Cyclic di-nucleotide compounds as sting agonists
A class of polycyclic compounds of general formula (I), wherein Base 1 , Base 2 , Y, Z a , X a , X a1 , X b , X b1 , X c , X c1 , X d , X d1 , R 1 , R 1a , R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , and R 9 are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
Base 1 and Base 2 are each independently selected from the group consisting of
wherein
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and
Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of —S—, —SO 2 —, —CH 2 —, and —CF 2 —;
X a and X a1 are each independently selected from the group consisting of —O—, —S—, and —CH 2 —;
X b and X b1 are each independently selected from the group consisting of —O—, —S—, and —CH 2 —;
X c and X c1 are each independently selected from the group consisting of —SR 9 , —OR 9 , and —NR 9 R 9 ,
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl, where said R 1 and R 1a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 2 and R 2a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl, where said R 2 and R 2a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl, where said R 3 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 4 and R 4a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl, where said R 4 and R 4a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 5 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl, where said R 5 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 6 and R 6a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl, where said R 6 and R 6′ C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 7 and R 7a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl, where said R 7 and R 7a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 8 and R 8a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl, where said R 8 and R 8a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O—C 1 -C 6 alkyl, —O—C 2 -C 6 alkenyl, and —O—C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
each R 9 is independently selected from the group consisting of H, C 1 -C 20 alkyl,
where each R 9 C 1 -C 20 alkyl is optionally substituted by 0 to 3 substituents independently selected from the group consisting of OH, —O—C 1 -C 20 alkyl, —S—C(O)C 1 -C 6 alkyl, and C(O)OC 1 -C 6 alkyl;
optionally R 1a and R 3 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 1a and R 3 are connected to form —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, said O is bound at the R 3 position;
optionally R 2a and R 3 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 2a and R 3 are connected to form —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, said O is bound at the R 3 position;
optionally R 3 and R 6′ are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 3 and R 6′ are connected to form —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, said O is bound at the R 3 position;
optionally R 4 and R 5 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 4 and R 5 are connected to form —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, said O is bound at the R 5 position;
optionally R 5 and R 6 are connected to form —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, or —O—C 2 -C 6 alkynylene, such that where R 5 and R 6 are connected to form C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, or —O—C 2 -C 6 alkynylene, said O is bound at the R 5 position;
optionally R 7 and R 8 are connected to form C 1 -C 6 alkylene or C 2 -C 6 alkenylene; and
optionally R 7a and R 8a are connected to form C 1 -C 6 alkylene or C 2 -C 6 alkenylene.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Y and Y a are each independently selected from the group consisting of —O— and —S—;
X a and X a1 are each independently selected from the group consisting of —O— and —S—;
X b and X b1 are each independently selected from the group consisting of —O and —S—;
X c and X c1 are each independently selected from the group consisting of —SR 9 , —OR 9 , and —NR 9 R 9 ;
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each H;
R 2 and R 2a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, where said R 2 and R 2a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl are substituted by 0 to 3 substituents selected from the group consisting of OH, CN, and N 3 ;
R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N 3 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, where said R 3 C 1 -C 6 alkyl or C 1 -C 6 haloalkyl are substituted by 0 to 3 substituents selected from the group consisting of OH, CN, and N 3 ;
R 4 and R 4a are each independently selected from the group consisting of H, F, Cl, I, Br, CN, OH, N 3 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, where said R 4 and R 4a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl are substituted by 0 to 3 substituents selected from the group consisting of OH, CN, and N 3 ;
R 5 is selected from the group consisting of H, F, Cl, Br, I, OH, N 3 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, where said R 5 C 1 -C 6 alkyl or C 1 -C 6 haloalkyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 6 and R 6a are each independently selected from the group consisting of H, F, Cl, I, Br, OH, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, where said R 6 and R 6a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N 3 ;
R 7 and R 7a are each independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, where said R 7 and R 7a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl are substituted by 0 to 3 substituents selected from the group consisting of OH, CN, and N 3 ;
R 8 and R 8a are each independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, where said R 7 and R 8a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl are substituted by 0 to 3 substituents selected from the group consisting of OH, CN, and N 3 ;
each R 9 is independently selected from the group consisting of H, C 1 -C 6 alkyl,
where each R 9 C 1 -C 6 alkyl is optionally substituted by 1 to 2 substituents independently selected from the group consisting of OH, —O—C 1 -C 20 alkyl, —S—C(O)C 1 -C 6 alkyl, and —C(O)OC 1 -C 6 alkyl;
optionally R 3 and R 6′ are connected to form C 2 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, said O is bound at the R 3 position; and
optionally R 5 and R 6 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 5 and R 6 are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, said O is bound at the R 5 position.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Base 1 and Base 2 are each independently selected from the group consisting of
wherein
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and
Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of —O— and —S—;
X a and X a1 are each independently selected from the group consisting of —O— and —S—;
X b and X b1 are each independently selected from the group consisting of —O— and —S—;
X c and X c1 are each independently selected from the group consisting of —OH, —SH,
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each H;
R 2 and R 2a are each independently selected from the group consisting of H, F, Cl, I, Br, OH, CN, N 3 , —CF 3 , —CH 3 , —CH 2 OH, and —CH 2 CH 3 ;
R 3 is selected from the group consisting of H, F, Cl, I, Br, OH, CN, N 3 , —CF 3 , —CH 3 , —CH 2 OH, and —CH 2 CH 3 ;
R 4 and R 4a are each independently selected from the group consisting of H, F, Cl, I, Br, OH, CN, N 3 , —CF 3 , —CH 3 , —CH 2 OH, and —CH 2 CH 3 ;
R 5 is selected from the group consisting of H, F, Cl, I, Br, OH, CN, N 3 , —CF 3 , —CH 3 , —CH 2 OH, and —CH 2 CH 3 ;
R 6 and R 6a are each independently selected from the group consisting of H, F, Cl, I, Br, OH, CN, N 3 , —CF 3 , —CH 3 , —CH 2 OH, —CH 2 CH 3 , —CH═CH 2 , —C≡CH, and —C≡C—CH;
R 7 and R 7a are each independently selected from the group consisting of H, —CF 3 , —CH 3 , and —CH 2 CH 3 ;
R 8 and R 8a are each independently selected from the group consisting of H, —CF 3 , —CH 3 , and —CH 2 CH 3 ;
optionally R 3 and R 6a are connected to C 2 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, said O is bound at the R 3 position; and
optionally R 5 and R 6 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 5 and R 6 are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, said O is bound at the R 5 position.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Base 1 and Base 2 are each independently selected from the group consisting of
wherein
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and
Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of —O— and —S—;
X a and X a1 are each —O—;
X b and X b1 are each —O—;
X c and X c1 are each independently selected from the group consisting of —OH and —SH;
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each H;
R 2 and R 2a are each independently selected from the group consisting of H, F, Cl, OH, CN, N 3 , and —CH 3 ;
R 3 is selected from the group consisting of H, F, Cl, OH, CN, N 3 , and —CH 3 ;
R 4 and R 4a are each independently selected from the group consisting of H, F, Cl, OH, CN, N 3 , and —CH 3 ;
R 5 is selected from the group consisting of H, F, Cl, OH, CN, N 3 , and —CH 3 ;
R 6 and R 6a are each independently selected from the group consisting of H, F, CN, N 3 , —CH 3 , —CH═CH 2 , and —C≡CH;
R 7 and R 7a are each H;
R 8 and R 8a are each H;
optionally R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, such that O is bound at the R 3 position; and
optionally R 5 and R 6 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 5 and R 6 are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, said O is bound at the R 5 position.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Base 1 and Base 2 are each independently selected from the group consisting of
wherein
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and
Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of —O— and —S—;
X a and X a1 are each O;
X b and X b1 are each O;
X c and X c1 are each independently selected from the group consisting of —OH and —SH;
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each H;
R 2 and R 2a are each independently selected from the group consisting of H, F, Cl, OH, CN, N 3 , and —CH 3 ;
R 3 is selected from the group consisting of H, F, Cl, OH, CN, N 3 , and —CH 3 ;
R 4 and R 4a are each independently selected from the group consisting of H, F, Cl, OH, CN, N 3 , and CH 3 ;
R 5 is selected from the group consisting of H, F, Cl, OH, CN, N 3 , and —CH 3 ;
R 6 and R 6a are each independently selected from the group consisting of H, F, CN, N 3 , —CH 3 , —CH═CH 2 , and —C≡CH;
R 7 and R 7a are each H;
R 8 and R 8a are each H;
optionally R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, such that where R 3 and R 6′ are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, said O is bound at the R 3 position; and
optionally R 5 and R 6 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, —O—C 1 -C 6 alkylene, or —O—C 2 -C 6 alkenylene, such that where R 5 and R 6 are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, said O is bound at the R 5 position.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Base 1 and Base 2 are each independently selected from the group consisting of
wherein
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and
Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of —O— and —S—;
X a and X a1 are each —O—;
X b and X b1 are each —O—;
X c and X c1 are each independently selected from the group consisting of —SH and —OH;
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each H;
R 2 and R 2a are each independently selected from the group consisting of H, F, and OH;
R 3 is selected from the group consisting of H, F, and OH;
R 4 and R 4a are each independently selected from the group consisting of H, F, and OH;
R 5 is selected from the group consisting of H, F, and OH;
R 6 and R 6a are each H;
R 7 and R 7a are each H;
R 8 and R 8a are each H; and
optionally R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, such that where R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene or —O—C 2 -C 6 alkenylene, said O is bound at the R 3 position.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Base 1 and Base 2 are each independently selected from the group consisting of
wherein
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and
Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of —O— and —S—;
X a and X a1 are each —O—;
X b and X b1 are each —O—;
X c and X c1 are each independently selected from the group consisting of —SH and —OH;
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each H;
R 2 is H;
R 2a is selected from the group consisting of H, F, and OH;
R 3 is selected from the group consisting of H, F, and OH;
R 4 is selected from the group consisting of H, F, and OH;
R 4a is H;
R 5 is selected from the group consisting of H, F, and OH;
R 6 and R 6a are each H;
R 7 and R 7a are each H;
R 8 and R 8a are each H; and
optionally R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene, such that where R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene, said O is bound at the R 3 position.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Base 1 and Base 2 are each independently selected from the group consisting of
wherein
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and
Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of —O— and —S—;
X a and X a1 are each —O—;
X b and X b1 are each —O—;
X c and X c1 are each independently selected from the group consisting of —SH and —OH;
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each H;
R 2 is H;
R 2a is selected from the group consisting of H, F, and OH;
R 3 is selected from the group consisting of H, F, and OH;
R 4 is selected from the group consisting of H, F, and OH;
R 4a is H;
R 5 is selected from the group consisting of H, F, and OH;
R 6 and R 6a are each H;
R 7 and R 7a are each H; and
R 8 and R 8a are each H.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Base 1 is selected from the group consisting of
Base 2 is selected from the group consisting of
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of —O— and —S—;
X a and X a1 are each —O—;
X b and X b1 are each —O—;
X c and X c1 are each independently selected from the group consisting of —SH and —OH;
X d and X d1 are each independently selected from the group consisting of O and S;
R 7 and R 1a are each H;
R 2 is H;
R 2a is selected from the group consisting of H, F, and OH;
R 3 is selected from the group consisting of H, F, and OH;
R 4 is selected from the group consisting of H, F, and OH;
R 4a is H;
R 5 is selected from the group consisting of H, F, and OH;
R 6 and R 6a are each H;
R 7 and R 7a are each H;
R 8 and R 8a are each H; and
R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene, such that where R 3 and R 6a are connected to form —O—C 1 -C 6 alkylene, said O is bound at the R 3 position.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Base 1 is selected from the group consisting of
Base 2 is selected from the group consisting of
at least one of Base 1 and Base 2 is each independently selected from the group consisting of
and Base 1 and Base 2 each may be independently substituted by 0-3 substituents R 10 , where each R 10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl, O(C 1-3 alkyl), O(C 3-6 cycloalkyl), S(C 1-3 alkyl), S(C 3-6 cycloalkyl), NH(C 1-3 alkyl), NH(C 3-6 cycloalkyl), N(C 1-3 alkyl) 2 , and N(C 3-6 cycloalkyl) 2 ;
Y and Y a are each independently selected from the group consisting of and —S—;
X a and X a1 are each —O—;
X b and X b1 are each —O—;
X c and X c1 are each independently selected from the group consisting of —SH and —OH;
X d and X d1 are each independently selected from the group consisting of O and S;
R 1 and R 1a are each H;
R 2 is H;
R 2a is selected from the group consisting of H, F, and OH;
R 3 is selected from the group consisting of H, F, and OH;
R 4 is selected from the group consisting of H, F, and OH;
R 4a is H;
R 5 is selected from the group consisting of H, F, and OH;
R 6 and R 6a are each H;
R 7 and R 7a are each H; and
R 8 and R 8a are each H.
11. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition, said pharmaceutical composition comprising:
(a) a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and
(b) a pharmaceutically acceptable carrier.
13. A method of inducing an immune response in a subject, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
14. A method of inducing an immune response in a subject, said method comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 12 .
15. A method of inducing a STING-dependent type I interferon production in a subject, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
16. A method of inducing a STING-dependent type I interferon production in a subject, said method comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 12 .
17. A method of treating a cell proliferation disorder in a subject, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein the cell proliferation disorder is cancer.
19. A method of treating a cell proliferation disorder in a subject, said method comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 12 .
20. The method of claim 19 , wherein the cell proliferation disorder is cancer.