Sting antagonists and uses thereof
The present disclosure provides compounds of Formula (I) a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, for use in, e.g. treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
1 . A compound represented by structural formula (I-B-1) or (I-B-2):
a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein
A 1 is CH or N;
R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, —(CH 2 ) (0 or 1) —C 3-7 cycloalkyl, —(CH 2 ) (0 or 1) —C 4-7 cycloalkenyl, or —(CH 2 ) (0 or 1) -3-7 membered heterocyclyl, wherein the cycloalkyl, cycloalkenyl, or heterocyclyl represented by R 1 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, oxo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and NR 11 R 12 ;
R 3 is H, halogen, CN, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(O)R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —NR 11 C(O)C 1-6 alkyl, NR 11 R 12 , —P(═O)R 11 R 12 , —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , —O (0 or 1) —C 3-7 cycloalkyl, —O (0 or 1) —C 4-7 cycloalkenyl, —O (0 or 1) -3-7 membered heterocyclyl, —O (0 or 1) -6-10 membered aryl, —O (0 or 1) -5-8 membered heteroaryl, —(CH 2 ) (0 or 1) —C 3-7 cycloalkyl, —(CH 2 ) (0 or 1) —C 4-7 cycloalkenyl, —(CH 2 ) (0 or 1) -3-7 membered heterocyclyl, or —(CH 2 ) (0 or 1) -aryl, wherein the alkyl, alkenyl, alkynyl, aryl, or heteroaryl represented by R 3 or in the group represented by R 3 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —NR 11 R 12 , and —N(R 11 )C(O)OR 12 , wherein the cycloalkyl, cycloalkenyl, or heterocyclyl represented by R 3 or in the group represented by R 3 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, oxo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)OC 1-6 alkyl, and NR 11 R 12 ;
R 4 , R 5 , and R 6 are independently H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, —C(O) R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —NR 11 C(O)C 1-6 alkyl, NR 11 R 12 , —P(═O) R 11 R 12 , —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , —O (0 or 1) —C 3-7 cycloalkyl, —O (0 or 1) —C 4-7 cycloalkenyl, —O (0 or 1) -3-7 membered heterocyclyl, —O (0 or 1) -6-10 membered aryl, —O (0 or 1) -5-8 membered heteroaryl, —(CH 2 ) (0 or 1) —C 3-7 cycloalkyl, —(CH 2 ) (0 or 1) —C 4-7 cycloalkenyl, (CH 2 ) (0 or 1) -3-7 membered heterocyclyl, or —(CH 2 ) (0 or 1) -aryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, or heteroaryl represented by R 4 , R 5 , or R 6 or in the group represented by R 4 , R 5 , or R 6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —NR 11 R 12 , and —N(R 11 )C(O)OR 12 , wherein the cycloalkyl, cycloalkenyl, or heterocyclyl represented by R 4 , R 5 , or R 6 or in the group represented by R 4 , R 5 , or R 6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, oxo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)OC 1-6 alkyl, and NR 11 R 12 ;
wherein at least one of R 3 , R 4 , R 5 , and R 6 is not hydrogen;
R 7 and R 8 are independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; and
each instance of R 11 and R 12 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or —C(O)OC 1-6 alkyl.
2 . The compound of claim 1 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 1 is H, C 1-4 alkyl, —(CH 2 ) (0 or 1) —C 3-4 cycloalkyl, or 3-6 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl represented by R 1 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, and C 1-4 alkyl.
3 . The compound of claim 2 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 7 and R 8 is independently H or halogen.
4 . The compound of claim 3 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 3 and R 5 is independently H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
5 . The compound of claim 4 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 4 is independently H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, —C(O) R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —NR 11 C(O)C 1-6 alkyl, NR 11 R 12 , —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , C 3-7 cycloalkyl, (CH 2 ) (0 or 1) -3-7 membered heterocyclyl, —O (0 or 1) -3-7 membered heterocyclyl, phenyl, or —O (0 or 1) -5-6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl, or heteroaryl represented by R 4 or in the group represented by R 4 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —NR 11 R 12 , and —N(R 11 ) C(O)OR 12 , wherein the cycloalkyl or heterocyclyl represented by R 4 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, oxo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)OC 1-6 alkyl, and NR 11 R 12 .
6 . The compound of claim 5 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 6 is independently H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, —C(O) R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —NR 11 C(O)C 1-6 alkyl, NR 11 R 12 , —P(═O) R 11 R 12 , —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or —O (0 or 1) -5-6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl, or heteroaryl represented by R 6 or in the group represented by R 6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —NR 11 R 12 , and —N(R 11 )C(O)OR 12 , wherein the cycloalkyl or heterocyclyl represented by R 6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, oxo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)OC 1-6 alkyl, and NR 11 R 12 .
7 . The compound of claim 1 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 1 is H, C 1-4 alkyl, (CH 2 ) (0 or 1) —C 3-4 cycloalkyl, or 4-6 membered oxygen-containing heterocyclyl.
8 . The compound of claim 7 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of A 1 is CH.
9 . The compound of claim 8 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 7 and R 8 is independently H or F.
10 . The compound of claim 9 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 3 and R 5 is independently H, F, C 1 , or CF 3 .
11 . The compound of claim 10 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 4 is independently H, halogen, CN, C 1-4 alkyl (optionally substituted with OH or —NR 11 R 12 ), C 1-4 haloalkyl, C 1-4 alkoxy optionally substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkynyl, —C(O)OR 11 , —C(O)NR 11 R 12 , —S(O) 2 R 11 , —(CH 2 ) (0 or 1) -5-6 membered heterocyclyl, —O (0 or 1) -5-6 membered heterocyclyl, or —O-5-6 membered heteroaryl, wherein the heteroaryl in the group represented by R 4 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy, wherein the heterocyclyl represented by R 4 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, oxo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —C(O)OC 1-4 alkyl, and NR 11 R 12 .
12 . The compound of claim 11 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 6 is independently H, halogen, CN, C 1-4 alkyl (optionally substituted with —NR 11 R 12 ), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —C(O)OR 11 , —C(O)NR 11 R 12 , —P(═O) R 11 R 12 , —S(O) 2R 11 , or 5-6 membered heterocyclyl, wherein the heterocyclyl represented by R 6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, oxo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —C(O)OC 1-4 alkyl, and NR 11 R 12 .
13 . The compound of claim 12 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 4 is independently H, halogen, CN, C 1-4 alkyl (optionally substituted with —NR 11 R 12 ), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkynyl, —C(O)NR 11 R 12 , or 5-6 membered oxygen containing heterocyclyl.
14 . The compound of claim 13 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein each instance of R 6 is independently H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, or —C(O)OC 1-4 alkyl.
15 . The compound of claim 1 , wherein the compound is represented by the following structural formula:
a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof.
16 . A pharmaceutical composition comprising an effective amount of the compound of claim 1 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, and a pharmaceutically acceptable carrier.
17 . A method of treating a subject with an autoimmune disease, inflammation-associated disorder or infectious disease, comprising administering to the subject an effective amount of the compound of claim 1 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof, wherein the autoimmune disease, inflammation-associated disorder or infectious disease is associated with increased STING signaling.
18 . A method of treating a subject with cancer associated with increased STING signaling, comprising administering to the subject an effective amount of the compound of claim 1 , a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof.
19 . A compound, wherein the compound is
or a pharmaceutically acceptable salt thereof.
20 . A pharmaceutical composition comprising an effective amount of the compound of claim 19 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.