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US-12617780-B2 - Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting

US12617780B2US 12617780 B2US12617780 B2US 12617780B2US-12617780-B2

Abstract

A compound of formula (I); wherein: W is O or NH; A 1 is CR A or N; A 2 is CR B or N; A3 is CR C or N; A 4 is CR D or N; where no more than two of A 1 , A 2 , A 3 , and A4 may be N; one or two of RA, RB, RC and RD, (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH; the remainder of R A, RB, RC and R D , (if present) are H; R N1 is H or Me; one of R C2 and RC3 is C(═O)NH 2 ; the other is selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF 3 , CH2OH, CH 2 OMe, C 2-4 alkenyl and C 5 heterocyclyl; R C1 and R C4 are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 alkenyl and C 5 heterocyclyl.

Inventors

  • Benjamin Joseph Morrow
  • Jonathan Grant Hubert
  • Matthew Lloyd Dennis
  • Anthony Nicholas Cuzzupe
  • Paul Anthony Stupple

Assignees

  • CTXT PTY LTD

Dates

Publication Date
20260505
Application Date
20200717
Priority Date
20190718

Claims (16)

  1. 1 . A compound of formula I: wherein: W is O or NH; R 1 is selected from: (i) H; (ii) C 3-6 cycloalkyl; (iii) C 3-7 heterocyclyl optionally substituted with a group selected from: methyl; and ester; and (iv) linear or branched C 1-4 alkyl optionally substituted with a group selected from: alkoxy; amino; amido; acylamido; acyloxy; alkyl carboxyl ester; alkyl carbamoyl; alkyl carbamoyl ester; phenyl; phosphonate ester; C 3-7 heterocyclyl optionally substituted with a group selected from methyl and oxo; and a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl and boc; A 1 is CR A or N; A 2 is CR B or N; A 3 is CR C or N; A 4 is CR D or N; where no more than two of A 1 , A 2 , A 3 , and A 4 may be N; one or two of R A , R B , R C and R D , are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH; the remainder of R A , R B , R C and R D , are H; R N1 is H or Me; one of R C2 and R C3 is C(═O)NH 2 ; the other is selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 alkenyl and C 5 heterocyclyl; R C1 and R C4 are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 alkenyl and C 5 heterocyclyl.
  2. 2 . The compound according to claim 1 , wherein W is O.
  3. 3 . The compound according to claim 1 , wherein R 1 is H.
  4. 4 . The compound according to claim 1 , wherein R 1 is selected from C 3-6 cycloalkyl, optionally substituted C 3-7 heterocyclyl, and optionally substituted linear or branched C 1-4 alkyl.
  5. 5 . The compound according to claim 1 , wherein R 1 is optionally substituted linear or branched C 1-4 alkyl.
  6. 6 . The compound according to claim 5 , wherein R 1 is optionally substituted ethyl.
  7. 7 . The compound according to claim 1 , wherein A 1 is CR A , A 2 is CR B A 3 is CR C , and A 4 is CR D .
  8. 8 . The compound according to claim 1 , wherein the compound is selected from compounds of formulae IIIb1, IIIc1, IIId1 and IIIe1:
  9. 9 . The compound according to claim 1 , wherein the compound is selected from compounds of formulae IIIb2, IIIc2, IIId2 and IIIe2:
  10. 10 . The compound according to claim 1 , wherein: R A is selected from Cl, Br and OMe; R B is H; R C is H; R D is selected from H, Me, F, Br, OMe.
  11. 11 . The compound according to claim 1 , wherein A 1 , A 2 , A 3 and A 4 are selected from combinations 1-9: Combination A 1 A 2 A 3 A 4 1 CCl CH CH CH 2 CCl CH CH CCH 3 3 CCl CH CH CBr 4 CBr CH CH CH 5 CCl CH CH CF 6 CCl CH CH C—OCH 3 7 CBr CH CH CF 8 C—OCH 3 CH CH CH 9 C—OCH 3 N CH CBr.
  12. 12 . The compound according to claim 1 , wherein R C1 ; R C2 or R C3 ; and R C4 are selected from combinations 1-5: Combination R C1 R C2 or R C3 R C4 1 H H H 2 H H F 3 OMe H H 4 Cl H H 5 OMe H F.
  13. 13 . The compound according to claim 1 , wherein R N1 is H.
  14. 14 . The compound according to claim 1 which is selected from:
  15. 15 . The compound according to claim 1 which is selected from:
  16. 16 . A pharmaceutical composition comprising the compound as defined in claim 1 , and a pharmaceutically acceptable excipient.

Description

SEQUENCE LISTING This application contains a sequence listing filed in ST.26 format entitled “M53094588_SequenceListing_STING2.xml” created on Sep. 22, 2025, and having a size of 5,429 bytes. The entire content of the sequence listing is incorporated herein in its entirety as if fully set forth herein. The present invention relates to substituted benzothiophenes, thienopyridines and thienopyrimidines and their use as pharmaceuticals, and in particular, in treating diseases ameliorated by the modulation of STING. BACKGROUND TO THE INVENTION Vertebrates are constantly threatened by the invasion of microorganisms and have evolved mechanisms of immune defense to eliminate infective pathogens. In mammals, this immune system comprises two branches; innate immunity and adaptive immunity. The innate immune system is the first line of defense which is initiated by Pattern Recognition Receptors (PRRs) which detect ligands from the pathogens as well as damage associated molecular patterns (Takeuchi 2010). A growing number of these receptors have been identified including Toll-like receptors (TLRs), C-type lectin receptors, retinoic acid inducible gene I (RIG-I)-like receptors and NOD-like receptors (NLRs) and also double stranded DNA sensors. Activation of PRRs leads to up-regulation of genes involved in the inflammatory response including type 1 interferons, pro-inflammatory cytokines and chemokines which suppress pathogen replication and facilitate adaptive immunity. The adaptor protein STING (Stimulator of Interferon Genes), also known as TMEM 173, MPYS, MITA and ERIS, has been identified as a central signalling molecule in the innate immune response to cytosolic nucleic acids (Ishikawa 2008; WO2013/166000). Activation of STING results in up-regulation of IRF3 and NFKB pathways leading to induction of type 1 interferons including Interferon-β and other cytokines. STING is critical for responses to cytosolic DNA of pathogen or host origin, and of unusual nucleic acids called Cyclic Dinucleotides (CDNs). CDNs were first identified as bacterial secondary messengers responsible for controlling numerous responses in the prokaryotic cell. Bacterial CDNs, such as c-di-GMP, are symmetrical molecules characterized by two 3′,5′ phosphodiester linkages. Direct activation of STING by bacterial CDNs has recently been confirmed through X-ray crystallography (Burdette 2013). Bacterial CDNs and their analogues have consequently attracted interest as potential vaccine adjuvants (Libanova 2012; WO2007/054279; WO2005/087238). More recently, the response to cytosolic DNA has been elucidated and shown to involve generation, by an enzyme called cyclic GMP-AMP synthase (cGAS, previously known as C6orfl50 or MB21 D1), of a novel mammalian CDN signalling molecule identified as cGAMP, which then activates STING. Unlike bacterial CDNs, cGAMP is an asymmetrical molecule characterized by its mixed 2′,5′ and 3′,5′ phosphodiester linkages (Gao 2013A). Interaction of cGAMP (II) with STING has also been demonstrated by X-ray crystallography (Cai 2014). Interferon was first described as a substance which could protect cells from viral infection (Isaacs 1957). In man, the type I interferons are a family of related proteins encoded by genes on chromosome 9 and encoding at least 13 isoforms of interferon alpha (IFNα) and one isoform of interferon beta (IFNβ). Recombinant IFNa was the first approved biological therapeutic and has become an important therapy in viral infections and in cancer. As well as direct antiviral activity on cells, interferons are known to be potent modulators of the immune response, acting on cells of the immune system. Administration of a small molecule compound which could modulate the innate immune response, including the activation or inhibition of type I interferon production and other cytokines, could become an important strategy for the treatment or prevention of human diseases including viral infections and autoimmune disease. This type of immunomodulatory strategy has the potential to identify compounds which may be useful not only in infectious diseases but also in cancer (Zitvogel 2015), allergic diseases (Moisan 2006), neurodegenerative diseases such as amyotrophic lateral sclerosis and multiple sclerosis (Lemos 2014; Cirulli 2015; Freischmidt 2015), other inflammatory conditions such as irritable bowel disease (Rakoff-Nahoum 2004), and as vaccine adjuvants (Persing 2002; Dubensky 2013). STING is essential for antimicrobial host defense, including protection against a range of DNA and RNA viruses and bacteria (reviewed in McNab 2015; Ma 2016). Herpesviridae, Flaviviridae, Coronaviridae, Papillomaviridae, Adenoviridae, Hepadnaviridae, ortho- and paramyxoviridae and rhabdoviridae have evolved mechanisms to inhibit STING mediated Type I interferon production and evade host immune control (Holm 2016; Ma 2015; Wu 2015; Liu 2016; Chen 2014; Lau 2013; Ding 2013; Nitta 2013; Sun 2012; Aguirre 2012; Ishikawa 2009). Thus, smal