IP Library › Granted Patent US 10,766,919

Granted Patent B2

US 10,766,919 · App. 15/886,578 · Granted Sep 8, 2020

Cyclic di-nucleotide compounds as sting agonists

Inventors: Michael D. Altman (Needham, MA); Brian Andresen (Sharon, MA); Wonsuk Chang (Princeton, NJ); Matthew Lloyd Childers (Medfield, MA); Jared N. Cumming (Winchester, MA); Andrew Marc Haidle (Somerville, MA); Timothy J. Henderson (Natick, MA); James P. Jewell (Newton, MA); Rui Liang (East Brunswick, NJ); Jongwon Lim (Lexington, MA); Hong Liu (Kenilworth, NJ); Min Lu (Brookline, MA); Alan B. Northrup (Belmont, CA); Ryan D. Otte (Natick, MA); Tony Siu (Brookline, MA); Benjamin Wesley Trotter (Medfield, MA); Quang T. Truong (Morganville, NJ); Shawn P. Walsh (Bridgewater, NJ); Kake Zhao (Westfield, NJ)

Assignee: Merck Sharp & Dohme Corp.

C07H21/04 A61K39/39 A61P35/00 C07H19/20 C07H19/23 C07H21/00 C07H21/02 A61K31/706 A61K31/708 A61K31/7064 A61K31/7076 A61K31/7084

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Quick Facts

Patent No.: US 10,766,919
App. No.: 15/886,578
Granted: Sep 8, 2020
Kind: B2

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Abstract

A class of polycyclic compounds of general formula (I), of general formula (I′), or of general formula (I″), wherein Base 1 , Base 2 , Y, Y 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 , and R 8a 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.

Claims (165)

1. A method of inducing e-STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I′) to the subject, wherein the compound of formula (I′) is:

or a pharmaceutically acceptable salt thereof, wherein

Base 1 and Base 2 are each independently selected from the group consisting of

where 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 OR 9 , SR 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 2 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, NH 2 , 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, NR 9 R 9 , 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 6a 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, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, or —O—C 2 -C 6 alkynylene, such that where R 1a and R 3 are connected to form —O—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 3 position;

optionally R 2a and R 3 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, or —O—C 2 -C 6 alkynylene, such that where R 2a and R 3 are connected to form —O—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 3 position;

optionally R 3 and R 6a 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 3 and R 6a are connected to form —O—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 3 position;

optionally R 4 and R 5 are connected to form are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, or —O—C 2 -C 6 alkynylene, such that where R 4 and R 5 are connected to form —O—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 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 —O—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, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; and

optionally R 7a and R 8a are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; and

with the provisos that

(a) when Y and Y a are each O, X a and X a1 are each O, X b and X b1 are each O, and X c and X c1 are each OH or SH, X d and X d1 are each O, R 1 and R 1a are each H, R 2 is H, 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 Base 1 and Base 2 are each selected from the group consisting of

then R 5 and R 3 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

2. 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

Base 1 and Base 2 are each independently selected from the group consisting of

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 OR 9 , SR 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 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, NR 9 R 9 , and N 3 ;

each R 9 is independently selected from the group consisting of H, C 1 -C 20 alkyl,

optionally R 7 and R 8 are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; and

optionally R 7a and R 8a are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; and

then R 5 and R 3 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

3. The method according to claim 1 , 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 OR 9 , SR 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, 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 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, 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 F, Cl, Br, I, OH, CN, and N 3 ;

R 4 and R 4a are each independently selected from the group consisting of H, 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 F, Cl, Br, I, OH, CN, and N 3 ;

R 5 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , 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, NR 9 R 9 , and N 3 ;

R 3 and R 5 are not both selected from the group consisting of OH, C 1 -C 6 alkyl substituted with OH, and C 1 -C 6 haloalkyl substituted with OH;

R 6 and R 6a are each independently selected from the group consisting of H, F, Cl, Br, I, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 haloalkyl, where said R 6 and R 6a 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 7 and R 7a are each H;

R 8 and R 8a are each H;

each R 9 is independently selected from the group consisting of H, C 2 -C 3 alkyl,

where each R 9 C 2 -C 3 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 6a are connected to form —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, and —O—C 2 -C 6 alkynylene, such that where R 3 and R 6a are connected to form —O—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 3 position; and

optionally R 4 and R 5 are connected by C 1 -C 6 alkylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, or —O—C 2 -C 6 alkynylene, such that where R 4 and R 5 are connected to form —O—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.

4. The method according to claim 1 , wherein the compound of formula (I) is a compound of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein

Base 1 and Base 2 are each independently selected from the group consisting of

X c and X c1 are each independently selected from the group consisting of OR 9 , SR 9 , and NR 9 R 9 ;

R 1a 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 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 2a 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 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 F, Cl, Br, I, and OH;

R 5 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH 2 , 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, and OH;

R 3 and R 5 are not both selected from the group consisting of OH, C 1 -C 6 alkyl substituted with OH, and C 1 -C 6 haloalkyl substituted with OH;

R 6a is selected from the group consisting of H, F, Cl, Br, I, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;

each R 9 is independently selected from the group consisting of H, C 2 -C 3 alkyl,

5. The method according to claim 1 , wherein the compound of formula (I′) is a compound of formula (I′c):

or a pharmaceutically acceptable salt thereof, wherein

Base 1 and Base 2 are each independently selected from the group consisting of

X c and X c1 are each independently selected from the group consisting of OR 9 , SR 9 , and NR 9 R 9 ;

R 4 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 4 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, and OH;

R 6a 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 6 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, and OH;

each R 9 is independently selected from the group consisting of H, C 2 -C 3 alkyl,

6. 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

Base 1 and Base 2 are each independently selected from the group consisting of

Y is selected from the group consisting of —O— and —S—;

X c and X c1 are each independently selected from the group consisting of OR 9 and SR 9 ;

X d and X d1 are each independently selected from the group consisting of O and S;

R 2a 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;

R 4 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;

R 6a 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;

each R 9 is independently selected from the group consisting of H, C 1 -C 20 alkyl,

with the provisos that

then R 5 and R 3 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.

7. The method according to claim 6 , wherein the compound of formula (I″) is a compound of formula (I″a):

or a pharmaceutically acceptable salt thereof, wherein

Base 1 and Base 2 are each independently selected from the group consisting of

Y is selected from the group consisting of —O— and —S—;

X c and X c1 are each independently selected from the group consisting of OR 9 and SR 9 ;

X d and X d1 are each independently selected from the group consisting of O and S;

each R 9 is independently selected from the group consisting of H, C 1 -C 20 alkyl,

8. The method according to claim 7 , wherein

Base 1 and Base 2 are each independently selected from the group consisting of

Y is selected from the group consisting of —O— and —S—;

X c and X c1 are each independently selected from the group consisting of OR 9 and SR 9 ;

X d and X d1 are each independently selected from the group consisting of O and S;

R 2a is F;

each R 9 is independently H.

9. The method according to claim 6 , wherein R 3 and R 6a 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 3 and R 6a are connected to form —O—C 2 -C 6 alkylene, —O—C 2 -C 6 alkenylene, or —O—C 2 -C 6 alkynylene, said O is bound at the R 3 position.

10. The method according to claim 6 , wherein the compound of formula (I″) is a compound of formula (I″b):

or a pharmaceutically acceptable salt thereof, wherein

Base 1 and Base 2 are each independently selected from the group consisting of

Y is selected from the group consisting of —O— and —S—;

X c and X c1 are each independently selected from the group consisting of OR 9 and SR 9 ;

X d and X d1 are each independently selected from the group consisting of O and S;

each R 9 is independently H; and

R 3 and R 6a 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 3 and R 6a are connected to form —O—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 3 position.

11. The method according to claim 10 , wherein Base 1 and Base 2 are each independently selected from the group consisting of

12. The method according to claim 6 , wherein at least one of Base 1 and Base 2 are each independently selected from the group consisting of

13. A method of inducing STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective amount of a compound to the subject, wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

14. The method according to claim 13 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

15. The method according to claim 13 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

Assignments (2)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 6, 2018

From: ALTMAN, MICHAEL D.; ANDRESEN, BRIAN; CHANG, WONSUK; CUMMING, JARED N.; HAIDLE, ANDREW MARC; HENDERSON, TIMOTHY J.; JEWELL, JAMES P.; LIANG, RUI; LIM, JONGWON; LU, MIN; OTTE, RYAN D.; SIU, TONY; TROTTER, BENJAMIN WESLEY; CHILDERS, MATTHEW LLOYD; LIU, HONG; NORTHRUP, ALAN B.; TRUONG, QUANG T.; WALSH, SHAWN P.; ZHAO, KAKE

To: MERCK SHARP & DOHME CORP.

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Continuity (5)

Continuation 15234182 · Aug 11, 2016

Provisional Application 62356125 · Jun 29, 2016

Provisional Application 62268723 · Dec 17, 2015

Provisional Application 62204677 · Aug 13, 2015

Related Publication 20180237469A1 · Aug 23, 2018

Cited By (1)

US 12,311,030