Cyclic di-nucleotide compounds as sting agonists

A method of inducing STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject, wherein said pharmaceutical composition comprises (a) a compound of formula (I′);

• and (b) a pharmaceutically acceptable carrier:
• wherein the compound of formula (I′) is:
• or a pharmaceutically acceptable salt thereof, wherein
• Base1 and Base2 are each independently selected from the group consisting of
• where Base1 and Base2 each may be independently substituted by 0-3 substituents R10, where each R10 is independently selected from the group consisting of F, Cl, I, Br, OH, SH, NH2, C1-3 alkyl, C3-6 cycloalkyl, O(C1-3 alkyl), O(C3-6 cycloalkyl), S(C1-3 alkyl), S(C3-6 cycloalkyl), NH(C1-3 alkyl), NH(C3-6 cycloalkyl), N(C1-3 alkyl)2, and N(C3-6 cycloalkyl)2;
• Y and Ya are each independently selected from the group consisting of —O— and —S—;
• Xa and Xa1 are each independently selected from the group consisting of O, and S;
• Xb and Xb1 are each independently selected from the group consisting of O, and S;
• Xc and Xc1 are each independently selected from the group consisting of OR9, SR9, and NR9R9;
• Xd and Xd1 are each independently selected from the group consisting of O and S;
• R1 and R1a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl, where said R1 and R1a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N3;
• R2 and R2a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl, where said R2 and R2a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N3;
• R3 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl, where said R3 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N3;
• R4 and R4a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl, where said R4 and R4a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N3;
• R5 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl, where said R5 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, NR9R9, and N3;
• R6 and R6a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl, where said R6 and R6a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N3;
• R7 and R7a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl, where said R7 and R7a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N3;
• R8 and R8a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl, where said R8 and R8a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl are substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, CN, and N3;
• each R9 is independently selected from the group consisting of H, C1-C20 alkyl,
• where each R9 C1-C20 alkyl is optionally substituted by 0 to 3 substituents independently selected from the group consisting of OH, —O—C1-C20 alkyl, —S—C(O)C1-C6 alkyl, and C(O)OC1-C6 alkyl;
• optionally R1a and R3 are connected to form C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, such that where R1a and R3 are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, said O is bound at the R3 position;
• optionally R2a and R3 are connected to form C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, such that where R2a and R3 are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, said O is bound at the R3 position;
• optionally R3 and R6a are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, such that where R3 and R6a are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, said O is bound at the R3 position;
• optionally R4 and R5 are connected to form are connected to form C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, such that where R4 and R5 are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, said O is bound at the R5 position;
• optionally R5 and R6 are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, such that where R5 and R6 are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, said O is bound at the R5 position;
• optionally R7 and R8 are connected to form C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene;
• and
• optionally R7a and R8a are connected to form C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene;
• and
• (a) when Y and Ya are each O, Xa and Xa1 are each O, Xb and Xb1 are each O, and Xc and Xc1 are each OH or SH, Xd and Xd1 are each O, R1 and R1a are each H, R2 is H, R6 and R6a are each H, R7 and R7a are each H, R8 and R8a are each H, and Base1 and Base2 are each selected from the group consisting of
• then R5 and R3 are not both selected from the group consisting of H, F and OH;
• and
• (b) the compound is not selected from the group consisting of

A method of inducing STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective amount of a compound of formula (I″) to the subject, wherein the compound of formula (I″) is:

• or a pharmaceutically acceptable salt thereof, wherein
• Base1 and Base2 are each independently selected from the group consisting of
• Y is selected from the group consisting of —O— and —S—;
• Xc and Xc1 are each independently selected from the group consisting of OR9 and SR9;
• Xd and Xd1 are each independently selected from the group consisting of O and S;
• R2a is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl;
• R3 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl;
• R4 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl;
• R5 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH2, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl;
• R6a is selected from the group consisting of H, F, Cl, Br, I, OH, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, —O—C1-C6 alkyl, —O—C2-C6 alkenyl, and —O—C2-C6 alkynyl;
• each R9 is independently selected from the group consisting of H, C1-C20 alkyl,
• where each R9 C1-C20 alkyl is optionally substituted by 0 to 3 substituents independently selected from the group consisting of OH, —O—C1-C20 alkyl, —S—C(O)C1-C6 alkyl, and C(O)OC1-C6 alkyl;
• and
• optionally R3 and R6a are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, such that where R3 and R6a are connected to form —O—C1-C6 alkylene, —O—C2-C6 alkenylene, or —O—C2-C6 alkynylene, said O is bound at the R3 position;
• and
• with the provisos that
• (a) when Y and Ya are each O, Xa and Xa1 are each O, Xb and Xb1 are each O, and Xc and Xc1 are each OH or SH, Xd and Xd1 are each O, R1 and R1a are each H, R2 is H, R6 and R6a are each H, R7 and R7a are each H, R8 and R8a are each H, and Base1 and Base2 are each selected from the group consisting of
• then R5 and R3 are not both selected from the group consisting of H, F and OH;
• and
• (b) the compound is not selected from the group consisting of
• and pharmaceutically acceptable salts thereof.