therapy, said method comprising administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the patient.
17. A method of inducing STING-dependent type I interferon production in a patient in need of therapy, said method comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim 13 to the patient.
18. A method of treating a cell proliferation disorder in a patient in need of therapy, said method comprising administering a therapeutically effective amount of a compound according claim 1 , or a pharmaceutically acceptable salt thereof, to the patient.
19. The method of claim 18 , wherein the cell proliferation disorder is cancer.
20. A method of treating a cell proliferation disorder in a patient in need of therapy, said method comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim 13 to the patient.
21. The method of claim 20 , wherein the cell proliferation disorder is cancer.