Locked nucleic acid cyclic dinucleotide compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11098077-B2
Application number	US-201716315612-A
Country	US
Kind code	B2
Filing date	Jul 1, 2017
Priority date	Jul 5, 2016
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention provides highly active locked nucleic acid cyclic-dinucleotide (LNA-CDN) immune stimulators that activate DCs via the cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the LNA-CDNs of the present invention are provided in the form of a composition comprising one or more cyclic dinucleotides that induce human STING-dependent type I interferon production, wherein the cyclic dinucleotides present in the composition have at least one 2′, 4′ locked nucleic acids within the cyclic dinucleotide.

First claim

We claim:

1. A compound having the structure selected from the group consisting of Formula Ib, Formula Ic, and Formula Id:

or a prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, wherein:
R1 and R2 are independently a pyrimidine or purine nucleic acid base or analog or derivative thereof;
R3 and R4 are independently —OH, —OR a , —SH or —SR a ;
Y 1 is —O—, —S— or —CRR— and Y 2 is absent, wherein each R is independently —H or —C 1-6 alkyl, or the two R together with the carbon to which they are attached form a 3-6 membered heterocycloalkyl or C 3-6 cycloalkyl spirocyclic ring; or
Y 1 is —O—, —CH 2 — or —CH═ and Y 2 is —CH 2 — or ═CH—, selected to provide —Y 1 -Y 2 — as —O—CH 2 —, —CH 2 —CH 2 — or —CH═CH—;
Y 3 is —O—, —S— or —CRR— and Y 4 is absent, wherein each R is independently —H or —C 1-6 alkyl, or the two R together with the carbon to which they are attached form a 3-6 membered heterocycloalkyl or C 3-6 cycloalkyl spirocyclic ring; or
Y 3 is —O—, —CH 2 — or —CH═ and Y 4 is —CH 2 — or ═CH—, selected to provide —Y 3 -Y 4 — as —O—CH 2 —, —CH 2 —CH 2 — or —CH═CH—;
X 1 , X 2 , and X 3 are all present, X 1 and X 2 are —C(R b R c )—, —N(R d ), —O— or —S(═O) 2 —, and X 3 is —C(R b R c )— or —O—, selected to provide —X 1 -X 2 -X 3 — as —C(R b R c )—C(R b R c )—C(R b R c )—, —C(R b R c )—N(R d )—C(R b R c )—, —C(R b R c )—O—C(R b R c )—, —C(R b R c )—C(R b R c )—O—, —O—C(R b R c )—C(R b R c )—, —O—N(R d )—C(R b R c )—, —S(═O) 2 —N(R d )—C(R b R c )—, —N(R d )—C(R b R c )—C(R b R c )—, —N(R d )—O—C(R b R c )— or —N(R d )—S(═O) 2 —C(R b R c )—; or
X 2 is absent, X 1 and X 3 are both present, X 1 is —C(R b R c )—, —N(R d ) or —O— and X 3 is —C(R b R c )— or —S(═O) 2 —, selected to provide —X 1 -X 3 — as —C(R b R c )—C(R b R c )—, —O—C(R b R c )—, —N(R d )—C(R b R c )— or —N(R d )—S(═O) 2 —;
X 4 ′ is —O— or —NH—;
X 4 is —O— or —NH—;
R5′ is selected from the group consisting of —H, —OH, halogen and —OR e ;
for Formula Ic, X 5 and X 6 are —C(R b R c )—, —N(R d ), —O— or —S(═O) 2 —, and X 7 is —C(R b R c )— or —O—, selected to provide —X 5 -X 6 -X 7 — as —C(R b R c )—C(R b R c )—C(R b R c )—, —C(R b R c )—N(R d )—C(R b R c )—, —C(R b R c )—O—C(R b R c )—, —C(R b R c )—C(R b R c )—O—, —O—C(R b R c )—C(R b R c )—, —O—N(R d )—C(R b R c )—, —S(═O) 2 —N(R d )—C(R b R c )—, —N(R d )—C(R b R c )—C(R b R c )—, —N(R d )—O—C(R b R c )— or —N(R d )—S(═O) 2 —C(R b R c )—;
for Formula Id, X 5 is —C(R b R c )—, —N(R d ) or —O— and X 7 is —C(R b R c )— or —S(═O) 2 —, selected to provide —X 5 -X 7 — as —C(R b R c )—C(R b R c )—, —O—C(R b R c )—, —N(R d )—C(R b R c )— or —N(R d )—S(═O) 2 —;
R a at each occurrence is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl and —C(═O)R f ; wherein alkyl, alkenyl, alkynyl or heteroalkyl are optionally independently substituted with one or more —R m , and carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally independently substituted with one or more —Re;
R b and R c , at each occurrence, are independently selected from the group consisting of —H, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —R′ and -L 1 -R g ; or R b and R c together on a carbon are ═O, ═CR h R h , ═N—OR i , ═N—R i , or ═N—NR i R i ; or R b and R c together with the carbon to which they are attached form a C 3-6 cycloalkyl or 3 to 6 membered heterocycloalkyl spirocyclic ring; wherein alkyl, alkenyl, alkynyl or heteroalkyl are optionally independently substituted with one or more —R m , and carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally independently substituted with one or more —R n ;
R d at each occurrence is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —R″ and -L 2 -R j ; wherein alkyl, alkenyl, alkynyl or heteroalkyl are optionally independently substituted with one or more —R m , and carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally independently substituted with one or more —R n ; or R d is a suitable nitrogen protecting group;
R e is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl and —C(═O)R f ; wherein alkyl, alkenyl, alkynyl or heteroalkyl are optionally independently substituted with one or more —R m , and carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally independently substituted with one or more —R n ; or R e is a suitable oxygen protecting group;
R f at each occurrence is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; wherein alkyl, alkenyl, alkynyl or heteroalkyl are optionally independently substituted with one or more —R m , and carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally independently substituted with one or more —R n ;
R′ at each occurrence is selected from the group consisting of —CN, —NO 2 , —OH, —SH, —NH 2 , —C(═W)—WH, —C(═W)—NH 2 , —C(═W)—NH—WH, —C═N—OH, —C(═NH)—NH 2 , —W—C(═W)—WH, —W—C(═W)—NH 2 , —S(═O) 2 —NH 2 , —S(═O) 2 —NH—W—, —NH—NH 2 , —NH—WH, —NH—C(═W)—WH, —NH—C(═W)—NH 2 , —NH—S(═O) 2 —NH 2 , and —NH—C(═NH)—NH 2 ;
R″ at each occurrence is selected from the group consisting of —OH, —SH, —NH 2 , —C(═W)—WH, —C(═W)—NH 2 , —C(═NH)—NH 2 , and —S(═O) 2 —NH 2 ;
L 1 is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O) 2 —, —C(═W)—, —C(═W)—W—, —C(═W)—NR k —, —C(═W)—NR k —W—, —C(═NR k )NR k —, —C(NR k R k )═N—, —W—C(═W)—, —W—C(═W)—NR k —, —S(═O) 2 —NR k —, —S(═O) 2 —NR k —W—, —NR k —, —N═CR h —, —NR k —W—, —NR k —NR k —, —NR k —C(═NR k )NR k —, —NR k —C(NR k R k )═N—, —NR k —C(═W)—, —NR k —C(═W)—W—, —NR k —C(═W)—NR k —, —NR k —S(═O) 2 —NR k — and —NR k —S(═O) 2 —;
L 2 is selected from the group consisting of —O—, —S—, —NR k —, —C(═W)—, —C(═W)—W—, —C(═W)—NR k —, —C(═NR k )NR k —, —C(NR k R k )═N—, —S(═O) 2 —NR k —, and —S(═O) 2 —;
R g and R j , at each occurrence, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; wherein alkyl, alkenyl, alkynyl or heteroalkyl are optionally independently substituted with one or more —R m , and carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally independently substituted with one or more —Re;
R h at each occurrence is independently selected from the group consisting of —H, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; wherein alkyl, alkenyl, alkynyl or heteroalkyl are optionally independently substituted with one or more —R m , and carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally independently substituted with one or more —Re;
R i and R k , at each occurrence, are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; wherein alkyl, alkenyl, alkynyl or heteroalkyl are optionally independently substituted with one or more —R m , and carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally independently substituted with one or more —Re;
R m at each occurrence is independently selected from the group consisting of ═O, halogen, carbocyclyl, heterocyclyl, aryl, heteroaryl, —R′ and -L 3 -R o , when substituted on an available carbon atom, and carbocyclyl, heterocyclyl, aryl, heteroaryl, —R″ and -L 4 -R″, when substituted on an available nit

Assignees

• Chinook Therapeutics Inc
• Novartis Ag

Inventors

• Kanne David Braun
• Ndubaku Chudi Obioma
• Bruml Jacob Robert
• Le Thanh Ngoc Lan
• Mckenna Jeffrey
• Tria George Scott
• Canham Stephen

Classifications

• A61K31/7084

  Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title