Cyclic di-nucleotide compounds as STING agonists

Patent metadata

Field	Value
Publication number	US-10738074-B2
Application number	US-201615752144-A
Country	US
Kind code	B2
Filing date	Aug 11, 2016
Priority date	Aug 13, 2015
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

A class of polycyclic compounds of general formula (II), of general formula (II′), or of general formula (II″), 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 3a , 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.

First claim

What is claimed is:

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

or a pharmaceutically acceptable salt thereof, wherein
Base 1 and Base 2 are each independently selected from the group consisting of

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—, —S—, —SO 2 —, —CH 2 —, and —CF 2 —;
X a and X a1 are each independently selected from the group consisting of O, CH 2 , and S;
X b and X b1 are each independently selected from the group consisting of O, C, and S;
X c and X c1 are each independently selected from the group consisting of O − , S − , 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 1 -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 3a 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 3a 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 alkynyl, 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 3 -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, 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 1 -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 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 1 -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 3a 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 3a 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 3a position;
optionally R 3a and R 4a 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 3a and R 4a 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 3a 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 th

Assignees

• Merck Sharp & Dohme
• Altman Michael D
• Andresen Brian
• Chang Wonsuk
• Childers Matthew Lloyd
• Cumming Jared N
• Haidle Andrew Marc
• Henderson Timothy J
• Jewell James P
• Lu Min
• Northrup Alan B
• Otte Ryan D
• Siu Tony
• Trotter Benjamin Wesley
• Truong Quang T

Inventors

• Altman Michael D
• Andresen Brian
• Chang Wonsuk
• Childers Matthew Lloyd
• Cumming Jared N
• Haidle Andrew Marc
• Henderson Timothy J
• Jewell James P
• Lu Min
• Northrup Alan B
• Otte Ryan D
• Siu Tony
• Trotter Benjamin Wesley
• Truong Quang T

Classifications

• C07H21/04 Primary

  with deoxyribosyl as saccharide radical · CPC title

• C07H21/02

  with ribosyl as saccharide radical · CPC title

• C07H21/00

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• C07H19/23

  Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22 · CPC title

• C07H19/20 Primary

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title