WO2019243825A1 - Modulateurs à petites molécules de protéine sting humaine, conjugués et applications thérapeutiques - Google Patents

Modulateurs à petites molécules de protéine sting humaine, conjugués et applications thérapeutiques Download PDF

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WO2019243825A1
WO2019243825A1 PCT/GB2019/051733 GB2019051733W WO2019243825A1 WO 2019243825 A1 WO2019243825 A1 WO 2019243825A1 GB 2019051733 W GB2019051733 W GB 2019051733W WO 2019243825 A1 WO2019243825 A1 WO 2019243825A1
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optionally substituted
compound
group
mono
bicyclic
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PCT/GB2019/051733
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Monali BANERJEE
Sandip MIDDYA
Sourav Basu
Rajib Ghosh
David Pryde
Dharmendra Yadav
Ritesh SHRIVASTAVA
Arjun SURYA
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Curadev Pharma Limited
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Priority claimed from PCT/GB2018/051730 external-priority patent/WO2018234808A1/fr
Priority claimed from GB201820991A external-priority patent/GB2574913A/en
Application filed by Curadev Pharma Limited filed Critical Curadev Pharma Limited
Publication of WO2019243825A1 publication Critical patent/WO2019243825A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/44—Antibodies bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Definitions

  • the present invention relates to conjugates of small molecule modulators of the 5 Stimulator of Interferon Genes (STING) protein. Accordingly, the small molecule conjugates maybe of use in the treatment of diseases, such as cancer and microbial infections, and so on.
  • the invention extends to the pharmaceutical compositions of the compounds per se wherein a STING ligand is covalently bonded to a targeting moiety through a linker, methods of making such conjugates and methods of modulating the 70 STING protein using these conjugates.
  • the human immune system has evolved to recognize and respond to different types of threats and pathogens to maintain a healthy host.
  • the immune system may generally be divided into two arms, referred to as the‘innate immune system’ and the‘adaptive ig immune system’.
  • the innate arm is mainly responsible for a rapid initial inflammatory response to danger signals associated with cellular or tissue damage from bacteria, viruses and other infectious threats via a number of factors such as cytokines, chemokines and complement factors. These factors act upon a number of different cell types including mast cells, macrophages, dendritic cells and natural killer cells to 0 directly attenuate pathogen viability and to stimulate an adaptive immune response.
  • the adaptive immune system recognises specific antigens not expressed naturally in the host to mount anti-antigen specific responses. Adaptive responses, which occur later and are longer lasting than the more immediate innate responses, are characterized by 5 antibody production together with CD8+ and CL + T-cell responses and B-lymphocyte responses that are critical for immunological memory.
  • the innate immune system senses pathogens or abberant cells by detecting damage- associated molecular patterns (DAMPs) or pathogen-associated molecular patterns 0 (PAMPs) through an array of sentinel proteins called pattern recognition receptors (PRRs) that provide broad and lasting protection to the host against a wide range of threats (reviewed in Broz, P. et. ah, Nat. Rev. Immunol, 2013, 13, 551-565).
  • DAMPs damage- associated molecular patterns
  • PAMPs pathogen-associated molecular patterns 0
  • PRRs pattern recognition receptors
  • PRRs include Toll -like receptors (TLRs; Horscroft, J. Antimicrob. Ther., 2012, 67(4). 789-801; Diebold et a!., Science, 2004, 303, 1529-1531), C-type lectin receptors, 5 retinoic acid inducible gene I (RIG-I like receptors; Pichlmair et. al., Science, 2006, 314, 997-1001) and NOD-like receptors (NLRs) and also double stranded DNA sensors (cGAS/STING) (Takeuchi, O et al, 2010, 140, 805-820).
  • TLRs Toll -like receptors
  • RLRs Toll -like receptors
  • Horscroft, J. Antimicrob. Ther., 2012, 67(4). 789-801 Diebold et a!., Science, 2004, 303, 1529-1531
  • C-type lectin receptors 5 retinoic acid inducible gene I
  • PRRs respond to DAMPs and PAMPs by up-regulating Type-I interferons and other pro-inflammatory cytokines.
  • Free cytosolic nucleic acids (DNA and RNA) are known PAMPs/ DAMPs.
  • the main sensor for cytosolic DNA is cGAS (cyclic GMP-AMP synthase).
  • cGAS cyclic GMP-AMP synthase
  • cGAMP hybrid cyclic dinucleotide cyclo-(AMP/GMP)
  • CDNs cyclic dinucleotides
  • CDNs cyclo-di(GMP) (c-diGMP), cyclo-di(AMP) (c-diAMP) and hybrid cyclo-(AMP/GMP) (cGAMP) derivatives all bind strongly to the ER- transmembrane adaptor protein STING (Burdette, D.L. et. al. Nature, 2012, 478, 515- 518; Ichikawa, H. et. al, Nature, 2008, 455, 674-678: DeFilippis, V.R. et. al, J.
  • STING has a critical role in the innate response to many bacterial, viral and eukaryotic pathogens (Watson et. al., Cell, 2012, iso. 803-815; de Almeida et. al, PLoS One, 2011, 6, 623135; Holm et. al, Nat Immunol, 2012, 13, 737-743; Stein et. al., J. Virol, 2012, 86, 4527-4537; Sharma et. al., Immunity, 2011, 35, 194-207).
  • Type I i nterferons IFNa and IFNp
  • pro-inflammatory cytokines pro-inflammatory cytokines on various cells of the immune system. They strongly potentiate T cell activation by enhancing the ability of dendritic cells and macrophages to present antigens to T cells. They upregulate co-stimulatory molecules such as CD80 and CD86, whichrapidly engage their cognate cell-surface receptors and trigger a phosphorylation cascade involving JAK kinases and STAT transcription factors to activate interferon-stimulated genes (ISGs) that themselves can contri bute to adaptive immune cell activation.
  • IFNa and IFNp interferon-stimulated genes
  • the IFN system is therefore able to render cells and tissues refractory to replication of viruses (Ireton, R.C. et. ah, Antiviral Res., 2014, 108, 156- 164) and drive T-cell priming against tumor-associated antigens for the treatment of cancer (Corrales et. ah, Clin. Cancer Res., 2015, 21, 4774-4779). Indeed, recombinant IFN a has become an important therapy in viral infections and cancer.
  • Alum triggers the release of host cell DNA, which induce T cell responses and the production of IgGi and IgE.
  • adjuvants should be molecularly defined and able to enhance the magnitude and timeframe of a specific immune response to an antigen resulting in en hanced protection against intracellular pathogens and/or reduced tumor burden.
  • tumor-associated antigens include proto-oncogenes, tumor suppressor genes, overexpressed proteins, antigens expressed by oncogenic viruses, oncofetal antigens, altered glycolipids and glycoproteins.
  • Activation of the STING protein can create an activated or primed immune system, similar to that generated by an adjuvant. This may produce a protective or prophylactic state that withstands challenge or re-challenge by intracellular pathogens or by tumors by inhibiting their growth.
  • a STING activator when administered therapeutically to a system in which tumors/ pathogens are present it can act beneficially in two different, but related, ways. First, by direct shrinkage of tumors/' pathogen eradication through up-regulation of Type-I interferons and cytokines to act directly upon the tumor/pathogens, as described above. Second, a STING activator will also induce a lasting immune response, such that re-challenge or re-inoculation with a pathogen or tumors will be resisted both through a general activation of the immune system and through a latent antigen-specific response to said pathogen or tumor.
  • STING is broadly expressed throughout the body in both immune cells and non- immune cells, for example in the spleen, heart, thymus, placenta, lung and peripheral leukocytes, indicating a role in triggering the innate immune system in response to PAMPs/DAMPs (Sun et. al., PNAS , 2009, 106. 8653-8658). Its expression in immune cells leads to rapid amplification of the initial immune signal and maturation of APCs. It is expressed in several transformed cell lines including HEK293 human embryonic kidney cells, A549 adenocarcinomic human alveolar basal epithelial cells, THP-i monocytic cells and U937 leukemic monocytic lymphoma cells. STING also has a central role in certain autoimmune disorders initiated by
  • STING is comprised of an N-terminal transmembrane domain, a central globular domain and a C-terminal tail.
  • the protein forms a symmetrical dimer in the ligand bound state, with the cyclic dinucleotides binding at a dimer interface binding pocket.
  • Binding of CDNs to STING activates a cascade of events whereby the protein recruits and activates TANK-binding kinase (TBKi), and following phosphorylation activates nuclear transcription factors (NFKB) and interferon regulatory factor s (IRF3), respectively.
  • TKi TANK-binding kinase
  • IRF3 interferon regulatory factor s
  • DMXAA 5,6-dimethyi-xanthenone acetic acid
  • the present invention has arisen from the inventors work in attempting to identify STING protein modulators.
  • L 1 and L 2 are linkers
  • T is a targeting moiety; a is an integer between 1 and 5;
  • b is an integer between 1 and 10;
  • z is an integer between 1 and 5;
  • X 1 is CR 1 or N
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N
  • Y is an optionally substituted C 1 -C 0 alkyl, C 1 -C3 polyfluoroalkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 6 cycloalkyl, or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle;
  • R 1 R 2 and R are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CON R'R ⁇ -, N R : R ⁇ -, NHCOR 1 , optionally substituted C -C 6 alkyl, C - C :3 polyfluoroalkyl, optionally substituted CrC & alkylsulfonyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C & alkynyl, optionally substituted C 1 -C 0 alkoxy, optionally substituted C - C 6 alkoxycarbonyl, mono or bicyclic optionally substituted C 5 -C 0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted aryloxy, optionally substituted
  • R 4 and R 5 are each independently selected from the group consisting of H, halogen, optionally substituted C -C & alkyl and optionally substituted C 3 -C 6 cycloalkyl; or R 4 and R5 together with the atom to which they are attached form a spirocyclic ring;
  • R 6 is a ring optionally substituted with one or more R 12 groups, wherein the ring is selected from the group consisting of a mono or bicyclic C 5 -C 0 aryl; a mono or bicyclic 5 to 10 membered heteroaryl; a C 3 -C 6 cycloalkyl; and a mono or bicyclic 3 to 8 membered heterocycle;
  • R 7 is H, optionally substituted C -C 6 alkyl, optionally substituted sulfonyi, optionally substituted C -Q, alkylsulfonyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 alkynyi;
  • R 8 is a mono or bicyclic optionally substituted C 5 -C 0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R?
  • R 10 are each independently selected from the group consisting of optionally substituted Ci-Cc, alkyl, H, halogen, CN, C0 2 H, CO R ’ RA azido, sulfonyi, C -C 3 polyfluoroalkyl, optionally substituted G-G, thioalkyl, optionally substituted C -C 6 alkylsulfonyl, optionally substituted C 3 -Cc, cycloalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyi, optionally substituted C -C 6 alkoxy, optionally substituted C -C 6 alkoxycarbonyl, mono or bicyclic optionally substituted C 5 -C 10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroary!oxy; or R? and R 10 together
  • R 11 is selected from the group consisting of optionally substituted G ⁇ G ; alkyl, H, hydroxyl, C -C 3 polyfluoroalkyl, optionally substituted C -C 6 thioalkyl, optionally substituted C-G, alkylsulfonyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyi, optionally substituted C -Cr alkoxy, optionally substituted C G, alkoxycarbonyl, mono or bicyclic optionally substituted C 5 -C 0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy;
  • the or each R 12 group is independently selected from the group consisting of halogen, OH, SH, 0P(0)(0H) 2 , NR J 3R I 4, CONR ⁇ R CN, COORA N0 2 , azido, S0 2 RA OSO . -R , ⁇ RAS0 2 R NR ; ’C(() )R 0(C11 2) consent0C(())R t XRAC! LpOCiOlR ()C(())R t
  • H optionally substituted C -C 6 alkyl, optionally substituted mono or bicyclic C 3 -C & cycloalkyl mono or bicyclic optionally substituted C 5 -C 0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, and optionally substituted mono or bicyclic 3 to 8 membered heterocycle; and
  • n is an integer between o and 6;
  • an‘agonist’, an‘effector’ or an‘activator’ as it relates to a ligand and STING, comprises a molecule, combination of molecul es, or a compl ex, that stimulates STING.
  • an‘antagonist’ as it relates to a ligand and STING, comprises a molecule, combination of molecules, or a compl ex, that inhibits, counteracts, downregulates, and/or desensitizes STING.
  • Antagonist encompasses any reagent that inhibits a constitutive activity of STING.
  • a constitutive activity is one that is manifest in the absence of a ligand/ STING interaction.
  • ‘Antagonist’ also encompasses any reagent that inhibits or prevents a stimulated (or regulated) activity of STING.
  • the compound of formula (I) is for use in activating, or agonising, the STING protein.
  • the compound of formula (I) may be an activator of the STING protein.
  • the compounds of the inventi on modulate the major human polymorphs of the human STING protein. There are several STING polymorphs reported, but the 5 polymorphs listed below are the major ones which comprise almost 99% of the total human population.
  • the STING protein may be a wild type polymorph (WT/R232), a HAQ polymorph, a REF polymorph (H232), an AQ polymorph or a Q polymorph.
  • the wild type polymorph has arginines at the 71, 232 and 293 positions and a glycine at the 230 position
  • the HAQ polymorph has a histidine at the 71 position, an alanine at the 230 position, an arginine at the 232 position and a glutamine at the 293 position
  • the REF polymorph has arginines at the 71 and 293 positions, a glycine at the 230 position and a histidine at the 232 position
  • the AQ polymorph has arginines at the 71 and 232 positions, an alanine at the 230 position and a glutamine at the 293 position
  • the Q polymorph has arginines at the 71 and 232 positions, a glycine at the 230 position and a glutamine at
  • STING protein By modulating the STING protein, it is possible to treat, ameliorate or prevent cancer, bacterial infection, viral infection, parasitic infection, fungal infection, immune- mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease.
  • a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof for use in treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, immune- mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease.
  • the disease is cancer. - to -
  • a method of modulating the Stimulator of Interferon Genes (STING) protein in a subject comprising administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
  • the method comprises activating the STING protein.
  • the STING protein may be a wild type polymorph, a HAQ polymorph, a REF polymorph, an AQ polymorph or a Q polymorph.
  • a method of treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease comprising administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
  • the neurodegenerative disease may be Alzheimer’s disease or dementia.
  • the viral disease may be Hepatitis.
  • the parasitic infection may be malaria.
  • the mood disorder may be depression.
  • the sleep disorder may be insomnia.
  • the disease is cancer.
  • the cancer may be selected from the group consisting of colorectal cancer, aero-digestive squamous cancer, lung cancer, brain cancer, neuroblastoma, glioblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, thyroid cancer, adrenal cancer, liver cancer, testicular cancer, urothelial cancer, stomach cancer, kidney cancer, hepatocellular carcinoma, cancer of the pharynx, rectal cancer, gastrointestinal stromal tumors, gastroesophageal cancer, sarcoma, adenosarcoma, pituitary adenoma, Kaposi’s sarcoma, neuroendocrine tumors, mesothelioma, leukaemia, acute myeloid leukaemia, small cell lung cancer, non-small cell lung cancer, lymphoma, lymphoid cancer, multiple myeloma, myelodysplasia syndrome, transitional cell carcinoma, malignant
  • “Optional” or“optionally” means that the subsequently described event, operation or circumstances can or cannot occur, and that the description includes instances where the event, operation or circumstance occurs and instances where it does not.
  • “STING” refers to Stimulator of Interferon Genes receptor, also known as TMEM173, ERLS, MGGA, MPYS, SAVI or NET23.
  • the terms“STING” or“STING receptor” are used interchangeably, and include different isoforms and variants of STING.
  • the terms“cancer” and“cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • tumor antigen refers to a molecule (typically a protein, carbohydrate or lipid) that is expressed on the surface of a cancer cell, either entirely or as a fragment and is useful for the preferential targeting of a pharmacological agent to the cancer cell.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • the alkyl group is a primary, secondary, or tertiary hydrocarbon.
  • the alkyl group includes one to six carbon atoms, i.e. Ci-C 6 alkyl.
  • C -C 6 alkyl includes for example methyl, ethyl, n-propyl (l-propyl) and isopropyl (2-propyl, l-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert- butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl group can be unsubstituted or substituted with one or more of halogen, OH, Sell, 0P(0)(0H) 2 , SR 1 , S0 2 RO GSO R 1 , NHSOJl 1 , optionally substituted C -C 6 alkoxy,
  • an optionally substituted C -Cc, alkyl maybe an optionally substituted C 1 -C 0 haloalkyl, i.e.
  • an optionally substituted C -Cc, alkyl may be an optionally substituted polyfiuoroalkyl.
  • R 1 and R 2 may each
  • alkylene refers to a bivalent saturated straight or branched hydrocarbon.
  • the alkylene group is a primary, secondary, or tertiary hydrocarbon.
  • the alkylene group includes one to six carbon atoms, i.e. C -C 6 alkylene.
  • C.-Ce al kylene includes for example methylene, ethylene, n-propylene and isopropylene, butylene, pentylene, hexylene, isobutylene, sec-butylene, terf-butylene, isopentylene,
  • An alkylene group can be unsubstituted or substituted with one or more of optionally substituted C-Gs alkyl, halogen, OH, QP(0)(0H) 2 , OSOaR 1 , NHSO 2 R 1 , C -Ce alkoxy, NRTl 2 , CONRTl 2 , CN, COOH, optionally substituted C 5 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, C 3 -C 6 cycloal kyl and 3 to 8 membered heterocycle.
  • an optionally substituted C -C 6 alkylene maybe an optionally substituted G-C f haloalkylene, i.e. a C - C t alkylene substituted with at least one halogen, and optionally further substituted with one or more of OH, C -Ca alkoxy, NR l R 2 , C0NR l R 2 , CN, COOH, an optionally substituted C 5 -C 0 aryl, an optionally substituted 5 to 10 membered heteroaryl, C 3 -C 6 cycloal kyl and 3 to 8 membered heterocycle.
  • an optionally substituted C -Ca alkylene may be an optionally substituted polyfluoroalkylene.
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C -C 6 alkyl.
  • alkylyne refers to a bivalent unsaturated straight or branched hydrocarbon.
  • the alkylyne group is a primary, secondary, or tertiary hydrocarbon.
  • the alkylyne group includes one to six carbon atoms, i.e. C 2 -C & alkylyne.
  • C 2 -C 6 alkylyne includes for example ethylyne, propylyne, butylyne, penty!yne or hexy yne.
  • An alkylyne group can be unsubstituted or substituted with one or more of optionally substituted C -Ce alkyl, halogen, OH, 0P(0)(0H) 2 , 0S0 2 R l , NHSO.R 1 , C.-Ce alkoxy, NR l R 2 , C0NR : R 2 , CN, COOH, optionally substituted C 5 -C 0 aryl, optionally substituted 5 to 10 membered heteroaryl, C 3 -C 6 cycloalkyl and 3 to 8 membered heterocycle Accordingly, it will be appreciated that an optionally substituted C 2 -Cc, alkylyne may be an optionally substituted C 2 -C 6 haloalkylyne,
  • an optionally substituted C 2 ⁇ C 6 alkylyne may be an optionally substituted polyfluoroalkylyne.
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C -C 6 alkyl
  • halo includes fluoro (-F), chloro (-C3), bromo ( ⁇ Br) and iodo (-1).
  • polyfluoroalkyl may denote a C 1 -C 3 alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms.
  • the term may include peril uoroalkyl groups, i.e. a C 1 -C 3 alkyl group in which all the hydrogen atoms are replaced by fluorine atoms.
  • C -C 3 polyfluoroalkyl includes, but is not limited to, difluoromethyl, trifluoromethyl 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3- trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,2-trifluoro-i- (trifluoromethyl)ethyl.
  • Alkoxy refers to the group R ⁇ -O- where R i5 is an optionally substituted C -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, an optionally substituted C 2 - C & alkenyl or an optionally substituted C 2 -C 6 alkynyl.
  • Exemplary C -C & alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy (i-propoxy), n-butoxy and tert- butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more of halogen, OH, GP(G)(0H) 2 , 0S0 2 R ! R N(H)S0 2 R i 3, alkoxy, NR'R 2 , CONR R-. CN.
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C -C 6 alkyl.
  • Thioalkyl refers to the group R's-S- where R 15 is an optionally substituted C -C 6 alkyl group or an optionally substituted C 3 -C 6 cycloalkyl group.
  • a thioalkyl group can be unsubstituted or substituted with one or more of halogen, OH, 0P(0)(0H) 2, alkoxy, NR ‘ R 2 , C0NR ‘ R 2 , CN, COOH, and, heteroaryl, cycloalkyl and heterocycle.
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C -C 6 alkyl.
  • Al refers to an aromatic 5 to 10 membered hydrocarbon group.
  • Examples of a C 5 - C 10 aryl group include, but are not limited to, phenyl, a-naphthy!, b-naphthyl, biphenyl, tetrahydronaphthyl and indanyl.
  • An aryl group can be unsubstituted or substituted with one or more of optionally substituted C 1 -C 0 alkyl, halogen, OH, 0P(0)(0H) 2 , optionally substituted C -Ce alkoxy, NfbR 2 , CONR ⁇ Ry CN, COOH, N0 2 , azido, C 1 -C 3 polyfluoroalkyl, aryloxy, heteroaryloxy, 5 to 10 membered heteroaryl, 3 to 8 membered heterocycle, SO 2 R 1 , NHCOR 1 , ()C(()j0R ! , 0C(0)NR R 2 and OCCOjR 1 .
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C -C 6 alkyl.
  • the ter “bicycle” or“bi cyclic” as used herein refers to a molecule that features two fused rings, which rings are a cycloalkyl, heterocyclyl, or heteroaryl.
  • the rings are fused across a bond between two atoms.
  • the bicyclic moiety formed therefrom shares a bond between the rings.
  • the bicyclic moiety is formed by the fusion of two rings across a sequence of atoms of the rings to form a bridgehead.
  • a“bridge” is an unbranched chain of one or more atoms connecting two bridgeheads in a polycyclic compound.
  • the bicyclic molecule is a“spiro” or“spirocyclic” moiety.
  • the spiroeyclic group may be a C 3 -C 6 cycloalkyl or a mono or bicyclic 3 to 8 membered heterocycle which is bound through a single carbon atom of the spirocyclic moiety to a single carbon atom of a carbocyclic or heterocyclic moiety.
  • the spirocyclic group may be a 0 3 -0 ⁇ 2 cycloalkyl or a mono or bicyclic 3 to 12 membered heterocycle which is bound through a single carbon atom of the spirocyclic moiety to a single carbon atom of a carbocyclic or heterocyclic moiety.
  • the spirocyclic group is a cycloalkyl and is bound to another cycloalkyl. In another embodiment, the spirocyclic group is a cycloalkyl and is bound to a heterocyc!yl. In a further embodiment, the spirocyclic group is a heterocyclyl and is bound to another heterocyclyl. In still another embodiment, the spirocyclic group is a heterocyclyl and is bound to a cycloalkyl.
  • a spirocyclic group can be unsubstituted or substituted with one or more of optionally substituted C -C 6 alkyl, halogen, OH, optionally substituted C -Ce alkoxy, R !
  • R 2 CONRNR 2 . CN, COOH, N0 2 , azido, C -C 3 polyfluoroalkyl and NHCOR 1 .
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted (N-CN alkyl.
  • Alkoxycarbonyl refers to the group alkyl-O-C(O)-, where alkyl is am optionally substituted C 1 -C 0 alkyl.
  • An alkoxycarbonyl group can be unsubstituted or substituted with one or more of halogen, OH, R'RA CN, C -C & alkoxy, COOH, C 5 -C 0 aryl, 5 to 10 membered heteroaryl or C 3 -C 6 cycloalkyl.
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C -C 6 alkyl.
  • Aryloxy refers to the group Ar-O- where Ar is a mono or bicyclic optionally substituted C 5 -C 0 aryl group, as defined above.
  • Cycloalkyl refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 6 membered ring system.
  • Representative examples of a C 3 -C 6 cycloalkyl include, but are not limited to, cyclopropyl,
  • a cycloalkyl group can be unsubstituted or substituted with one or more of optionally substituted C -C 6 alkyl, halogen, CN, hydroxyl, COOH, CONR'RA NR : RA NHCOR 1 , C -C 6 alkoxy, azido, C 1 -C 3
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C - C t alkyl.
  • Heteroaryi refers to a monocyclic or bicyclic aromatic 5 to 10 membered ring system in which at least one ring atom is a heteroatom. The or each heteroatom maybe independently selected from the group consisting of oxygen, sulfur and nitrogen.
  • Examples of 5 to 10 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-i, 2, 4-triazole, lH-tetrazole, l-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N- methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline.
  • Bicyclic 5 to 10 membered heteroaryl groups include those where a phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring.
  • a heteroaryl group can be unsubstituted or substituted with one or more of optionally substituted C -Ce alkyl, halogen, OH, CN, NR'R 2 , azido, COOH, C -Cc, alkoxycarbonyl, C 1 -C 3 polyfluoroalkyl, C0NR‘R 2 , N0 2 , NHCOR* and SO 2 R 1 .
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C -Ce alkyl.
  • Heterocycle or“heterocyclyi” refers to a 3 to 8 membered monocyclic, bicyclic or bridged molecules in which at least one ring atom is a heteroatom.
  • the or each heteroatom maybe independently selected from the group consisting of oxygen, sulfur and nitrogen.
  • a heterocycle may be saturated or partially saturated.
  • Exemplary 3 to 8 membered heterocyclyi groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrrol ine, pyrrolidine, dihydrofuran, tetrahydrofuran,
  • a heterocyclyi group can be
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C -C 6 alkyl.
  • Alkenyl refers to olefmically unsaturated hydrocarbon groups which can be unbranched or branched.
  • the alkenyl group has 2 to 6 carbons, i.e. it is a C 2 -C 6 alkenyl.
  • C 2 -C 6 alkenyl includes for example vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl.
  • An alkenyl group can be unsubstituted or substituted with one or more of C-Co alkyl, halogen, OH, C C (: alkoxy, C C 3
  • alkynyf refers to acetyl enically unsaturated hydrocarbon groups which can be unbranched or branched. In certain embodiments, the alkynyl group has 2 to 6 carbons, i.e.
  • C 2 -C, 5 alkynyl includes for example propargyl, propynyl, butynyl, pentynyl and hexynyl.
  • An alkynyl group can be unsubstituted or substituted with one or more of C -C 6 alkyl, halogen, OH, C -C 6 alkoxy, C 1 -C 3 polyfluoroalkyl, NRR 2 .
  • R 1 and R 2 may each independently be selected from the group consisting of H, halogen and optionally substituted C 1 -C 0 alkyl.
  • Alkylsulfonyl refers to the group alkyl-S0 2 - where alkyl is an optionally substituted C -C 6 alkyl, and is as defined as above.
  • Heteroaryloxy refers to the group heteroaryl-O- where the heteroaryl is a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, and is as defined above.
  • Heterocyelyloxy refers to the group heterocycle-O- where heterocycle is an
  • the targeting moiety targets an antigen and/or a receptor expressed on a cell surface.
  • the compound of formula (I) is configured to release a compound of formula (II), or a cleavage product comprising the compound of formula (II).
  • the compound of formula (I) is configured to release a compound of formula (II), or the cleavage product comprising the compound of formula (II), when the compound of formula (I) is substantially adjacent to the cell expressing the antigen and/or receptor on the surface thereof.
  • the compound of formula (II) may be configured to deliver the compound of formula (II), or the cleavage product comprising the compound of formula (II), directly to a targeted cell.
  • L 1 may be absent or may be:
  • A is absent or is selected from the group consisting of -L ⁇ 3 -, -X 4 L 3 -, -L 3 X 4 -, ⁇ C(0)X 4 ,
  • W is either absent or is selected from the group consisting of -L7NH-, -L 3 L 7 NH-,
  • 0 D is either absent or has formula -(D J ) q - or -(D J ) q C(0)-, wherein (D X is either linear or cyclic;
  • the or each L 3 and L 6 are each independently an opti onally substituted C -C 25 alkylene or an optionally substituted C 2 -C 25 alkylyne;
  • L 4 and L3 ⁇ 4 are each independently selected from the group consisting of an optionally 5 substituted mono or bicyclic C 5 -C 10 aryl; an optionally mono or bicyclic 5 to to
  • heteroaryl an optionally C 3 -C 12 cycloalkyl; and an optionally mono or bicyclic 3 to 12 membered heterocycle;
  • L 7 and L 8 are each independently an optionally substituted mono or bicyclic C 5 -C 0 aryl; or an optionally substituted mono or bicyclic 5 to 10 membered heteroaryl, wherein the 0 aryl or heteroaryl is optionally further substituted with at least one -OR 18 group; the or each of X 4 , X 5 , X 6 and X 7 is independently O, S or NR 1 ;
  • R 17 is hydrogen or an optionally substituted C -6 alkyl
  • R 18 is an optionally substituted C 3 -C 6 cycloalkyl, or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle;
  • each D 1 independently has general formula
  • Sc is a side chain of a natural or unnatural amino acid and R iy is H, or Sc and R iy together with the atoms to which they are attached form a ring;
  • q is an integer between 2 and 20.
  • L 2 may be absent or may be:
  • G is either absent or is ( G 1 ) a -G 2 -(G 3 -) Z ,
  • G 2 is either absent or is selected from the group consisting of
  • a wavy line indicates either the attachment of G 2 to G 1 or, in embodiments where G 1 is absent, to L 1 , or the attachment of the G 2 to G 3 or, in embodiments where G 3 is absent, to S, and each G 2 , in
  • each G 2 in embodiments where it is present, is attached to at least one G 3 or, in embodiments where G 3 is absent, to at least one group S;
  • the or each G 3 is independently either absent or selected from the group consisting of -
  • the or each G 4 is independently either absent or selected from the group consisting of
  • S is either absent or is selected from the group consisting of -X 4 -, -X 4 -, -X 8 -, -C(X 9 )-, -X 4 C(X 9 )-, -X 4 C(X 9 )L 3 -, -X 4 C(X 9 )L3C(0)-, -X 8 L3-, -X 4 X 8 L 3 -, X 8 L 3 C(Q)-, -L 3 -, -L 4 -, -L 4 L 3 -, -L 4 C(0)-, -C(0)L 4 C(0)-, -L 3 C(0)L 4 C(0)-, -L 4 L 3 L5-, L 4 L3L5C(0)-,
  • L 9 is a poly(ethylene glycol) (PEG) chain between l and 25 units long;
  • X 8 is— S(O)- or -SO 2 -;
  • X 9 is O or S
  • R 20 is an optionally substituted C -Cs alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -Cfi alkynyl, -L 9 H, -C(0)L 3 H, -C(0)L 9 H, -X 4 L 3 H, -X 4 L 9 H, -X 4 C(0)L 3 H, -X 4 C(Q)L 9 H, -C(0)X 4 L 3 H or -C(0)X 4 L 9 H; and
  • p is an integer between 1 and 25.
  • a may be 1, 2, 3, 4 or 5.
  • a is an integer between 1 and 3.
  • z may be 1, 2, 3, 4 or 5.
  • z is an integer between 1 and 3.
  • L 1 and L 2 are present.
  • 3 or less of A, W, D, G and S are absent, and more preferably 2 or less or 1 or less of A, W, D, G and S are absent. In some embodiments, none of A, W, D, G and S are absent.
  • A may be -L 3 -.
  • L 3 may be an optionally substituted C -C- 6 alkyiene.
  • L 3 is an optionally substituted C -C 2 alkyiene or an optionally substituted C alkyiene.
  • A may be -LAX 4 - L 3 may be an optionally substituted C -C 6 alkyiene, and is preferably -CH 2 CH 2 - or -CH a CH a CH a -. Accordingly, A may be -CH 2 CH 2 0-, -CH 2 CH 2 NH-,
  • A may be -C(0)X 4 or -L 3 C(0)X 4 .
  • X 4 may be O.
  • L 3 may be an optionally substituted G- C 6 alkyiene, and is preferably a C 1 -C3 alkyiene, and most preferably is -CH 2 -.
  • A maybe -('(())() or -CH 2 C(0)0-.
  • A may maybe -O- or -NR 1 -.
  • X 5 maybe -O- or NR 1 -.
  • R 1 may be methyl or -CH 2 CH 2 0CH 2 CH 2 0H.
  • A may 4 may be -0-, -S- or -NH-.
  • X 3 maybe -O- or -NR 1 -.
  • A may maybe an optionally substituted C -C 10 alkylene, and is preferably an optionally substituted C Q alkylene.
  • L3 may be -O- or -NR 1 -.
  • X 5 maybe -O- or NR 1 -.
  • L3 may be
  • a 3 °Y° r be an optionally substituted C alkylene. Accordingly, A may be O
  • L 3 is an optionally substituted C -C 2 alkylene or an optionally substituted Ck alkylene.
  • A may be -0-, -S- or -NH-.
  • X 4 may be -O- or -NR 1
  • A may be -0-.
  • X- ⁇ may be -O- or NR 1 -.
  • L 3 may an optionally substituted (k-C & alkylene, and is preferably CH 2 CH 2 -.
  • X 6 may be -O- or NR 1 -.
  • X may be -0-. Accordingly, A may be: Preferably, X 4 is -0-. Preferably, X 3 is -0-.
  • A may be -X 4 L 3 L4 ⁇ or -X 4 L 3 L 4 L 3 - X 4 may be -0-.
  • L ⁇ 3 may be an optionally substituted Ci-C 6 alkylene, and is preferably a C 1 -C 2 alkylene, and more preferably is -CH 2 -.
  • L 4 may be an optionally substituted 3 to 12 membered heterocycle, preferably L 4 may is an optionally substituted 3 to 8 membered heterocycle, and most preferably L 4 is an
  • L 4 may be or , where R 22 may be a hydrogen, a C 1 -C 6 alkyl or a mono or bicyclic C 5 -C 0
  • L 4 maybe ' or may be an optionally substituted mono or bicyclic C 5 -C 0 aryl.
  • A may be
  • A may be -L 3 X 4 L 4 X 5 L 6 - L 3 and L 6 may independently be an optionally substituted C -C 6 alkylene, and are preferably independently a C 1 -C 2 alkylene.
  • L 3 maybe -CH 2 CH 2 -.
  • L 6 may be -CH 2 -.
  • X 4 may be -0-.
  • X 5 may be -O-.
  • L4 may be an optionally substituted 3 to 12 membered heterocycle.
  • L 4 is preferably an optionally substituted 6 to 12 membered bicyclic heterocycle, and more preferably an optionally substituted 6 to 12
  • L 4 may be , where
  • R 22 may be a hydrogen, a C -C 6 alkyl or a mono or bicyclic C 5 -C 0 aryl. Accordingly, L 4 may preferably . Accordingly,
  • A may be .
  • X 4 is preferably -0-.
  • L :? may be an optionally substituted C -Cc, alkylene, and preferably is a C -C 2 alkylene, and more preferably is
  • R 17 maybe an optionally substituted C -6 alkyl, and is preferably a C -3 alkyl and more preferably is a methyl.
  • X 7 is preferably -NH- or -0-.
  • L 4 may be an optionally substituted mono or bicyclic C 5 -C 0 aryl.
  • L 4 is an optionally substituted phenyl, and in some embodiments is an unsubstituted phenyl. Accordingly, A may be
  • W is -I NH-, -L3L7NH-, -L 7 NHC(0)-, -SM .
  • L3 may an optionally substituted C -C 6 alkylene or C -C 6 alkylyne, preferably C 1 -C3 alkylene or C 1 -C3 alkylyne, and most preferably is -CH 2 - or -CH 2 CHCH-.
  • L 7 and L 8 are each independently a mono or bicyclic C 5 -C 0 aryl; or a mono or bicyclic 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally 7 substituted with one -OR 18 group.
  • L 7 maybe a phenyl, napthalenyl or a 2H-chromen-2-only r group, wherein each group may be further substituted with one -OR 18 group.
  • L 8 is preferably a phenyl.
  • R 18 is preferably an optionally substituted mono or bicyclic 3 to 8 membered heterocycle. More preferably, R 18 is an optionally substituted 6 membered heterocycle, and most preferably an optionally substituted tetrahydropyranyl.
  • the heterocycle is substituted with between i and 9 substituents, more preferably between 2 and 7 or between 3 and 5 substituents, and most preferably with 4 substituents.
  • the substituents may be selected from CVC & alkoxy, OH and COOH.
  • the C -C 6 alkoxy is a C 1 -C 4 alkoxy, more preferably a C -C 2 alkoxy, and most preferably -CH 2 0H.
  • the heterocycle is substituted with between 1 and 9 OH groups, more preferably between 2 and 5 OH groups, and most preferably with 3 OH groups.
  • the heterocycle is substituted with between 1 and 9 C -C 6 alkoxy and/or COOH groups, more preferably between 1 and 5 C -C 6 alkoxy and/or COOH groups, and most preferably with 1 C -C & alkoxy or COOH group.
  • W may be:
  • Sc may be H, an optionally substituted C -C 6 alkyl, an optionally substituted mono or bicyclic C 5 -C 0 aryl, an optionally mono or bicyclic 5 to io membered heteroaiyl, an optionally C 3 -C 2 cycloalkyl, or an optionally mono or bicyclic 3 to 12 membered heterocycle.
  • Sc is H, an optionally substituted C -C 6 alkyl, a mono or bicyclic C 5 -C 0 aryl, a mono or bicyclic 5 to 10 membered heteroaryl, a C 3 -C 12 cycloalkyl, or a mono or bicyclic 3 to 12 membered heterocycle.
  • the alkyl may be substituted with at least one of NR J R 2 , NHC(NH)NH 2 , OH, COOH, CONR : R ⁇ -, Sell, SR 1 , an optionally substituted C 5 -C 10 aryl, an optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted 3 to 8 membered heterocycle.
  • R 2 maybe H.
  • R 1 may also be H.
  • R 1 may be C(0)NH 2 .
  • the alkyl may be substituted with NHC(0)NH 2 .
  • R 2 When the alkyl is substituted with C0NR‘R 2 then R 2 may be H. R 1 may also be H. Alternatively, R 1 may be C(0)NH 2 .
  • R 1 When the alkyl Is substituted with SR 1 , R 1 may be H or a C -C 6 alkyl, preferably R 1 is H or methyl.
  • the optionally substituted C 5 -C 10 aryl the optionally substituted C 5 -C w aryl is preferably optionally substituted phenyl.
  • the phenyl may optionally be substituted with an -OH.
  • the optionally substituted 5 to 10 membered heteroaryl is preferably imidazolyl or iH-indolyl
  • R 1 may be a C -C 6 alkyl, and preferably is methyl.
  • Sc is H or a Cr&, alkyl optionally substituted with at least one substituent selected from the group consisting of NH 2 , NHC(NH)NH 2 , OH, COOH, CONRe H, SeH, SH, SCH 3 , a phenyl optionally substituted with an OH, imidazolyl and iH-indolyl.
  • Sc is a C -Ce alkyl optionally substituted with NHC(0)NH 2 or COOH. More preferably, Sc is methyl, isopropyl, - C H 2 C H 2 C H 2 N H C( () ) N H 2 or -CH 2 CH 2 C00H.
  • D 1 may more preferably q may be an integer between 1 and 10, more preferably between 2 and 7, and most preferably between 3 and 5.
  • D may be:
  • D is:
  • G 1 and G 3 may each independently be -L 3 -, -(X 4 L 3 ) P - or - ⁇ (L 3 X 4 -) P .
  • p may be 1 or 2.
  • L 3 may be an optionally substituted C 1 -C 15 alkylene, more preferably an optionally substituted C -C l0 alkylene, and most preferably optionally substituted C -Ce alkylene.
  • L 3 may be substituted with one or more optionally substituted Ci-C 6 alkyl.
  • the C -Cg alkyl is unsubstituted.
  • G 1 and G 3 may each independently be substituted with one or more methyl groups.
  • G 1 and G 3 may each independently be -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -CH 2 C(Me)H-, CH 2 CMe 2 -, -CH 2 CMe 2 S- -CH 2 0-, -CH 2 CH 2 0-, -CH 2 CH 2 0CH 2 CH 2 0- or -(CH 2 ) 5 NH-.
  • G may be -CH 2 ⁇ , -(CH 2 ) 2 -, -(CH 2 ) 3 ⁇ , -(CH 2 ) 4 -, -(CH 2 ) 5 -, - CH 2 C(Me)H-, CH 2 CMe 2 -, -CH 2 CMe 2 S- or ⁇ (CH 2 ) 5 NH-.
  • G may be -CH 2Q CH 2 CH 2Q CH 2 CH 2Q -.
  • G 1 and G 3 may each independently be .
  • U and L 6 may independently be an optionally substituted C -C 0 alkylene, and more preferably an optionally substituted C -Cc, alkylene.
  • X 4 may be Ni .
  • X 4 may be NH. Accordingly, G 1 and/or G 3 may be In embodiments where G 2 and G 3 are absent, G
  • G 1 and G 3 may each independently be may be -! . ; X 'C(O)- or -C(0)L 3 X 4 C(0)L 6 -.
  • L 3 is an optionally substituted C 1 -C 15 alkylene, more preferably an optionally substituted C -C 0 alkylene, and most preferably an optionally substituted C -C 6 alkylene.
  • the alkylene maybe substituted with an optionally substituted C -C 6 alkyl or -COOH.
  • the alkyl may be substituted with NH 2 .
  • X 4 is -NH-.
  • L 6 is preferably, an optionally substituted C -C 15 alkylene, more preferably an optionally substituted C -C 0 alkylene, and most preferably an optionally substituted C -C 6 alkylene.
  • the alkylene may be substituted with an optionally substituted C -C 6 alkyl or -COOH.
  • the alkyl maybe substituted with NH 2 .
  • the alkylene may be unsubstituted.
  • G 1 and G 3 may each independently be-(CH 2 ) 5 NHC(0)-, More preferably, G 1
  • G may be--
  • G 1 and G 3 may each independently be an optionally substituted C 3 -C 6 cycloalkyl, a mono or bieyclic optionally substituted C 5 -C 0 aryl, a mono or bieyclic optionally substituted 5 to 10 membered heteroaryl or a mono or bieyclic optionally substituted 5 to 10 membered heterocycle.
  • G may be -L 3 X 4 C(0)-.
  • G 2 may be absent.
  • G 3 may be ---L 4 -
  • G 1 and G 3 may each independently be-O, -S-, -NR 1 -, -S(Q)-, -S0 2 -, -C(G)L 3 -,-
  • G 1 and G 3 may each independently be -C(0)L 3 - or -C(0)L 3 C(0)- where L 3 is an optionally substituted C -Ce alkylene, and more preferably an optionally substituted C 4 -C 5 alkylene.
  • G may be -C(0)L ⁇ 3 - or -C(0)L 3 C(0)- where L 3 is an optionally substituted CVC.r, alkylene, and more preferably an optionally- substituted C4-C5 alkylene.
  • G 1 and/or G 3 may be -L 4 -. Accordingly, G 1 and/or G 3 may be an optionally substituted mono or bieyclic C 5 -C 0 aryl. G 1 and/ or G 3 may be an optionally substituted phenyl. In embodiments where G 2 and G 3 are absent, G maybe
  • G 1 and/or G 3 maybe a polyfethylene glycol) (PEG) chain of between 1 and 25 units.
  • the PEG chain may be a cyclic PEG chain, branched PEG chain or a linear PEG chain.
  • G 1 and/or G 3 may be a cyclodextrin.
  • the cyclodextrin may be a, b or g cyclodextrin.
  • G 1 and/or G 3 maybe -0(0)IAE 3 -, -L9L 3 C(Q) ⁇ , -C(Q)L9L 3 C(0)- or -L ⁇ L 3 - L 3 maybe an optionally substituted C -C 6 alkyl ene, and is more preferably methylene or ethylene.
  • G 2 and/or G 3 may be P .
  • p may be an integer between 1 and 15, more preferably between 2 and 10 or between 3 and 5.
  • G 2 and G 3 are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integers that are integer between 1 and 15, more preferably between 2 and 10 or between 3 and 5.
  • G 2 may be .
  • Each G 4 maybe absent, -3>- or -X 4 C(0)-.
  • one G 4 is absent and one G 4 is -X 4 C(0)-.
  • X 4 maybe -NH-. Accordingly,
  • G 2 may more preferably is V H
  • G 2 may preferably more
  • R 20 may be -LAI, -C(0)L a H, -X 4 L 9 H,
  • X 4 C(Q)L 9 H or -C(0)X 4 L 9 H Preferably R 20 is -C(())X 4 L 3 ⁇ 4 H.
  • X 4 may be -NH-.
  • L 9 - may
  • p may be an integer between 2 and 10, more preferably between 3 and
  • G 1 and G 3 may each independently be an optionally substituted G-C o alkylene, more preferably an optionally substituted C -Ce alkylene.
  • G 1 may be ethylene.
  • G 3 may be
  • G may
  • R 20 may be an optionally substituted C -C 6 alkyl, an optionally substituted C 2 -C6 alkenyl or an optionally substituted C 2 -C 6 alkynyl. More preferably, R 20 is an optionally substituted C -C 3 alkyl, and most preferably is optionally substituted methyl. Preferably, the alkyl, alkenyl or C 2 -C fi alkynyl is substituted with -
  • R 1 and R 2 are H. Accordingly, G 2 maybe more
  • G 1 may be an optionally substituted C -C 0 alkylene, more preferably an optionally substituted C -C 6 alkylene. G 1 may be ethylene. G 3 may be absent. Accordingly, G may
  • G 2 may be and one G 4 is absent if -L 3 -.
  • -L 3 - may be an optionally substituted C 1 -C 12 alkylene, more preferably an optionally substituted C -C 6 alkylene, and most preferably methylene or ethylene. Accordingly, G 2
  • R 20 may be an optionally substituted C -C 6 alkyl, and in some embodiments is methyl. Accordingly, G 2 may be
  • G 1 and G 3 may be absent. Accordingly, in some or
  • Each G 4 may independently be absent, or selected from the group consisting of -L 3 X 4 C(Q)-, -C(0)X 4 L 3 -,-L 3 C(0)X 4 , -X 4 C(G)L 3 -,
  • At least one G 4 group may be -X 4 C(0)L 3 -.
  • X 4 may be -NH-.
  • -L 3 - may be an optionally substituted C - C alkylene, more preferably an optionally substituted C -Cc alkyl ene, and most preferably methylene or ethylene.
  • At least one G 4 group may be -L 3 X 4 L 6 C(0)X 5 -.
  • G 4 groups are -L 3 X 4 L 6 C(0)X 5 -.
  • Each X 4 may be -NH-.
  • Each X % may be -NH-.
  • Each -L 3 - and -L 6 - may independently be an optionally substituted C -C alkylene, more preferably an optionally substituted C -Ce alkylene, and most preferably methylene or ethylene.
  • G 2 may be:
  • Each G 1 and G 3 may independently be absent, -L 3 -, -IA -X 4 U -U>L 3 -,-L 3 X 4 C(Q)- - L 3 C(0)X 4 , -L 3 X 4 C(0)L 6 - or -L 3 C(0)X 4 L 6 -.
  • the G group may comprise at least one G 1 group. Accordingly, a may be l, 2 or 3 Preferably, a is 1.
  • G 1 may be -IX- or -X 4 IX-
  • G 1 is -X 4 IX-.
  • X 4 is -
  • G- Preferably, -IX- is P and p is an integer between 1 and 10, more preferably between 2 and 5, most preferably p is 3. Accordingly, G 1 may be
  • the G group may comprise at least one, at least two or at least three G 3 groups.
  • z may be 1, 2 or 3.
  • z is 3.
  • G 3 may be -L 3 X 4 C(0)-, -L 3 C(G)X 4 , - L 3 X 4 C(0)L 6 - or -L 3 C(0)X 4 L 6 -.
  • G 3 is -L 3 X 4 C(0)L 6 -.
  • -L 3 - and -L 6 - may independently be an optionally substituted C -C alkylene, more preferably an optionally substituted C -C 6 alkylene, and most preferably a C 2 -C 5 alkylene.
  • C 2 -C 5 alkylene Preferably,
  • each G 3 may be
  • G may be:
  • G 2 may be .
  • Each G 4 may independently be absent, -L 3 -, -X 4 -, -X 8 -, -
  • X 4 C(()) ⁇ or -Ci OjX 4 - X 4 C(()) ⁇ or -Ci OjX 4 - .
  • at least one, and more preferably at least two G 4 groups are -L 3 -.
  • -L 3 - may be an optionally substituted C -C 12 alkylene, more preferably an optionally substituted C -C 6 alkylene, and most preferably methylene or ethylene.
  • at least one G 4 group is -X 4 C(0)-.
  • X 4 is -NH-.
  • G 3 is - X 4 C(G)- or -C(0)X 4 -.
  • X 4 is -NH-.
  • G 2 may be
  • R 20 is -C(G)X 4 L 9 H.
  • -L 9 - is P and p is an integer between i and 10, more preferably between 2 and 5, and most preferably p is 3.
  • G 2 may more
  • G 1 may be absent.
  • G 3 may be -L 3 -, -L 9 -, or -L 9 L 3 -.
  • -L 9 - is P and p is an integer between 1 and 10, more preferably between 2 and 5, and most preferably p is 4.
  • -L 3 - maybe an optionally substituted C -C 12 alky!ene, more preferably an optionally substituted C-Co alkyiene, and most preferably ethylene.
  • G may more
  • L3 ⁇ 4 may an optionally substituted C -C 0 alkylene, more preferably an optionally substituted C 1 -C 0 alkylene.
  • the alkylene is unsubstituted.
  • S may be -X ⁇ L 3 -.
  • X4 may be -NH-.
  • L 3 may be a C 1 -C 12 optionally substituted alkylene, more preferably a C.-Ce optionally substituted alkylene and most preferably methylene or ethylene. Accordingly, S maybe -NHCH 2 -.
  • S may be an optionally substituted mono or bicyclic C 5 -C 10 aryl, an optionally substituted mono or bicyclic 5 to to membered heteroaryl, an optionally substituted C 3 - C 12 cycloalkyl, or an optionally substituted mono or bicyclic 3 to 12 membered heterocycle.
  • S is an optionally substituted mono or bicyclic 5 to 10 membered heteroaryl or an optionally substituted mono or bicyclic 3 to 12 membered heterocycle. More preferably, S is an optionally substituted mono or bicyclic 5 membered heteroaryl or an optionally substituted mono or bicyclic 5 membered heterocycle.
  • G is a succinimidyl group, a triazolyl group or a tetrazolyl group. The triazolyl group maybe a 1,2,3-trazolyl group. Accordingly, S may be an optionally substituted mono or bicyclic C 5 -C 10 aryl, an optionally substituted mono or bicyclic 5 to
  • S may be attached to the same targeting moiety at two separate points.
  • S may be -0-, -NH-, -S- or -C(G)-
  • S may be LA ⁇ b may be an optionally substituted C 1 -C 15 alkylene, more preferably an optionally substituted C -C 0 alkylene, and most preferably an optionally substituted O,- C 6 alkylene. In some embodiments, the alkylene is unsubstituted.
  • S may be -X (X9)L3-, -X CXe)-, -C4q(C9) ⁇ o>, -X 8 LA, -XflPL?- or -x3 ⁇ 4?C(0)-.
  • X 4 may be NH.
  • X' ! may be O or S.
  • IX may be an optionally substituted C -C 6 alkylene, and more preferably an optionally substituted C -C 2 alkylene.
  • the alkylene may be substituted with COOH or a C -C & alkyl which is optionally substituted with COOH or
  • S may Preferably X 4 and X 5 are O.
  • X 4 is O or NH. Accordingly, S maybe o-V
  • S may be -L ⁇ Ls-.
  • I b may be an optionally substituted C -C 6 alkylene, and more preferably a C -C 2 alkylene.
  • L 4 may be an optionally substituted mono or bicyclic C 5 -C 0 aryl or an optionally substituted mono or bicyclic 5 to 10 membered heteroaryl, and preferably is a phenyl or a 6 membered heteroaryl. Accordingly, S may be , wherein a wavy line and asterisk indicate the attachment of the group
  • L 3 may be an optionally substituted CrC & alkylene, more preferably a C -C 2 alkylene, and most preferably methylene.
  • L 4 maybe an optionally substituted C 3 -C 2 cycloalkyl or an optionally substituted mono or bicyclic 3 to 12 membered heterocycle, more preferably is an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 6 membered heterocycle, even more preferably is an optionally substituted mono or bicyclic 5 membered heterocycle, and most preferably is a succinimidyl.
  • li> may be an optionally substituted C 3 -C 2 cycloalkyl or an optionally substituted mono or bicyclic 3 to 12 membered heterocycle, more preferably is an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 6 membered heterocycle, and most preferably is a cyclohexyl.
  • S may , wherein a wavy line and asterisk indicate the attachment of the group S to the targeting moiety T
  • S may be -L3C(0)L 4 C(0)-.
  • Ib may be an optionally substituted C Co alkylene, more preferably a C 1 -C 2 alkylene, and most preferably methylene.
  • U maybe an optionally substituted C 3 -C 12 cycloalkyl or an optionally substituted mono or bicyclic 3 to 12 membered heterocycle, more preferably is an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 6 membered heterocycle, most preferably is a mono or bicyclic 6 membered heterocycle.
  • S may be , wherein a wavy line and asterisk indicate the attachment of the group S to the targeting moiety T.
  • A may be absent, -L 3 X 4 -, -C(Q)X 4 -, -L 3 C(G)X 4 ,
  • L 3 may be an optionally substituted Ch-C ⁇ alkylene, and is preferably a C -C 6 alkylene, and more preferably is -CH 2 -, -CH 2 CH 2 - or- CH 2 CH 2 CH 2 -.
  • X 4 is O. Accordingly, A may be -CH 2 0-, -CH 2 CH 2 0- or -
  • X 4 maybe -0-.
  • L 3 may be an optionally substituted C -C 6 alkylene, and is preferably a C 1 -C3 alkylene, and most preferably is -CH 2 -. Accordingly A may be -C(0)0- or -CH 2 C(0)0-.
  • X 4 is preferably -0-.
  • L 3 may be an optionally substituted C 1 -C0 alkylene, and is preferably a C -C 2 alkylene, and more preferably is CH a -.
  • L 4 may be an optionally substituted 3 to 12 membered heterocycle, preferably L 4 may is an optionally substituted 3 to 8 membered heterocycle, and most preferably L 4 is
  • L 4 may be
  • X 4 is preferably -O-.
  • Ls may be an optionally substituted C -C 6 alkyl ene, and preferably is a C 1 -C 2 alky!ene, and more preferably is -CH 2 -.
  • R 17 may be an optionally substituted C - 6 alkyl, and is preferably a C - 3 alkyl and more preferably is a methyl Xs is preferably -NH- or -0-.
  • L 4 maybe an optionally substituted mono or bicyclie C 5 -C 0 aryl.
  • L 4 is an optionally substituted phenyl, and in some embodiments is an unsubstituted phenyl. Accordingly,
  • A may
  • W is absent or is -IAICNH-. In some embodiments, W is
  • D is absent or is -(D ! )qC(0)-, where q is an integer between 2 and to, and more preferably between 3 and 4.
  • D 1 may have general
  • each Sc group is an optionally substituted C -C- 6 alkyl.
  • the alkyl is optionally substituted with NHC(0)NH 2 or COOH.
  • D may be
  • X4 may be -NH-.
  • L 3 may be a C 1 -C 12 optionally substituted alkylene, more preferably a C -Ca optionally substituted alkylene and most preferably methylene or ethylene.
  • S may be an optionally substituted mono or bicyclic 5 to 10 membered heteroaryl or an optionally substituted mono or bicyclic 3 to 12 membered heterocycle. More preferably, S is an optionally substituted mono or bicyclic 5 membered heteroaryl or an optionally substituted mono or bicyclic 5 membered heterocycle.
  • S is -X4C(X 9 )L 3 -,-X 8 L 3 - or -X4X 8 L 3 -
  • X may be NH.
  • X 9 may be O.
  • C 8 may be -S0 2 -.
  • L 3 may be an optionally substituted C ; -C cramp alkylene, and more preferably an optionally substituted C -C 2 alkylene.
  • the alkylene may be unsubstituted or substituted with COOH or a C -C 6 alkyl which is optionally substituted with COOH.
  • L 3 may be an optionally substituted C -Ca alkyiene, and more preferably a C -C 2 alkyiene.
  • L 4 may be an optionally substituted mono or bicyclic C 5 -C 0 aryl or an optionally mono or bieyclic 5 to 10 membered heteroary!, and preferably is a phenyl or a 6 membered heteroaryl.
  • S may be -(CH 2 ) 5 -, -NH-, -S-, -C(O)-, -
  • A, W, D, G and S may all be present.
  • a is i and z is
  • the linker may be:
  • linker may be:
  • A, G and S may all be present.
  • D may be absent.
  • W may be absent.
  • a is i and z is i. Accordingly, the linker maybe:
  • the linker may be:
  • the linker may be:
  • a and G may both be present D may be absent W may be absent. S may be absent.
  • a is i and z is l. Accordingly, the linker may be:
  • a is i and z is 2 or 3. Accordingly, a may be 1 and z may be 3.
  • G and S may both be present.
  • A may be absent.
  • D may be absent.
  • W may be absent. Accordingly, the linker may be:
  • a is 2 or 3 and z is a. Accordingly, a may be 2 and z may be a. In some embodiments, W, D, G and S may all be present. A may be absent. Accordingly, the linker may be:
  • the linker will be known to those skilled in the art as either‘stable’ linkers which are resistant to degradation in cells and in the systemic circulation or‘cleavab!e’ or ‘conditionally labile’ linkers which are designed to degrade under intracellular conditions and/or in the systemic circulation following a defined trigger event, which may be a change in pH or a metabolic process such as ester or amide hydrolysis.
  • Conjugates of the present invention may comprise two or more cleavage elements which may be selected from acid-induced cleavage, peptidase-induced cleavage (for example, a peptide linker cleaved by an intracellular protease, such as a lysosomal protease or an endosomal protease, see Trout et.
  • cleavage elements which may be selected from acid-induced cleavage, peptidase-induced cleavage (for example, a peptide linker cleaved by an intracellular protease, such as a lysosomal protease or an endosomal protease, see Trout et.
  • valine-citrulline dipeptide moiety Ducry et ah, Bioconj. Chem., 2010, 21, 5-13 contained in the clinically precedented ADC brentuximab vedotin, a phenylalanine-lysine dipeptide, malei idoeaproyl or a male; midocaproyl- valine-citrulline linker.
  • the self-immolative group para- aminobenzyloxycarbonyl (PABC) may also form part of the linker structure in which, in response to a suitable trigger event, will eliminate from the conjugate to release the parent structure (Carl et. ah, J Med.
  • linkers include those linkers that are cleaved at a specific pH or pH range such as a hydrazone e.g. the hydrazone moiety in gemtuzumab ozogamicin.
  • a non-eleavable linker may be protease insensitive.
  • Non-cleavable linkers include that contained in the clinically precedented ADC trastuzumab emtansine and will require the conjugate to be degraded intracellularly to release the active drag C. See for example; Wong, Chemistry of Protein Conjugation and Cross-Linking, CRC Press Inc , Boca Raton, 1991.
  • the linker may be dendritic in nature, in that more than one small molecule C may be covalently attached through a branched, multifunctional unit to the targeting moiety (US2006/116422, US2005/271615). Dendritic linkers can increase the molar ratio of drug to targeting group which is related to the potency of the conjugate. Thus, where a targeting group contains for example just a single thiol group, a multitude of small molecules may be attached through a dendritic or branched linker.
  • the linker maybe attached to a targeting moiety T in a variety of ways at any suitable available position on the targeting moiety through a reactive group thereon.
  • suitable reactive groups include a surface lysine, an oxidised carbohydrate and a cysteine residue.
  • Suitable reactive groups will be known by the skilled person.
  • ADC antibody-drug conjugate
  • thiol groups, or cysteine residues may be bonded to the linker or spacer group via a maleimide group.
  • Alternative conjugation chemistries include lysine-reactive groups, such as succinyl or HQBt esters, pentafluorophenyl esters, b-lactam amides, isocyanates, and isothiocyanates; azide reactive groups, such as alkynes and strained alkynes; cysteine reactive groups, such as maleimides, a-haloacetamides, pyridyl disulfides and vinyl sulfoxides; and ketone reactive groups, such as hydroxylamines, hydrazines and acyl hydrazides.
  • the number of drag/linker moieties conjugated per antibody molecule ranges fro 1 to 10.
  • the drug antibody ratio (DAR) is typically from 1 to 10, and may be from 2 to 5 or 2 to 3. Accordingly, b may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • DAR drug antibody ratio
  • Such conjugates maybe designed to specifically target certain cell types or tumour types via the targeting moiety. Accordingly, the targeting moiety may be configured to direct the compound of formula (I) to a specific cell or tumour type, and thereby deliver the STING modulator in a cell-specific manner. The conjugate can therefore be used accordingly in a therapeutic setting.
  • the principle of this targeted delivery will be known to those skilled in the art as being closely related to ADC technology, for example as described in Polakis, P., Pharmacol.
  • the conjugate may then be taken up inside a cell or tumour through receptor-mediated endocytosis.
  • the target antigen or receptor may be part of a cell or tumour or can be an extracellular matrix protein within the microenvironment of the cell or tumour.
  • one or more specific peptide sequences within the conjugate may be hydrolytically cleaved by one or more cell or tumour proteases.
  • a tumour-associated protease for example, a tumour-associated protease, cathepsin B, C or D, or a plasmin protease to cleave the linker and release the active compound either in the target cells or in the tumour microenvironment of the target cells.
  • the active drug is then free to migrate within the cell or microenvironment and thereby contact and subsequently modulate the STING protein.
  • the active drug may be cleaved from the targeting moiety outside of cells or tumours and the active drug subsequently acts at the cell surface or penetrates the cell or tumour.
  • T is a targeting moiety and may comprise an antibody, an antibody fragment, a nucleic acid based molecule, a carbohydrate, a peptide, a modified peptide or a small molecule.
  • T may be configured to target a tumour antigen.
  • T may be configured to target the Human Epidermal Growth Factor Receptor (EGFR), a plasminogen activator, a cytotoxic T-lymphoeyte associated antigen (CTLA) such as CTLA-4, vascular endothelial growth factor (VEGF), neurotrophic factors such as BDNF, fibroblast growth factor receptor (FGFR), a nerve growth factor, platelet-derived growth factor (PDGF), transforming growth factor (TGF), tissue factor (TF), EpCAM, CEACAM5, CEACAM6, colon-specific antigen p, FLT3, PSA, PSMA, PSCA, STEAP, BCMA, CEA, folate receptor, cathepsin D, estrogen receptor, progesterone receptor, NCA-95, NCA-90, A3, A33, Ep-CAM, the CD33/CD3o/CD37/CD52/CD66e,
  • EGFR Human Epidermal Growth Factor Receptor
  • CTL-4 cytotoxic
  • CD56/CD74/CD79/CD22 receptors the SLC34A2 gene product, SLC44A4, the mesothelin protein, the integrin anb3, PD-i, PD-Li, EGP-i, EGP-2, the EphA2 tyrosine kinase, the mucin cell-surface antigens e.g.
  • MUC16 the n Lewis Y antigen, carbonic anhydrase IX, 5T4, EFNA4, DLL4, Axl, B7, ALK, Fyny, HLA, HIF, IGF, CC49, AFP, NaPiab, brc-abl, caspase-8, guanyiyl cyclase C, CD19, CD20, CD21, CD22, CD40, CD ga, CD79D, CD98, CD123, PTK7, CDK4, RANTES, CD44, CD48, CD133, CD70, CD72, CD74, CD166, c-kit, cMet, ErbB2/Here, ErbBs/Hers, ErbB4/Her4, OX40, pss, a-fetoprotein, Ri, PAP PAX3, PAX5, Ras, Rho, ROR2, nectin-4, E-cadherin, P- cadherin, cadherin-6, LRRC15, BMPRiB E
  • T is configured to target
  • HER2 may also be called Erbb2, and is a biomarker for breast cancer, gastric cancer, ovarian cancer and/or lung cancer.
  • T is an antibody, or a fragment thereof.
  • Certain antibodies have been applied in the field of immune oncology pre viously.
  • Exemplary anti-PDi antibodies include lambrolizumab (MK-3475, Merck), nivo!umab (BMS-936558, Bristol-Myers Squibb), AMP-224 (Merck) and pidi!izumab (CT-011, Curetech Ltd.).
  • Known anti-PDLi antibodies include MDX-1105 (Medarex), MEDI4736 (Medimmune), MPDL4280A (Genentech) and BMS-936559 (Bristol-Myers Squibb).
  • Exemplary anti- CTLA4 antibodies include ipilimumab (Yervoy, Bristol-Myers Squibb) and
  • tremelimumab tremelimumab (Pfizer).
  • exemplary anti-ErbB2/Here antibodies include trastuzumab (Roche) pertuzumab (Genentech), margetuximab (Macrogenics) and HT-19 (Mersana Therapeutics)
  • T is trastuzumab or a fragment or derivative thereof
  • conjugates which comprise an anti-HER2 antibody can be specifically targeted to HER2-positive cancer cells or tumours.
  • trastuzumab Herceptin or
  • Herclon is a humanized monoclonal antibody that binds to the juxtamembrane portion of the extracellular domain of the HER2 recep tor (Hudis et. a!., N. Engl. J. Med., 2007, 357, 39-51; Cho et. al., Nature, 2003, 21, 756-760).
  • Trastuzumab gained IJS FDA approval in September 1998 for the treatment of metastatic breast cancer in patients whose tumours overexpress HER2 and who received one or more
  • the invention extends to both whole antibodies, as well as to antigen-binding fragments or regions of the corresponding full-length antibody.
  • the antibody or antigen-binding fragment thereof maybe monovalent, divalent or polyvalent.
  • Monovalent antibodies are dimers (HL) comprising a heavy (H) chain associated by a disulphide bridge with a light chain (L).
  • Divalent antibodies are tetramer (H2L3) comprising two dimers associated by at least one disulphide bridge.
  • Polyvalent antibodies may also be produced, for example by Sinking multiple dimers.
  • the basic structure of an antibody molecule consists of two identical light chains and two identical heavy chains which associate non-covalently and can be linked by disulphide bonds.
  • Each heavy and light chain contains an amino-terminal variable region of about 110 amino acids, and constant sequences in the remainder of the chain.
  • the variable region includes several hypervariable regions, or Complementarity Determining Regions (CDRs), that form the antigen-binding site of the antibody molecule and determine its specificity for the antigen or variant or fragment thereof (e.g. an epitope).
  • CDRs Complementarity Determining Regions
  • On either side of the CDRs of the heavy and light chains is a framework region, a relatively conserved sequence of amino acids that anchors and orients the CDRs.
  • Antibody fragments may include a bi-specific antibody (BsAb) or a chimeric antigen receptor (CAR).
  • the constant region consists of one of five heavy chain sequences (m, g, z, a, or e) and one of two light chain sequences (K or A).
  • the heavy chain constant region sequences determine the isotype of the antibody and the effector functions of the molecule.
  • the antibody or antigen-binding fragment thereof is isolated or purified.
  • the antibody or antigen-binding fragment thereof comprises a polyclonal antibody, or an antigen-binding fragment thereof.
  • the antibody or antigen-binding fragment thereof may be generated in a rabbit, mouse or rat.
  • the antibody or antigen-binding fragment thereof comprises a monoclonal antibody or an antigen-binding fragment thereof.
  • the antibody is a human antibody.
  • the term“human antibody” can mean an antibody, such as a monoclonal antibody, which comprises substantially the same heavy and light chain CDR amino acid sequences as found in a particular human antibody exhibiting immunospecificity.
  • An amino acid sequence which is substantially the same as a heavy or light chain CDR, exhibits a considerable amount of sequence identity when compared to a reference sequence. Such identity is definitively known or recognizable as representing the amino acid sequence of the particular human - 6i - antibody.
  • Substantially the same heavy and light chain CDR amino acid sequence can have, for example, minor modifications or conservative substitutions of amino acids.
  • human monoclonal antibody can include a monoclonal antibody with substantially or entirely human CDR amino acid sequences produced, for example by recombinant methods such as production by a phage library, by lymphocytes or by hybridoma cells.
  • humanised antibody can mean an antibody from a non-human species (e.g. mouse or rabbit) whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans.
  • the antibody may be a recombinant antibody.
  • the term“recombinant human antibody” can include a human antibody produced using recombinant DNA technology.
  • the term“antigen-binding region” can mean a region of the antibody having specific binding affinity for its target antigen or a variant or fragment thereof. Preferably, the fragment is an epitope.
  • the binding region maybe a hypervariable CDR or a functional portion thereof.
  • the term“functional portion” of a CDR can mean a sequence within the CDR which shows specific affinity for the target antigen.
  • the functional portion of a CDR may comprise a ligand which specifically binds to the target antigen or a fragment thereof.
  • the ter “CDR” can mean a hypervariable region in the heavy and light variable chains. There may be one, two, three or more CDRs in each of the heavy and light chains of the antibody . Normally, there are at least three CDRs on each chain which, when configured together, form the antigen-binding site, i.e. the three-dimensional combining site with which the antigen binds or specifically reacts. It has however been postulated that there maybe four CDRs in the heavy chains of some antibodies.
  • CDR also includes overlapping or subsets of amino acid residues when compared against each other.
  • residue numbers which encompass a particular CDR or a functional portion thereof will van, ' depending on the sequence and size of the CDR.
  • Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.
  • the term“functional fragment” of an antibody can mean a portion of the antibody which retains a functional activity.
  • a functional activity can be, for example antigen binding activit or specificity.
  • a functional activity can also be, for example, an effector function provided by an antibody constant region.
  • the term“functional fragment” is also intended to include, for example, fragments produced by protease digestion or reduction of a human monoclonal antibody and by recombinant DNA methods known to those skilled in the art.
  • Human monoclonal antibody functional fragments include, for example individual heavy or light chains and fragments thereof, such as VL, VH and Fd; monovalent fragments, such as Fv, Fab, and Fab'; bivalent fragments such as F(ab') 2 ; single chain Fv (scFv); and Fe fragments.
  • VL fragment can mean a fragment of the light chain of a human monoclonal antibody which includes all or part of the light chain variable region, including the CDRs.
  • a VL fragment can further include light chain constant region sequences.
  • VH fragment can means a fragment of the heavy chain of a human monoclonal antibody which includes all or part of the heavy chain variable region, including the CDRs.
  • Fd fragment can mean the heavy chain variable region coupled to the first heavy chain constant region, i.e. VH and CH-i. The“Fd fragment” does not include the light chain, or the second and third constant regions of the heavy chain.
  • the term“Fv fragment” can mean a monovalent antigen-binding fragment of a human monoclonal antibody, including all or part of the variable regions of the heavy and light chains, and absent of the constant regions of the heavy and light chains.
  • the variable regions of the heavy and light chains include, for example, the CDRs.
  • an Fv fragment includes all or part of the amino terminal variable region of about no amino acids of both the heavy and light chains.
  • Fab fragment can mean a monovalent antigen-binding fragment of a human monoclonal antibody that is larger than an Fv fragment.
  • a Fab fragment includes the variable regions, and all or part of the first constant domain of the heavy and light chains.
  • a Fab fragment additionally includes, for example, amino acid residues from about no to about 220 of the heavy and light chains.
  • the term“Fab' fragment” can mean a monovalent antigen-binding fragment of a human monoclonal antibody that is larger than a Fab fragment.
  • a Fab' fragm ent includes all of the light ch ain , all of the variable region of the heavy chain, and all or part of the first and second constant domains of the heavy chain.
  • a Fab' fragment can additionally include some or all of amino acid residues 220 to 330 of the heavy chain.
  • F(ab’) 2 fragment can mean a bivalent antigen-binding fragment of a human monoclonal antibody.
  • An F(ab’) 2 fragment includes, for example, all or part of the variable regions of two heavy chains-and two light chains, and can further include all or part of the first constant domains of two heavy chains and two light chains.
  • single chain Fv can mean a fusion of the variable regions of the heavy (VH) and light chains (VL) connected with a short linker peptide.
  • bispecific antibody can mean a bispecific antibody comprising two scFv linked to each other by a shorter linked peptide.
  • a functional fragment of the antibody may comprise or consist of a fragment with substantially the same heavy and light chain variable regions as the human antibody.
  • the antigen-binding fragment thereof may comprise or consist of any of the fragments selected from a group consisting of VH, VL, Fd, Fv, Fab, Fab’, scFv, F (ab') 2 and Fc fragment.
  • the antigen-binding fragment thereof may comprise or consist of any one of the antigen binding region sequences of the VL, any one of the antigen binding region sequences of the VH, or a combination of VL and VH antigen binding regions of a human antibody.
  • the appropriate number and combination of VH and VL antigen binding region sequences may be determined by those skilled in the art depending on the desired affinity and specifi city and the intended use of the antigen-binding fragment.
  • Functional fragments or antigen-binding fragments of antibodies may be readily produced and isolated using methods well known to those skilled in the art. Such methods include, for example, proteolytic methods, recombinant methods and chemical synthesis. Proteolytic methods for the isolation of functional fragments comprise using human antibodies as a starting material.
  • Enzymes suitable for proteolysis of human immunoglobulins may include, for example, papain, and pepsin.
  • the appropriate enzyme maybe readily chosen by one skilled in the art, depending on, for example, whether monovalent or bivalent fragments are required.
  • papain cleavage results in two monovalent Fab' fragments that bind antigen and an Fc fragment.
  • Pepsin cleavage for example, results in a bivalent F fab’) fragment.
  • An F (ab% fragment of the invention maybe further reduced using, for example, DTT or 2- mereaptoethanol to produce two monovalent Fab' fragments.
  • Functional or antigen-binding fragments of antibodies produced by proteolysis maybe purified by affinity and column chromatographic procedures. For example, undigested antibodies and Fc fragments may be removed by binding to protein A. Additionally, functional fragments may be purified by virtue of their charge and size, using, for example, ion exchange and gel filtration chromatography. Such methods are well known to those skilled in the art.
  • the antibody or antigen-binding fragment thereof may be produced using techniques well known in the art. For example, by recombinant methodology (see US Pat. No. 4,816,567), hydridoma technology (Kohler et. al., Nature, 1975, 495), phage
  • Such regions may include, for example, all or part of the variable region of the heavy and light chains.
  • such regions can particularly include the antigen binding regions of the heavy and light chains, preferably the antigen binding sites, most preferably the CDRs.
  • the polynucleotide encoding the antibody or antigen-binding fragment thereof according to the invention may be produced using methods known to those skilled in the art.
  • the polynucleotide encoding the antibody or antigen-binding fragment thereof may be directly synthesized by methods of oligonucleotide synthesis known in the art. Alternatively, smaller fragments maybe synthesized and joined to form a larger functional fragment using reco binant methods known in the art.
  • Antibodies of use may be commercially obtained from a wade variety of known sources e.g the American Type Culture Collection (ATCC, Manassas, Va.). A large number of antibodies against a wade variety of disease targets and tumor-associated antigens have been deposited at the ATCC and/ or have published variable region sequences and are available for use in the claimed methods and compositions.
  • ATCC American Type Culture Collection
  • Cysteine-engineered antibodies have been designed as Fab antibody fragments
  • ThioFab and expressed as full-length IgG monoclonal (thioMab) antibodies (US. Pat. 7,521,541).
  • ThioFab and ThioMab antibodies have been conjugated through linkers at the newly introduced cysteine thiols to prepare site-specific antibody-drug conjugates (US. Pat. 7521541, US2008/0050310, WO2008/052187).
  • Polytherics have described a method for bridging a pair of sulfhydryl groups contained in antibody proteins derived from reduction of a native disulfide hinge (Badescu et. ah,
  • transglutaminases used to enzymatically conjugate primary amine- containing linker/payloads to glutamine residues (Dorywalska, M. et. al, Bioconj.
  • the term“immunospecificity” can mean the binding region is capable of immunoreacting with the target antigen, or a variant or fragment thereof by
  • the antibody or antigen-binding fragment thereof can selectively interact with an antigen with an affinity constant of approximately icm to 10 J 3 M 1 , preferably 10 to to ? M 1 , even more preferably, io 10 to icr 12 MA
  • the term“immunoreact” can mean the binding region is capable of eliciting an immune response upon binding with the target antigen, or an epitope thereof.
  • the term“epitope” can mean any region of an antigen with the ability to elicit, and combine with, a binding region of the antibody or antigen-binding fragment thereof.
  • T comprises a nucleic acid based molecule.
  • the nucleic acid based molecule may be an aptamer.
  • the nucleic acid based molecule may target the
  • CD33/CD34 antigen as described in Zaimy, M.A. et. al., Cancer Gene Ther., 2016, 23,
  • Aptamers are nucleic acid or peptide molecules that assume a specific, sequence- dependent shape and bind to specific target ligands based on a lock-and-key fit between the aptamer and ligand.
  • aptamers may comprise either single- or double-stranded DNA molecules (ssDNA or dsDNA) or single-stranded RNA molecules (ssRNA).
  • Peptide aptamers consist of a short variable peptide domain, attached at both ends to a protein scaffold. Aptamers maybe used to bind both nucleic acid and non-nucleic acid targets. Suitable aptamers may be selected from random sequence pools, from which specific aptamers may be identified which bind to the selected antigen with high affinity. Methods for the production and selection of aptamers having desired specificity are well known to those skilled in the art, and include the SELEX
  • T comprises a peptide or a modified peptide.
  • the peptide or modified peptide may comprise the RGD sequence motif, as described in Mousavizadeh, A., Colloids Surfaces B., 2017, us 8. 507-517 to include linear RGD peptide sequences or eyclised versions thereof as described in Belvisi, L et. al., Curr. Top., Med Chem., 2016, 16, 314-329.
  • Exemplary embodiments of an RGD ligand which the targeting moiety may target and bind are as follows:
  • the peptide or modified peptide may comprise transferrin, or modified versions of transferrin, which has been described as showing promise for the targeted delivery of xenobiotics (Kratz et. ah, Cancer Chemother. Pharmacol., 1998, 41, 155-160), including crossing the blood-brain barrier (Fishman et. ah, J. Cell Bioh, 1987, 101. 423- 427).
  • the peptide or modified peptide may also comprise albumin, or modified versions of albumin, in which the albumin protein may be conjugated to a suitable linker via Cys34 or other suitable residue as described in Larsen et. ah, Mol Cell Ther., 2016, 4, 3.
  • T comprises a carbohydrate or a modified carbohydrate molecule which can target a tumour-associated carbohydrate antigen receptor on target tumours and cells.
  • glycosphingolipids, gang!iosides, sialic acids and mucins are indicative of malignant transformation and an aberrant glycosylation pattern on cancer cells (as reviewed in Feng, D. et. al., ACS Chem. Biol. 2016, 11, 850- 863; Hakomori, S., Ann. Rev. Immunol, 1984, 2, 103-126; Dube, D.H. and Bertozzi, C.R., Nat Rev.
  • Drug Disc., 2005, 4, 477-488) and targeting ligands based on carbohydrate molecules have been designed against them, for example mannose, galactose or cerebrosidase derivatives.
  • cell-surface receptors on tissues of interest may also be targeted; a recent example includes derivatives of N- acetyl-ga!actosamine (Ga!NAc) which have been developed to target the
  • Exemplary embodiments of carbohydrates which may be used as the targeting moiety are as follows:
  • T comprises a small molecule ligand with affinity for a cell or tumour-surface receptor.
  • folic acid or derivatives thereof may be used to target folate receptors a, b or g (FRa, FRp and FRy).
  • FRa in particular is known to be expressed in multiple endothelial tumour types such as breast, lung and kidney (see Fernandez, M. et ai, 2018, 4, 790-810 for a recent review) and conjugates of folate derivatives and toxins have been described previously (Vlahov, I. and Leamon, C.P., Bioconjugate Chern., 2012, 23 . , 1357-1369).
  • a small molecule ligand (a folate derivative) which targets a folate receptor on the target cell surface conjugated to a linker has the structure:
  • conjugate designs may be combined with the linker designs outlined above to provide composite folate receptor-targeting designs, for example;
  • T may be a folate or a derivate thereof.
  • T may be:
  • T maybe:
  • CCK2R cholecystokinin 2 receptor
  • CCK2R is a transmembrane receptor primarily found in epithelial cells of the GI tract and the brain. CCK2R is overexpressed in many cancers of the lung, pancreas, liver and GI tract (Reubi, J.C. et. ai, Cancer Res , 1997, 57, 1377-1386).
  • a recent report has described conjugates of a potent CCK2 receptor antagonist, Z-360, linked to a vinblastine derivative (Wayua, C. et. ai, Mol. Pharm., 2015, 12, 2477-2483).
  • Another exemplary embodiment of a small molecule ligand (a CCK2R antagonist) which targets CCK2R on the target cell surface is shown below conjugated to a linker.
  • T may be a CCK2R antagonist.
  • T may be a CCK2R antagonist.
  • ligand-targeted small molecules are described in Srinivasarao, M. et. ai, Chem. Revs., 2017, 117. 12133-12164.
  • vintafolide targeting folate receptors
  • glufosfamide targeting b-D-g!ucose
  • vitamin D targeting vitamin D receptors
  • cholesterol and lipophilic esters targeting the liver
  • C is a small molecule modulator of the STING protein of formula (II) as described above.
  • C can therefore be attached to the linker through a C atom, an O atom, an N atom or an S atom at any available position, for example through the R -R * groups.
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • R 1 , R 2 and R 3 may each independently be selected from the group consisting of H, halogen, and optionally substituted C 1 -C 0 alkyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, halogen, and C 1 -C 3 alkyl. More preferably, R 1 , R 2 and R 3 are each independently selected from the group consisting of H, halogen, and methyl.
  • R 1 , R 2 and R 3 are each H.
  • one or two of X , X 2 and X 3 is N. Accordingly, X 1 may be N, X 2 may be CR 2 and X 3 may be CR 3 , X 1 may be CR 1 , X 2 may be N and X 3 may be CR 3 or X 1 may be CR 1 , X 2 may be CR 2 and X 3 may be N.
  • X 2 is CR 2 .
  • X 1 may be CR‘ or N and X 3 may be CR 3 or N.
  • X 1 may be N
  • X 2 may be CR 2 and X 3 may be CR 3
  • X 1 may be CR 1
  • X 2 may be CR 2 and X 3 may be N
  • R 2 is H, halogen or C 1 -C 3 alkyl. More preferably, R 2 is H, halogen or methyl. Most preferably, R 2 is each H.
  • R and/or R 3 in embodiments where they are present, are independently H, halogen or C 1 -C 3 alkyl. More preferably, R and/or R 3 , in embodiments where they are present, are independently H, halogen or methyl. Most preferably, R and/or R 3 , in embodiments where they are present, are H.
  • Compounds of formula (II) may include one or more stereogenic centres and so may exist as optical isomers, such as enantiomers and diastereomers. All such isomers and mixtures thereof are included within the scope of the present invention.
  • the compound of formula (I) will include a first stereogenic centre.
  • the first stereogenic centre, or stereocentre is the carbon atom to which R 9 and R 10 are covalently bonded.
  • Compounds of formula (II) may be represented by a formula (Il)-ent. i or (Il)-ent. 2:
  • the first stereogenic centre defines an S enantiomer.
  • At least one of R 9 and R 10 is an optionally substituted C -C 6 alkyl, halogen, H, a C 3 -C 6 cycloalkyl or C -C 3 polyfluoroalkyl. More preferably, at least one of R 9 and R 10 is a C -C 6 alkyl, H or a C 3 -C6 cycloalkyl, even more preferably a C -C 3 alkyl, H or a C 3 -Ca cycloalkyl, and most preferably at least one of R 9 and R 10 is H, methyl, ethyl, isopropyl or cyclopropyl. In one embodiment, R 9 and R 10 are both H.
  • both R 9 and R 10 are methyl and the other is H.
  • both R 9 and R 10 are an optionally substituted C -C 6 alkyl or II.
  • both R 9 and R 10 are a C -C 6 alkyl, more preferably a C -C 3 alkyl, even more preferably methyl, ethyl or isopropyl, and most preferably both R 9 and R 10 are methyl.
  • one of R 9 and R 10 is methyl and the other is
  • the compound is a compound of formula (Il)-ent.
  • R 9 is H and R 10 is an optionally substituted C t -C 6 alkyl, halogen, a C 3 -C 6 cycloalkyl or C 1 -C 3 polyfluoroalkyl.
  • R 10 is a C -C 6 alkyl or a C 3 -C 6 cycloalkyl, more preferably R 10 is a C -C 3 alkyl or a C 3 -C 6 cycloalkyl, and most preferably R 10 is methyl, ethyl, isopropyl or cyclopropyl. In a most preferred embodiment, R 10 is methyl.
  • R 10 may be absent, and the linker may be bonded directly to the carbon atom. Accordingly, the compound of formula (I) maybe a compound of formula (I- A):
  • Q may be CR 4 R 5 . Accordingly, the compound maybe a compound of formula (Il)-ent 3 or (Il)-ent 4:
  • L is a branched alkyl group Accordingly, the compound may be a compound of formula (Il)-ent 5 or (Il)-ent 6:
  • the compound could possess two chiral centres and could be represented by a compound of formula (II-I-IV)-ent 1, formula (Il-I-IV)-ent 2, formula (Il-I-IV)-ent 3 or formula (Il-I-IV)-ent 4:
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallizati on and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chi ral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from o to 50% by volume of isopropanol, typically from 2% to 20%, and from o to 5% by volume of an alkylamine, typically 0.1% diethylamine.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from o to 50% by volume of isopropanol, typically from 2% to 20%, and from o to 5% by volume of an alkylamine, typically 0.1% diethylamine.
  • R u is selected from the group consisting of optionally substituted C -C 6 alkyl, H, hydroxyl, C -C 3 polyfluoroalkyl, optionally substituted C 3 -Cc, cycloalkyl, optionally substituted C-Ce alkoxy and optionally substituted C 2 -C6 alkenyl.
  • the linker may be bonded to the oxygen in the alkoxy. Accordingly, the compound of formula (I) may be a compound of formula (I-B-a):
  • f is an integer between 1 and 6.
  • R 11 is selected from the group consisting of C -Ce alkyl, C 2 -C 4 alkenyl and H. More preferably, R is a C -C 3 alkyl or H, and most preferably is methyl or H. Preferably, R 11 is an optionally substituted C 1 -C 0 alkyl, an optionally substituted C 2 -C6 alkenyl, a C 3 -C & cycloalkyl or C -C 3 polyfluoroalkyl.
  • R 11 is a C -C 6 alkyl, a C a -Ce alkenyl, or a C 3 -C 6 cycloalkyl, even more preferably a C 1 -C 3 alkyl, a C 2 -C 3 alkenyl or a C 3 -C 6 cycloalkyl, and most preferably R u is methyl, ethyl, isopropyl or cyclopropyl.
  • R n is methyl.
  • R 4 and R 5 are each independently selected from the group consisting of H, halogen, optionally substituted C C b alkyl, optionally substituted C 3 -C 6 cycloalkyl or R 4 and Rs together with the atom to which they are attached form a spirocyclic ring. More preferably, R 4 and R 5 are each independently selected from the group consisting of H and optionally substituted C -C 6 alkyl. Accordingly, R 4 and R 5 may both be H. Alternatively, R 4 and R 5 may both be Me or R 4 may be Me and R 5 may be H.
  • C is attached to the linker through the R 6 group. Accordingly, the R 6 group may be substituted by the linker.
  • the compound of formula (I) may be a compound of formula (I-C):
  • R 6 is a ring optionally substituted with one or more R 12 groups, wherein the ring is selected from the group consisting of a mono or bicyclic C 5 -C 0 and; mono or bicyclic 5 to 10 membered heteroaryl; and a C 3 -C 6 cycloalkyl. More preferably, R 6 is a ring optionally substituted with one or more R 12 groups, wherein the ring is selected from the group consisting of a mono or bicyclic C 5 -C 0 aryl; and mono or bicyclic 5 to 10 membered heteroaryl. Most preferably, R 6 is a mono or bicyclic C 5 -C 10 aryl optionally substituted with one or more R 12 groups.
  • the ring may be directly substituted to the linker. Alternatively, the linker may substitute an R 12 group. In some embodiments R 6 is unsubstituted or only substituted by the linker.
  • R 6 may comprise a ring substituted with between i and 5 R i2 .
  • the ring could be substituted with 1, 2, 3, 4 or 5 R 12 groups.
  • the ring may further be directly substituted with the linker.
  • the linker may substitute an R 12 group.
  • An R 12 group may be a halogen.
  • the halogen maybe fluorine, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine, even more preferably fluorine or chlorine, and most preferably fluorine.
  • An R 12 group may be an optionally substituted C ; -C Intel alkyl, and more preferably an optionally substituted C -C :3 alkyl.
  • the alkyl may be
  • an R 12 group may be methyl, ethyl, n-propy! (i-propyl) and isopropyl (2-propyl, i-methyl ethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, ferf-butyl, isopentyl, neopentyl, isohexyl or neohexyl.
  • the alkyl may be substituted with one or more groups selected from a halogen, OH, NH 2 or CN.
  • a H in the OH or NH 2 group could be omitted and the oxygen or nitrogen could be bonded directly to the linker.
  • the halogen is a chlorine or fluorine and most preferably a fluorine.
  • an R 12 group is an optionally substituted methyl or ethyl.
  • the optionally substituted alkyl may be a fluorinated methyl or ethyl.
  • an R 12 group is a methyl, -CHF 2 , -CF a , - CH 2 0H or -CH(OH)CH 3 .
  • the H could be omitted and the oxygen could be bonded directly to the linker.
  • R 12 group may be an optionally substituted C-Co alkoxy. Accordingly, an R 12 group maybe -OR 15 , where R 15 is an optionally substituted C -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, an optionally substituted C 2 -C o alkenyl or an optionally substituted C 2 -Cfi alkynyl. Preferably, R 15 is an optionally substituted C -C 3 alkyl group, an optionally substituted C 2 -C 3 alkenyl or an optionally substituted C 2 -C 3 alkynyl. In some embodiments, the C -C 6 al koxy may be unsubstituted.
  • an R 12 group may be methoxy, ethoxy, n-propoxy (l-propoxy), n-butoxy and tert- butoxy.
  • an R 12 group is methoxy or -0CH 2 CHCH 2 .
  • the C -C 6 alkoxy may be substituted with one or more groups selected from -OH, - -NH 2 , CN, 0P(0)(0H) 2 , COOH, a halogen, OSCRRA N(H)S0 2 RA a C 3 -C 6 cycloalkyl and a 3 to 8 memhered heterocycle.
  • a H in the OH or NH 2 group or R i3 in the OSO 2 R 13 or N(H)SQ 2 R i3 group could be omitted and the oxygen or nitrogen could be bonded directly to the linker.
  • a H in the OH or NH 2 group or R i3 in the OSO 2 R 13 or N(H)SQ 2 R i3 group could be omitted and the oxygen or nitrogen could be bonded directly to the linker.
  • R 13 may be independently selected from the group consisting of H and optionally substituted C -C 6 alkyl.
  • R 13 is selected from the group consisting of H and C 1 -C 0 alkyl, more preferably H and C 1 -C3 alkyl.
  • R i3 is Me.
  • the C 3 -C 6 cycloal kyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the 3 to 8 membered heterocycle may be aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-i-yl, tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane or oxazine.
  • the 3 to 8 membered heterocycle is morpholine.
  • an R 12 group is an optionally substituted alkoxy, i.e. -OR 15 .
  • R 15 may be an optionally substituted C -C 6 alkyl.
  • R 13 is a C -C 6 alkyl substituted with a halogen, preferably a chlorine or fluorine and most preferably a fluorine.
  • the R 15 group is a halogenated methyl, more preferably a fluorinated methyl and most preferably ⁇ CHF 2 or -CF g, Accordingly, an R 12 group may be -0CHF 2 or -OCF 3 .
  • R 13 may be a C -C 6 alkyl substituted with one or more substituents selected from the group consisting of OH, 0P(0)(0H) 2 , OSO s -R 1 , NHSO ⁇ R 1 , Ck-Cs alkoxy, NR R 2 , CONR'R 2 , CN, COOH, optionally substituted C 5 -C 0 aryl, optionally substituted 5 to 10 membered heteroaryl, C 3 -Ce cycloalkyl and 3 to 8 membered heterocycle, more preferably R 13 is a C -C 6 alkyl substituted with one or more substituents selected from the group consisting of OH, GP(Q)(QH) 2 , NHS0 2 R : , COOH and 3 to 8 membered heterocycle.
  • the optional ly substituted C 5 -C 0 aryl or optionally substituted 5 to 10 membered heteroaryl may be substituted with the linker.
  • NHS0 2 R 1 or CQNRTl 2 group could be omitted and the oxygen or nitrogen could be
  • an R i2 group may be integer between i and 6, and d and e are both integers between o and 5 wherein the sum of d and e is an integer between o and 5.
  • the R 12 group may be connected to the linker like so:
  • c may be 1, 2, 3, 4, 5 or 6, and is preferably 1, 2 or 3.
  • d and e may be o, 1, 2, 3, 4 or 5.
  • d and e are both integers between o and 2 wherein the sum of d and e is an integer between o and 2
  • d is 1 and
  • R 12 may be -OH or -SH, or the hydrogen may be omitted and the oxygen or sulphur may be bonded directly to the linker.
  • R 12 group may be NR i3 R 14 , or the Rw may be omitted and the nitrogen is bonded directly to the linker R 14 , and R 13 in embodiments where it is present, may each be independently selected from the group consisting of H and optionally substituted Cr&, alkyl.
  • R 14 , and R 13 in embodiments where it is present, are each
  • R 13 and R 14 are both H. Accordingly, an R 12 group may be NH 2 or a hydrogen may be omitted and the nitrogen may be bonded directly to the linker. Alternatively, at least one of R 13 and R 14 maybe an optionally substituted C -C 6 alkyl, preferably an optionally substituted C -C 3 alkyl. The or each alkyl maybe unsubstituted.
  • the or each alkyl may be methyl, ethyl, n-propyl (l-propyl) and isopropyl (2-propyl, l-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert- butyl, isopentyl, neopentyl, isohexyl or neohexyl.
  • an R 12 group may be N (H )Me or N (Me) 2 or the hydrogen may be omitted and the nitrogen may be bonded directly to the linker.
  • the or each alkyl may be substituted with a halogen, -OH, CN or NH 2 group.
  • an R 2 group may be -NH(CH 2 ) m 0H, wherein m is an integer between i and 6, more preferably between i and 3, or the hydrogen bonded to either the nitrogen or the oxygen may be omitted and the nitrogen or oxygen may be bonded directly to the linker.
  • m is 2 or 3.
  • R 12 group may be CONR 13 R 14 , or the R 13 may be omitted and the nitrogen may be bonded directly to the linker.
  • R 14 , and R 13 in embodiments where it is present may each be independently selected from the group consisting of H and optionally substituted C -Ca alkyl.
  • R 14 , and R 13 in embodiments where it is present are each independently selected from the group consisting of H and optionally substituted C 1 -C 3 alkyl.
  • R 13 and R 14 are both H. Accordingly, an R 12 group may be C0NH 2 or a hydrogen may be omitted and the nitrogen may be bonded directly to the linker.
  • R 13 and R 14 may be an optionally substituted C - Co alkyl, preferably optionally substituted C 1 -C 3 alkyl.
  • the alkyl is substituted with an OH group.
  • an R 12 group may be
  • n is an integer between 1 and 6.
  • n is an integer between 1 and 3, and most preferably n is 2.
  • the R i2 maybe bonded directly to the linker like s
  • n is as defined above.
  • R 12 group may be CQOR 13 , or the R 13 may be omitted and the oxygen may be bonded directly to the linker.
  • R 13 may be independently selected from the group consisting of H and optionally substituted C -Ce, alkyl.
  • R 13 is selected from the group consisting of H and C r C & alkyl, more preferably H and C -C 3 alkyl.
  • R 13 is H or Me.
  • An R 12 group may be QS0 2 R 13 , or the R 13 may be omitted and the oxygen may be bonded directly to the linker.
  • R 13 may be selected from the group consisting of H and optionally substituted C ; -C fatigue alkyl.
  • R 13 is selected from the group consisting of H and C -Cc, alkyl, more preferably H and C -C 3 alkyl.
  • R 13 is Me.
  • R 12 group may be NR 13 S0 2 R 14 , or the R 13 or R 14 may be omitted and the nitrogen or oxygen may be bonded directly to the linker.
  • R 13 and R 14 in embodiments where they are present, may be independently selected from the group consisting of H and optionally substituted C -C 6 alkyl.
  • R 13 and R 14 in embodiments where they are present, are selected from the group consisting of H and C 1 -C 0 alkyl, more preferably H and C -C 3 alkyl.
  • R 13 is H and R 14 is Me.
  • R 12 group may be NR 13 C(0)R 14 , or the R 13 may be omitted and the nitrogen may be bonded directly to the linker.
  • R 13 and R 14 in embodiments where they are present, may be independently selected from the group consisting of H and optionally substituted Cr&, alkyl.
  • R 13 and R 14 in embodiments where they are present, are selected from the group consisting of H and an optionally substituted C -C 3 alkyl.
  • the or each alkyl maybe substituted with a halogen, -OH, CN or NH 2 group, or a hydrogen may be omitted and the oxygen or nitrogen may be bonded directly to the linker.
  • R 13 is H and R 14 is an optionally substituted methyl.
  • R 14 is Me or -CH 2 NH 2 , or a hydrogen may be omitted and the linker may be bonded directly to the nitrogen.
  • an R 12 group may be - NHC(0)CH 3 or --N H Ci 0)CH N H .
  • the R 12 group may be directly bonded
  • R 12 group may be ()i(TkJ OC(()jR i:! .
  • n is preferably an integer between 1 and 6, more preferably between 1 and 3.
  • n is 2.
  • RA may be H or optionally substituted C.-Ce alkyl.
  • R 13 is an optionally substituted C -Ce alkyl, more preferably an optionally substituted C -C 3 alkyl, and most preferably an optionally substituted methyl.
  • the alkyl may be substituted with a halogen, OH, CN, NRTl 2 or an optionally substituted mono or bieyclic C 5 -C 10 aryl, or a hydrogen or the R 1 group may be omitted and the oxygen or nitrogen may be bonded directly to the linker.
  • the aryl may be substituted with the linker.
  • the alkyl is substituted with NR : R ⁇ - or R 1 is omitted and the nitrogen is bonded directly to the nitrogen.
  • R 1 and R 2 are each independently selected from the group consisting of H and C -C 6 alkyl, more preferably H and C 1 -C 3 alkyl. Most preferably, R 1
  • an R 12 group may where m is an integer between i and 6, more preferably between i and 3, and most preferably is
  • R 12 group may be and
  • the R 12 group may be bonded to the linker like so
  • R 12 group may be QC(0)0R 13 , or the R 13 may be omitted and the oxygen may be bonded directly to the linker.
  • R i3 may be H or optionally substituted C -C 6 alkyl.
  • R 13 is an optionally substituted C -Ce alkyl, more preferably an optionally substituted C -C 3 alkyl, and most preferably an optionally substituted methyl.
  • the al kyl may be substituted with a halogen, OH, CN, NfbR 2 or an optionally substituted mono or bicyclic C 5 -C 0 aryl, or a hydrogen or the R 1 group may be omitted and the oxygen or nitrogen may be bonded directly to the lin ker.
  • the aryl may be substituted with the linker.
  • the alkyl is substituted with an optionally substituted mono or bicyclic C 5 -C 0 aryl.
  • the optionally substituted mono or bicyclic C 5 -C 0 aryl is preferably optionally substituted phenyl.
  • an R 12 group may , wherein m is an integer between t and 6, p is an integer between o and 5 and the or each R 16 is independently selected from the group consisting of an optionally substituted C -C 6 alkyl, halogen, OH, 0P(0)(0H) 2 , optionally substituted C -C 6 alkoxy, NR3 ⁇ 4 2 , C0NR l R 2 ,
  • R 1 is a C -Co alkyl, more preferably a C -C 3 alkyl and most preferably a methyl. Accordingly, in a preferred embodiment, an R 12 group may be
  • each R 16 is independently selected from the group consisting of an optionally substituted Cr-Gs alkyl, halogen, OH, 0P(0)(0H) 2 , optionally substituted C 1 -C 0 alkoxy, NfbR 2 .
  • R 12 group may be O C (() ) N R : (C H 2 ) i; CO O R i or the R 33 or R 14 group may be omitted and the linker may be bonded directly to the nitrogen or oxygen.
  • R 33 may be H or optionally substituted C 1 -C 0 alkyl, preferably H or a C -C o alkyl, more preferably H or a C -C 3 alkyl and most preferably methyl.
  • n is an integer between 1 and 6. Accordingly, n maybe 1, 2, 3, 4, 5 or 6, and is most preferably 1, 2 or 3. In a preferred embodiment, n is 2.
  • R 14 may be H or optionally substituted C -C 6 alkyl.
  • R 14 is an optionally substituted C 1 -C 0 alkyl, more preferably an optionally substituted C 1 -C 3 alkyl, and most preferably an optionally substituted methyl.
  • the €rC & alkyl maybe substituted with an optionally substituted mono or bicyclic C 5 -C 0 aryl.
  • the aryl may be substituted with the linker.
  • the optionally substituted mono or bicyclic C 5 -C 0 aryl is preferably optionally substituted phenyl.
  • the mono or bicyclic C 5 - C 10 aryl is unsubstituted.
  • an R 12 group maybe , wherein each n is independently an integer between o and 6, preferably between 1 and 6, more preferably between 1 and 3 In a most
  • an R 12 group may
  • R 12 group may be 0C(0)NR i3 R 14 , or the R 13 group may be omitted and the nitrogen bonded directly to the linker.
  • R i3 may 7 be H or optionally substituted C -C 6 alkyl, preferably H or a C -C 6 alkyl, more preferably H or a C 1 -C 3 alkyl and most preferably methyl.
  • R 14 may be H or an optionally substituted C 1 -C 0 alkyl, preferably H or an optionally substituted C 1 -C 3 alkyl, more preferably an optionally substituted C -C 2 alkyl.
  • the alkyl maybe substituted with one or more of halogen, OH, 0P(0)(0H) 2 , C 1 -C 0 a! koxy, NR l R 2 , C0NR l R 2 , CN or COOH, or a hydrogen or R 1 group may be omitted and the linker may be bonded directly to an oxygen or nitrogen.
  • the alkyl is substituted with NR ! R 2 , or the R 1 is omitted and the nitrogen is bonded directly to the linker.
  • R 2 , and R 1 in embodiments where it is present, may each independently be selected from the group consisting of H, halogen and optionally substituted C -C- 6 alkyl, more H or a Cr-Cc, alkyl, even more preferably H or a C -C 3 alkyl, and most preferably H or methyl.
  • R 1 is H and R 2 is methyl. Accordingly, in a preferred embodiment, an R 12
  • an R 12 group may be
  • An R 12 group may be an optionally substituted mono or bicyclic C 5 -C 0 aryl.
  • the optionally substituted mono or bicyclic C 5 -C 10 aryl may be an optionally substituted phenyl.
  • the mono or bicyclic C 5 -C 0 aryl group maybe substituted with one or more of an optionally substituted C -C 6 alkyl, halogen, OH, optionally substituted C.-Ce alkoxy, CN and/or the linker.
  • the mono or bicyclic C 5 -C 10 aryl is substituted with a C.-Ce alkyl, more preferably a C -C 3 alkyl and most preferably methyl.
  • the mono or bicyclic C 5 -C 0 aryl is substituted with a halogen, more preferably a fluorine or chlorine and most preferably a fluorine.
  • An R 12 group may be an optionally substituted C 3 -C 6 cycloalkyl.
  • the cycloalkyl may be substituted with the linker.
  • the C 3 -C 6 cycloalkyl may be unsubstituted.
  • the C 3 -C- 6 cycloalkyl may be a cyclopropyl, a cyclobutyl, a cyclopentyl or a cyclohexyl.
  • an R i2 group is a cyclopropyl.
  • an R 12 group maybe CN, OH, 0P(0)(0H) 2 or azido, or a hydrogen may be omitted and the oxygen may be bonded directly to the linker.
  • R 6 is a mono or bicyclic C 5 -C 0 aryl or a mono or bieyclic 5 to 10 membered heteroaryl, optionally substituted with one or more R 12 groups, and optionally further substituted with the linker. More preferably, R 6 is a phenyl or a pyridinyl, optionally substituted with one or more R 12 groups, and optionally further substituted with the linker.
  • the mono or bicyclic C 5 -C 0 ary! or the mono or bicyclic 5 to 10 membered heteroaryl are substituted with one or more R 12 groups, and optionally further substituted with the linker.
  • the compound of formula (I) may be a compound of formula (I-C-a):
  • the one or more R 12 groups may be as defined above and q may be an integer between o and 4. More preferably, the or each R 12 group is independently selected from
  • n is an integer between 1 and 6. More preferably, m is an integer between 1 and 3.
  • the compound of formula (I) may be a compound of formula (I-C-b), (I-
  • r is an integer between o and 4.
  • the one or more R 12 groups preferably comprise one or more halogens.
  • the one or more R 12 groups may comprise one or 2 halogens.
  • the one or more halogens comprise one or more chlorines and/or fluorines, most preferably one or more fluorines.
  • the one or more R 12 groups may further comprise one or more groups selected from methyl, OH, QMe, C(0)NH 2 , 0CH 2 CH 2 0H, 0CH 2 CH 2 CH 2 0H,
  • the hydrogen may be omitted and the oxygen or nitrogen maybe bonded directly to the linker.
  • R 6 may comprise:
  • the compound of formula (I) may be a compound of one of formula (I-C- e) to (I-C-h):
  • the compound of formula (I) is a compound of one of formula (I-C-i) to (I-C-l):
  • each R is a halogen, and more preferably is independently Cl or F.
  • R 7 is preferably H or an optionally substituted C -Cc, alkyl, more preferably H or a C 1 -C 3 alkyl, and most preferably R 7 is H.
  • Y is an optionally substituted C -C 6 alkyl, more preferably a C -C 3 alkyl, even more preferably -CH 2 -, -CH 2 CH : CH a CH a CH -CH(F)- and -CF 2 - and most preferably -CH 2 -.
  • the compound of formula (I) may be a compound of formula (I-D):
  • R 8 is a mono or bicyclic optionally substituted C 5 -C 0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C 3 -Cfi cycloalkyl or an optionally substituted C 3 -Co heterocyclyl, wherein the aryl, heteroaryl, cycloal kyl or heterocyclyl may optionally be substituted with the linker.
  • R 8 may be an optionally substituted C 3 -C 6 cycloalkyi or C 3 -Cfi heterocyclyl, which may optionally be substituted with the linker.
  • R 8 may comprise a C 6 cycloalkyi or a 6 membered heterocycle.
  • the C 6 cycloalkyi or 6 membered heterocycle may be substituted with an optionally substituted C-Co alkyl, a mono or bicyclic optionally substituted C 5 -C 0 aryl and/or the linker.
  • the C 6 cycloalkyi or 6 membered heterocycle is substituted with a phenyl or a C -C 3 alkyl substituted with a phenyl, more preferably the C 6 cycloalkyi or 6 membered heterocycle is substituted with a phenyl or -CH 2 -phenyi.
  • R 8 is a mono or bicyclic optionally substituted C 5 - C 10 aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, which may optionally be substituted with the linker.
  • R 8 may be an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted furanyl, an optionally substituted benzofuranyl, an optionally substituted thiophene, an optionally substituted pyridofuran, an optionally substituted benzoxazo!e or an optionally substituted benzothiazole.
  • the mono or bicye lie C 5 -C 10 ary!
  • the mono or bicyelie C 5 -C 10 ary! or the mono or bicyelie 5 to 10 membered heteroaryl may be substituted with 1, 2,
  • the mono or bicyelie C 5 -C 10 aryl or the mono or bicyelie 5 to 10 membered heteroaryl is substituted with 3 substituents.
  • the aryl or heteroaryl may be substituted directly with the linker.
  • the or each substituent may independently be selected from the list consisting of C -Cc, alkyl, halogen, OH, Ci-Ce a!koxy, CONR'R 2 , CN, azido, N0 2 , NH 2 , QCH 2 CH 2 0H, 0CH 2 C(0)0H, 0P(0)(0H) 2 and an optionally substituted mono or bicyelie 3 to 8 membered heterocycle, or in a group comprising an OH or NH or R 1 , the H or R 1 may be omitted and the oxygen or nitrogen maybe bonded directly to the linker.
  • the optionally substituted mono or bicyelie 3 to 8 membered heterocyele preferably is a 6 membered heterocycle, more preferably is an optionally substituted piperazinyl, and most preferably is N-methylpiperazinyl.
  • the mono or bicyelie C 5 -C 0 aryl or the mono or bicyelie 5 to 10 membered heteroaryl may be substituted with at least one C -C o alkyl, Ci-C 6 alkoxy or halogen, even more preferably at least one C -C 3 alkyl, C 1 -C 3 alkoxy or halogen, and most preferably at least one methyl, OMe and/ or fluorine.
  • R 8 is an optionally substituted benzofuranyl.
  • R 8 is an optionally substituted benzofuranyl.
  • R 8 is an unsubstituted benzofuranyl or is only substituted with the linker.
  • R 8 is an optionally substituted furanyl.
  • the furanyl may be an unsubstituted furanyl or may only be substituted with the Sinker.
  • the furanyl may be substituted.
  • the furanyl is substituted with at least one of C 1 -C 3 alkyl or halogen, and optionally also the linker, more preferably at least one of methyl or fluorine and most preferably with one methyl group.
  • R 8 is an optionally substituted phenyl.
  • the phenyl may be unsubstituted or may only be substituted with the linker.
  • the phenyl maybe substituted.
  • the phenyl is substituted with at least one of C 1 -C 3 alkyl, C 1 -C 3 alkoxy or halogen, and may optionally be further substituted with the linker, more preferably at least one of methyl, methoxy or fluorine and most preferably with 1, 2 or 3 fluorines.
  • the compound of formula (I) maybe a compound of formula (I-D-a):
  • each R 21 is independently a C 1 -C 3 alkyl, a C -C 3 a!koxy or a halogen. More preferably, each R 21 is independently a methyl, methoxy or fluorine and most preferably, each R is a fluorine.
  • the linker maybe bonded to a substituent on the phenyl ring.
  • the compound of formula (I) may be a compound of formula (I-D-b), (I- D-c) or (I-D-d):
  • X 1 is CR 1 ;
  • X 2 is CR 2 ;
  • X 3 is CR 3 ;
  • Q is CR 4 R 3 ;
  • Y is -CII 2 -; and
  • R 7 is H.
  • X 1 is CR 1 .
  • X 2 is CR 2 .
  • X 3 is CR 3 .
  • L is optionally substituted C 1 -C 3 alkyl.
  • L is most preferably C -C 2 alkyl.
  • Y is an optionally substituted C -C & alkyl, more preferably a C ⁇ C 3 alkyl, and most preferably a C -C 2 alkyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, halogen, CN, optionally substituted C -C 6 alkyl, C 1 -C 3 polyfluoroalkyl, and optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl.
  • R 4 and R 3 are each independently selected from the group consisting of H and C -C 6 alkyl.
  • R 6 is a ring optionally substituted with one or more R 12 groups, wherein the ring is selected from the group consisting of a mono or bicyclic C 5 ⁇ C 10 aryl; a mono or bicyclic 5 to 10 membered heteroaryl; and a C 3 -C 6 cycloalkyl.
  • R 6 is substituted, either directly or indirectly, with the linker.
  • R 7 is H.
  • R 8 is a mono or bicyclic optionally substituted C 5 -C 0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl.
  • R 9 and R 10 are each independently selected from the group consisting of optionally substituted C -C 6 alkyl, H, halogen, CN, hydroxyl, azido, NR R 2 , C 1 -C 3 polyfluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C -Ca alkoxy or optionally substituted C 2 -C 6 alkenyl.
  • R 11 is selected from the group consisting of optionally substituted C -C 6 alkyl, H, hydroxyl, NR3 ⁇ 4 2 , C 1 -C 3 polyfluoroalkyl, optionally substituted C 3 -Cfi cycloal kyl, optionally substituted C -C 6 alkoxy or optionally substituted C 2 -C 6 alkenyl.
  • the first stereogenic centre defines an S enantiomer.
  • X 1 is CH.
  • X 2 is CH.
  • X 3 Is CH.
  • L is a C -C 2 alkyl. More preferably, L is -CH 2 -.
  • Y is a C -C 2 alkyl. More preferably, Y Is -CH 2 -.
  • R 6 is a ring optionally substituted with one or more R 12 groups, wherein the ring is selected from the group consisting of a mono or bicyclic C 5 -C 10 aryl; and a mono or bicyclic 5 to 10 membered heteroaryl.
  • R 6 is substituted, either directly or indirectly, with the linker.
  • R 6 is a phenyl or a pyridinyl optionally substituted with one or more R 12 groups.
  • R 6 is substituted with at least one R 12 group selected from the group consisting of a halogen, -OH, optionally substituted C,-C 4 alkoxy, amino, optionally substituted C -C 3 alkyl or C(0)NH 2 , or a hydrogen is omitted and an oxygen or nitrogen in a substituent of the R 6 ring which is bonded directly to the linker.
  • R 6 is substituted with one or two halogens.
  • the or each halogen is preferably independently chlorine or fluorine.
  • R 6 is further substituted, either directly or indirectly with the linker.
  • the C 5 -C 0 aryl may also be substituted w th a hydroxyl or an oxygen bonded directly to the linker.
  • R 7 is H.
  • R 8 is a mono or bicyc!ic optionally substituted C 5 -C 0 aryl or a mono or bi cyclic optionally substituted 5 to 10 membered heteroaryl.
  • R 8 is an optionally substituted phenyl ring.
  • R 8 is substituted with at least one halogen.
  • R 8 is substituted with 1, 2 or 3 halogens, more preferably 2 or 3 halogens.
  • the or each halogen is fluorine.
  • R 9 and R 10 are each independently selected from the group consisting of optionally substituted C -C 6 alkyl, optionally substituted C 2 -C 4 alkenyl, H, halogen, CN and azido. More preferably, R 9 and R 10 are each independently selected from the group consisting of C -C 3 alkyl and H. More preferably, R 9 and R 10 are each independently selected from the group consisting of CH 3 and H.
  • R n is selected from the group consisting of optionally substituted C -C 6 alkyl, optionally substituted C 2 -C 4 alkenyl and H. More preferably, R 11 is selected from the group consisting of C -C 3 alkyl and H. More preferably, R u is selected from the group consisting of CH 3 and H.
  • the first stereogenic centre defines an S enantiomer.
  • the compounds described herein or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof may be used in a medicament which may be used in a monotherapy (i.e use of the compound alone), for modulating the STING protein and/or treating, ameliorating or preventing a disease.
  • a second therapeutic agent may be administered with a compound of formula (I)
  • the compound of formula (I) may be administered before, after, and/or together with the second therapeutic agent.
  • the second therapeutic agent may comprise an antiviral agent, an anti-inflammation agent, conventional
  • the second therapeutic agent may comprise a By costimulatory molecule, interleukins (IL-2, IL-15, IL-7, IL-21), interferons, GM-CSF, a CTLA-4 antagonist (such as Ipilimumab and tremilimumab), an IDO inhibitor or IDO/TDO inhibitor (such as Epacadostat and GDC-0919), a PD-i inhibitor (such as Nivolumab, Pembrolizumab, Pidilizumab, AMP-514, MDX-1106, REGN2810, PF-6801591, INCSHR1210), a PD-Li inhibitor (such as Durvalumab/MEDI-4730, MDX-1105, Avelumab and Atezolizumab), an OX-40 ligand, a LAG3 inhibitor (LAG525, BMS-986016, TSR-033), a T-cell immunoglobin, interleukins (IL-2, IL-15, IL-7,
  • the disease is cancer and a chemotherapeutic agent maybe administered with a compound of Formula (I)
  • the chemotherapeutic agent may be selected from a group further consisting of a cancer vaccine, a targeted drug, a targeted antibody, an antibody fragment, an antimetabolite, an angiogenesis inhibitor an antineoplastie, an antifolate, a toxin, an alkylating agent, a DNA strand breaking agent, a DNA minor groove binding agent, a pyrimidine analogue, a ribonucleotide reductase inhibitor, a tubulin interactive agent, an anti-hormonal agent, an immunomodu!ator, an anti- adrenal agent, a cytokine, radiation therapy, a cell therapy, cell depletion therapy such as B-cell depletion therapy and a hormone therapy.
  • the combination agent may target MEK, EGFR, BRAF, PI3K, HER2/HER3, IGFR, SHP2, mTQR, CDK, IAP, Bcl-2, Mcl-i, CHK, heat shock protein, HDAC, EZH2, LSDi, EED
  • the chemotherapeutic agent may comprise abiraterone, Erlotinib, Linifanib, Sunitinib, Bosutinib, Dasatinib, Pazopanib, Sorafenib, Zactima, Imatinib, Gefitinib, Vandetanib, Lapatinib, Canertinib, Mubritinib, Pelitinib, Afatnib, Neratinib, Cetuximab, Panitumumab, Matuzumab, Nimotuzumab, Zalatumumab, Cabozantinib, Foretinib, Tivant
  • cyclophosphamide docetaxol, doxetaxel, carboplatin, cysplatin, cytarabine, dactinomycin, daunorubicin, decitabine, doxorubicin, etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea, streptozocin, mitomycin, methotrexate, taxanes, tamoxifen, vinblastine, vincristine and/or vindesine.
  • the compound of Formula (I) maybe combined in compositions having a number of different forms depending, in particular, on the manner in which the composition is to be used.
  • the composition may be in the form of a liquid, aerosol, spray, micellar solution or any other suitable form that may be administered to a person or animal in need of treatment.
  • the vehicle of medicaments according to the invention should be one which is well -tolerated by the subj ect to whom it is given .
  • Medicaments comprising the compounds described herein maybe administered parenterally, or intra-tumorally.
  • medicaments comprising the
  • compounds of the invention may be delivered intravenously, subcutaneously, nasally, topically, reetally, intramuscularly, intracerebrally or by inhalation. Most preferably, the compounds of the invention are delivered intravenously,
  • the compounds of the invention may be administered directly into the blood stream, into muscle, or into an internal organ.
  • suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and
  • Suitable devices for parenteral administration include needle
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water (see e.g. Hardman et. ah,
  • the pharmaceutical composition comprising the conjugate is a lyophilisate which contains the conjugate, sucrose, histidine, polysorbate, sodium succinate, citrate, water and saline.
  • the compounds of the invention may also be administered directly to a site of interest by injection of a solution or suspension containing the active drug substance.
  • the site of interest may be a tumour and the compound may be administered via intratumoral injection.
  • Typical injection solutions are comprised of propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which maybe used instead of propylene glycol include glycerol and polyethylene glycol.
  • the amount of the compound that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the compound, and whether it is being used as a monotherapy, or in a combined therapy.
  • the frequency of administration will also be influenced by the half-life of the compound within the subject being treated.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the pharmaceutical composition, the mode of
  • compositions comprising the conjugate may be provided by continuous infusion or by doses at intervals of e.g. one day, one week, several times a week, once ever) ' other week, once every' three weeks, once every four weeks, once every' five weeks, once ever ' six weeks, once every' seven weeks or once every eight weeks.
  • the total daily dose of the compounds of the invention is typically in the range o.oooi mg/kg to 10 mg/kg of the patient’s body weight.
  • the total daily dose maybe administered in single or divided doses and may, at the physician’s discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 6okg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • agents that modulate the immune system both the dose and the frequency of administration may be different to those of more traditional therapies.
  • agents that stimulate the immune system for example through modulation of STING, they maybe administered in small doses, and quite infrequently, for example twice weekly, weekly or monthly.
  • Administration may then be repeated.
  • the compound may be administered before, during or after onset of the disease to be treated.
  • a pharmaceutical composition comprising a compound according to the first aspect, or a
  • the invention also provides, in an eighth aspect, a process for making the composition according to the seventh aspect, the process comprising contacting a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt, solvate tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.
  • A“subject” may be a vertebrate, mammal, or domestic animal.
  • compounds, compositions and medicaments according to the invention may be used to treat any mammal, for example livestock (e.g a horse), pets, or maybe used in other veterinary applications. Most preferably, however, the subject is a human being.
  • A“therapeutically effective amount” of compound is any amount which, when administered to a subject, is the amount of drug that is needed to treat the target disease, or produce the desired effect, i.e. modulate the STING protein.
  • the therapeutically effective amount of compound used may be from about 0.001 mg to about 1000 mg, and preferably from about 0.01 mg to about 100 mg. It is preferred that the amount of compound is an amount from about 0.05 mg to about 50 mg, and most preferably from about 0.1 mg to about 20 mg.
  • A“pharmaceutically acceptable vehicle” as referred to herein, is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions.
  • the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in preparing solutions,
  • compositions suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • compound according to the invention maybe dissolved or suspended in a
  • liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid vehicle can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents,
  • thickening agents thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators.
  • liquid vehicles for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e g. glycols) and their derivatives, and oils (e.g.
  • the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral
  • liquid vehicle for pressurized compositions can be a
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intrathecal, epidural,
  • the compound may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • the scope of the invention includes all pharmaceutically acceptable isotopically- label!ed compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as U C, i3 C and 14 C, chlorine, such as 36 C1, fluorine, such as l8 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and l5 N, oxygen, such as 13 0, i3 0 and i8 Q, phosphorus, such as 32 P, and sulphur, such as 33 S.
  • Certain isotopically-iabelled compounds of the invention for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.
  • compounds of formula I may include but are not limited to:
  • the compound of formula (I) may be:
  • the sulphur shown in the above compounds may be a sulphur from a cysteine residue on the trastuzumab.
  • Compounds of formula II may include but are not limited to:
  • the linker maybe directly bonded to the R 6 or R 8 phenyl ring in any of the above compounds.
  • the linker may replace a hydrogen bonded to a nitrogen, oxygen or sulphur in any of the above groups.
  • the linker may replace R 10 .
  • L 1 , a and C may be as defined in relation to the first aspect
  • L 2a is either L 2 -Lg z , where L 2 and z are as defined in relation to the first aspect and Lg is a leaving group, or L 2a is a linker which is the same as L 2 , as defined in relation to the first aspect, except that the Sinker comprises a terminal double bond.
  • the compound of formula (III) may be used to produce a compound of formula (I).
  • Lg may be a halogen, -OH, -NH 2 or SH.
  • a terminal double bond may be a double bond disposed adjacent to the atom through which the L 2a group would otherwise be bonded to T
  • the terminal double bond forms part of a conjugated system.
  • the conjugated system further comprises at least one carbonyl group.
  • L 2a may comprise multiple terminal double bonds, with one terminal double bond on each branch of the linker. Accordingly, L 2a may comprise z terminal double bonds, where z is as defined in relation to the first aspect.
  • the compound of formula (III) may be:
  • the compound of formula (III) maybe:
  • Figure 1 shows some of the major polymorphisms of human STING
  • Figure 6 shows SDS-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of examples 28 and 29, where lane 1 shows the results for Novex Sharp Markers; lane 2 shows the results for trastuzumab in reaction buffer; lane 3 shows the results for reduced trastuzumab in reaction buffer; lane 4 shows the results for example 28 in PBS; and lane 5 shows the results for example 29 in PBS.
  • SDS-PAGE SDS-polyacrylamide gel electrophoresis
  • Compounds of formula (VI) can be synthesized from a compound of formula (IV) and (V) under basic conditions using for example a bicarbonate or carbonate base to generate an amide bond. Compounds of formulae (VI) are then used to make a further amide bond.
  • Typical conditions employ activation of the carboxylic acid function using a suitable organic base and a suitable coupling agent.
  • Preferred coupling agents include HBTU with HOBt or HATU and HO At or EDCI with HOBt or EEDQ.
  • Preferred organic bases comprise either DIPEA or TEA in a suitable organic solvent such as DCM, DCM- MeOH, DMF, DMA or MeCN. The reaction may be shaken or stirred at room temperature to give a compound of formula (VII).
  • the compound of formula (VII) may undergo bromination with brominating agents such as PBr 3 or POBr :?, to give a compound of formula (XI).
  • brominating agents such as PBr 3 or POBr :?
  • the Fmoc group of a compound of formula (VII) can be deproteeted with, for example, diethyl amine in THF to give a compound of formula (VIII) which may be further subjected to an amide coupling reaction with another amino acid such as glutamic acid using the typical conditions outlined above to give a tripeptide compound of formula (IX).
  • Compounds of formula (IX) may then be brominated as above to provide a compound of formula (X).
  • Compounds of formula (XIII) may be prepared from a compound of formula (VIII) as depicted in the below scheme, where Sc is an optionally substituted alkyl or aryl and R is a silyl protecting group.
  • Linkers that connect the targeting moiety and the active payload may be prepared according to methods known to those skilled in the art.
  • a compound of formula (XIV) may undergo a Michael addition reaction to an unsaturated ester to provide a compound of formula (XV).
  • the remaining free alcohol functional group may then be converted into a suitable leaving group, for example a tosylate (XVI), and then displaced with an azide reagent such as sodium azide in a polar solvent such as DMF to give the azide (XVII).
  • an azide reagent such as sodium azide in a polar solvent such as DMF
  • Reduction of the azide using either chemical means or hydrogenolysis, for example using palladised charcoal and hydrogen gas, subsequently allows access to the amines (XVIII).
  • Compounds of formula (VII) maybe attached to maleimide-containing acids such as compounds of formula (XXI) using a standard amide-bond forming reaction, for example using HBTU, HATU or EDCI with a suitable base in a suitable polar solvent such as DMF to provide the extended linkers (XXII).
  • a standard amide-bond forming reaction for example using HBTU, HATU or EDCI with a suitable base in a suitable polar solvent such as DMF to provide the extended linkers (XXII).
  • Reacting compounds of the formula (XXII) with p-nitrophenyl-chloroformate in the presence of an organic base such as TEA or DIPEA in a suitable solvent such as DCM gives the carbonate (XXIII) ready for attachment to a payload.
  • compounds of formula (IV) maybe reacted with maleic anhydride (XXIV) in a two-step process starting with acetic acid treatment, followed by heating at temperatures up to 120°C in a polar solvent such as DMA in the presence of a base, for example TEA
  • a polar solvent such as DMA
  • the ensuing maleimide-acid (XXV) may then be reacted with compounds of formula (VII) in a standard HATU, EDCI or HBTU amide forming reaction to give the extended linkers (XXVI).
  • BOC-protected lysine (XXVIII) may be reacted with an acid chloride or other activated acyl reagent in the presence of an inorganic base such as potassium or caesium carbonate in mixtures of THE and water to give the amides (XXIX)
  • amides may then be subjected to a standard HATU, i,5 EDCI or HBTU amide forming reaction with amines (VII) to give the extended linkers of formula (XXX).
  • Deprotection may then be carried out using acidic conditions, for example with solutions of HC1 in dioxane to reveal the free amine in compounds of formula (XXXI).
  • Said amines may then be converted to the maleimides (XXXII) using the same reagent (XVIII) and procedure described in Scheme 2a.
  • the maleimides (XXXII) may then be reacted with p-nitrophenyl-chloroformate in the presence of an organic base such as TEA or DIPEA in a suitable solvent such as DCM or DMF to give the carbonate (XXXIII) ready for attachment to a payload.
  • an organic base such as TEA or DIPEA
  • a suitable solvent such as DCM or DMF
  • the resulting linked payloads (XL) may then be used directly to append the targeting moiety.
  • Said amines may then he reacted with compounds of formula (XXI) in a standard amide bond forming reaction using, for example, HATU, EDCI or HBTU in mixtures of an organic base and a polar solvent to give the fully linked payloads (XLVI) which may then be used directly to append the targeting moiety.
  • XXI compounds of formula (XXI) in a standard amide bond forming reaction using, for example, HATU, EDCI or HBTU in mixtures of an organic base and a polar solvent to give the fully linked payloads (XLVI) which may then be used directly to append the targeting moiety.
  • amines of formula (XLV) maybe reacted with compounds of formula (XX) in a standard amide bond forming reaction using, for example, HATU, EDCI or HBTU in mixtures of an organic base and a polar solvent to give the fully linked payloads (CIL ⁇ I) which may then be used directly to append the targeting moiety.
  • CIL ⁇ I fully linked payloads
  • ethylene diamines of formula (XXXIX) maybe used in a displacement reaction with compounds of formula (XXVII) in the presence of a base and a polar solvent to give the carbamate fully linked payloads (XLVIII) which may then be used directly to append the targeting moiety.
  • amines of formula (XXXIX) maybe reacted with compounds of formula (XXXIII) in the presence of a base and a polar solvent to give the carbamate fully linked payloads (XLIX) which may then be used directly to append the targeting moiety.
  • the linked payloads (pre-conjugates) (XL), (XLIII), (XLVI), (XLVII), (XLVIII),
  • Linked payloads (XL), (XLIII), (XLVI), (XLVII), (XLVIII) and (XLIX) were attached to a thiol-containing biomolecule using the following general method.
  • the antibody or protein was first treated with between 2 and 3 equivalents of a suitable reducing agent such as TCEP (tris(2-carboxyethyl)phosphine), DTT (dithiothreitol) or BME (beta-mercaptoethanol) at between 25 and 50°C for 1 h at a concentration of between 2 and 10 mg/mL in a suitable solvent such as phosphate buffered saline or isopropanol in admixture with either sodium phosphate or ammonium sulfate to produce free thiol-containing antibody.
  • TCEP tris(2-carboxyethyl)phosphine
  • DTT dithiothreitol
  • BME beta-mercaptoethanol
  • aqueous buffer solution for example phosphate-buffered saline, HEPES or TEN buffer
  • organic co-solvent for example DMF, DMA, polysorbate, ethylene glycol or propylene glycol
  • HIC hydrophobic interaction chromatography
  • SEC size exclusion chromatograp hy
  • Preparative HPLC was carried out on a Waters auto purification instrument using either a YMC Triart C18 column (250 x 20 mm, 5 pm) or a Phenyl Hexyl column (250 x 21.2 mm, 5 um) operating at between ambient temperature and 50 °C with a flow rate of 16.0 - 50.0 mL/min.
  • IJPLC was carried out on a Waters auto purification instrument using a Zorbax Extend C18 column (50 x 4.6 mm, 5 , um) at ambient temperature and a flow rate of i.ymi/min.
  • Linked payloads were attached to a thiol-containing antibody using the following general method
  • the antibody was first treated with between 2 and 3 equivalents of TCEP at between 25 and 50°C for 1 h at a concentration of between 2 and 10 mg/mL in a suitable solvent such as phosphate buffered saline or isopropanol in admixture with either sodium phosphate or ammonium sulfate to produce free thiol-containing antibody.
  • a suitable solvent such as phosphate buffered saline or isopropanol
  • a suitable co-solvent such as DMF or propylene glycol
  • HIC chromatography
  • SEC size exclusion chromatography
  • Analytical HIC was carried out using a TOSOH TSKgel Butyl-NPR column (4.6 mm x 3.5 cm, 2.5 pm), connected to a Dionex Ultimate 3000 UPLC system.
  • the mobile phase was buffer A: 1.5 M ammonium sulfate, 50 mM sodium phosphate, pH 7.0.
  • a linear gradient (10-100% B in 10.5 min) was applied using Buffer B (20 % isopropanol, 50 mM sodium phosphate, pH 7.0) at a flow rate of 1.35 mL/min to elute bound species.
  • the column was maintained at 30 °C throughout the analysis.
  • the analysis was carried with UV detection at 280 nm and 248 nm. 10 pg of ADC were injected for analysis.
  • the percentage of each DAR species was calculated by comparing the peak areas of each assigned peak with total peak area. Average DAR was calculated as a weighted average of peak areas.
  • LC-MS analysis was carried out using a Waters XEVO G2S TOF mass spectrometer and a POROSHELL 300SBC3 column (2.1 x 12.5 mm, 5 pm) connected to a Waters Acquity H Class UPLC system.
  • the mobile phase was buffer A (0.1 % formic acid in water).
  • a gradient (2.5 min 10% B, 10-80% B gradient in 3.5 min) was applied using Buffer B (acetonitrile, 0.1 % formic acid) at a flow rate of 0.6 mL/ min and column temperature of 60 °C.
  • Maleimide ADCs were analysed after reduction (10 mM DTT, 1 h at 40 °C) and then diluted to 0.02 mg/mL with PBS. 10 pL of diluted ADC solution were injected for analysis.
  • SDS-PAGE analysis SDS-PAGE analysis
  • SDS-PAGE analysis was carried out using NuPAGE® 4-12% Bis-Tris gels (Invitrogen) under non-reducing conditions with MES buffer. Prior to analysis, samples were incubated at 40 °C for ih in 10% SDS solution. For analysis, 1 pg of ADC sample (based on protein) was loaded onto the gel per lane. Electrophoresis was carried out at 200 V for 35 min. The gels were stained with InstantBlueTM (Expedeon) for protein detection and analysed using XmageQuantTM imaging equipment (GE Healthcare).
  • the concentration of the conjugate was determined by UV absorbance at 280 nm (A280) using a Nanodrop spectrophotometer.
  • the extinction coefficient used was the extinction coefficient of the antibody (for example, for
  • trastuzumab 8280 1.480 mL/(mg.cm)). Measurements were taken in triplicate and the average value was used to determine the conjugate concentration:
  • Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (6) are given in parts-per-mil!ion downfield from tetramethylsilane (for ‘ H-NMRj and up-field from trichloro-fluoro- methane (for 9 F NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCI4,
  • Flash column chromatography was carried out using pre-packed silica gel cartridges in a Combi-Flash platform.
  • Prep-HPLC purification was carried out according to the General purification and analytical methods described above.
  • Example 7 was prepared according to the methods described in General Procedures 1,2, 4, 6, 10, 12, 15, 17-18 and the methods described below
  • Step i iS)-2-ifS)-2-ffffQH-Fluoren-Q-yl)methoxy)carbonyl)amino)-3- methylbutanamidol-fi-ureidopentanoic acid
  • Step 1 To a stirred suspension of (S)-2-((S)-2-((((9H-f[uoren-9-yl)methoxy)carbonyl)amino)- 3-methylbutanamido)-5-ureidopentanoic acid (Step 1) (11 0 g, 0.022 mol) in a mixture of DCM and MeOH (2:1, 220 mL) was added p-aminobenzyl alcohol (8.18 g, 0.066 mol) followed by EEDQ (10.96 g, 0.044 mol) at RT. The reaction mixture was stirred at 40 °C for 12 h.
  • Step 4 0-f2, -DiQxo-2. -dihydro-iPI-pyrroi-i-y0-N-ifS)-i-iifS)-i-if4.- (hvdroxymethvDphenyl)amino)-i-oxo- -ureidopentan-2-yl)amino)-3-methyl-i- oxobutan-2-yl)hexanamide
  • Step 5 4-(YS)-2-(YS)-2-i6-(2. -Pioxo-2. -dihvdro-iH-pynOl-i-yl)hexanamido)-3- methylbutanamidoVfi-ureidopentanamidolbenzyl i4-nitrophenyr) carbonate
  • Step l Benzyl-ferf-butyl ethane-i,2-
  • Step 2 text- Butyl methylf2-fmethylamino)ethyl)earbamate
  • Step 3 (S)-ter -Butyl (2-chloro-3-((3.4-dimethyl-2-oxo-7-((2.4.6- trifluorobenzyl)carbamoyl)-3.4-dihvdroquinazolin-i -v0methyl)-4-fluorophenv0
  • Step 4 (S)-2-Ch3 ⁇ 4oro-2-((2.4-dimethvI-2-QXQ-7-((2.4.6-trifluorobenzvi)carbamoyri-2.4- dihvdroquinazoiin-i(2H)-vDmethvi)-4-fluorophenyl methyl(2- ( methylamino)ethvI)earbamate hvdrochlorid
  • Examples 6 and 8 were prepared according to the above method used to make Example 7 and those methods described in General Procedures i, 2, 4, 10 12, 15 17 using the product of Preparation 2 step 4 and the appropriate product of Preparation 1, step 4. Purification was as stated in the aforementioned methods.
  • Example Q 2-Chloro-:3 ⁇ 4-((fS)-:3 ⁇ 4,4-dimethyl-2-oxo-7-((2,4,6- trifliiorobenz i>earhamovD-3 ⁇ 4.4.-dihvdroqpmazolm-if2H)-yl)methyl)-4.- flporophenyl- .-f(i , 7S.2oS3 ⁇ 4-i-C2. f ;-di03 ⁇ 4o-2.
  • Example 9 was prepared according to the methods described in General Procedures 1, 2, 4, 5-12, 15, 17-18, 20 and the methods described below.
  • Step 2 tert-Butyl i-ftosyloxy)-3,6,Q,i2-tetraoxapentadecan-i5-oate
  • Step 3 tert-Butyl-i-azido- ⁇ .e.Q. ⁇ -tetraoxapentadecan-is-oate
  • Step 4 tert-Butyl i-amino-2.6.Q.i2-tetraoxapentadecan-i i s-oate
  • Step 5 tert-Butyl i-i2. -dioxo-2. -dihvdro-iH-pyrrol-i-yl)-3,6.Q.i2- tetraoxapentadecan-i -oate
  • Step 1 (qH-Fiuoren-Q-yl)methyl-((S)-i-(((S)-i-((4-(((tert- butyldimethylsilyl)oxy)methvDphenyl)amino)-i-oxo-. -ureidopentan-2-yl)amino)-.q- methyl-i-oxobutan-2-v0 carbamate
  • Step 2 fS)-2-ffS)-2-AminQ-3-methyibutanamido)-N-f4-ffftert- hutyldimethyisiiyl)oxy)methyi)phenyl)- -ureidopentanamide
  • Step 3 fe?T-Butyl-ffS)-i-fffS)-i-ff4-ffftert- butyldimethyisilvi)oxy)methyl)phenvi)amino)-i-oxo- g ;-ureidopentan-2-yi)amino)- - methvi-i-oxobutan-2-yl)carbamate
  • Step 4 tert-Butyl-ifS)-i-ffiS)-i-if4-ihydroxymethyl)phenyl)amino)-i-oxo-
  • Step 5 ferUButyl-(iS)-3-methyl-i-(T(S)-i-((4-(T((4- nitrophenoxy)carbonyi)oxy)methyl)phenyi)amino)-i-oxo-f;-ureidopentan-2-yl)amino)- i-oxobutan-2-yl)carbamate
  • Preparation-8 2-Chloro-3-(((S)-3.4-dimethyl-2-oxo-7-((2.4.6- trifluorobenzyl)carbamoylV2.4-dihvdroquinazolin-ii2H)-yl)methylV4-fluoiOphenyl 4- iii7S.2oS)-i-i2. i: ;-dioxo-2.
  • Example 10 fS -i-f2-Chloro-3 ⁇ 4-ff4.-ffS -2-f(S)-2-f6-f2. ⁇ -dioxo-2. ⁇ -dihvdro-
  • Example 10 was prepared according to the methods described in General Procedures 1 ⁇ 4, 19 and the methods described below.
  • Preparation Q ( ' QH-Fluoren-Q-yDmethyl (YSVi-iffSVi-ff - (bromomethvi)phenyl)amino)-i-oxo-5-ureidopentan-2-yr)amino)-3-methyl-i- oxobutan-2-yl)carbamate
  • Example 11 was prepared according to the above method used to make Example 7 and those methods described in General Procedures 1,2, 4, 6, 10, 12, 15, 17-18 using the product of Preparation 2 step 4 and the appropriate product of Preparation 1 step 5. Purification was as stated in the aforementioned methods.
  • Example 12 fS)-i-f2-Chloro-.3 ⁇ 4-ff .-ffi7S.2oSl-i-f2.s-dioxo-2.. ⁇ -dihydro-iH- pyrrol i yl) ⁇ i7-igopropyl-i g ;.iS-dioxo-20-f;3 ⁇ 4 UreidopropyD-2.0.Q.i2- tetraexa-i0,iQ-diazahemeoganamido)bei3 ⁇ 4zyDexy)-0-fluerQbem;yi)-?3 ⁇ 4,4- dimethyl-2-oxo-N-(2,4,6-trifliiorobenzvl)-i,2,:3 ⁇ 4,4-tetrahvdroqiiinazoline-7- carboxamide
  • Example 12 was prepared according to the methods described in General Procedures 1- 4, 7-12, 19 and the method described below. Preparation ir3 ⁇ 4:
  • Example 1 was prepared according to the methods described in General Procedures 2, 7-12 and the methods described below.
  • Preparation 14 (Sl-i-f -f2-Aminoethoxy>2-chloiO-6-fluoiObenzyD- .4.-dimethy3 ⁇ 4-2- oxo-N-(2,4,6-tr3 ⁇ 4fluorobenzyl)-i,2,r3 ⁇ 4,4-tetrahvdroquinazoline-7-carboxamide
  • Step i iSVi-i2-Chloro-: ⁇ -icyanQmethoxy)-6-fluorobenzyl)- ,4-d3 ⁇ 4methyl-2-oxo-N- (2.4,6-trifluorobenzyP-i.2,.q,4-tetrahydroquinazoline-7-carboxamide
  • Step 2 fS)-i-f -f2-Aminoethoxy)-2-chloro-6-fluorobenzyl)-3.4.-dimethyl-2-oxo-N- i2.4.6-trifluorobenzyi)-i.2.2.4-tetrahydroquinazoline-7-carboxamide
  • Example 2 was prepared according to the methods described in General Procedures 2- 3, 7-12 and the methods described below.
  • Step 1 fS)-i-f2-Chloro-6-fluoro-3-(T4-nitrobenzy0oxy)benzyl)-3..4-dimethyl-2-oxo-N- i2.4.6-trifluorobenzyrj-i.2.2.4-tetrahydroquinazoline-7-carboxamide
  • Step 2 (S )-i-( -f f4-Aminobenzv0oxy)-2-chloro-6-fluorobenzv0-3,4-dimethyl-2-oxo-
  • Example 3 was prepared according to the methods described in General Procedures 2, 7-12 and the methods described below.
  • Step i 2.2,2-Tr3 ⁇ 4fluoro-N-f4-n3 ⁇ 4trQ

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Abstract

La présente invention concerne des conjugués de modulateurs à petites molécules de la protéine Stimulateur de gènes d'interféron (STING).
PCT/GB2019/051733 2018-06-21 2019-06-20 Modulateurs à petites molécules de protéine sting humaine, conjugués et applications thérapeutiques WO2019243825A1 (fr)

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WO2021161230A1 (fr) * 2020-02-12 2021-08-19 Curadev Pharma Pvt. Ltd. Antagonistes de sting à petites molécules
WO2021206158A1 (fr) 2020-04-10 2021-10-14 小野薬品工業株式会社 Méthode de cancérothérapie
WO2021250530A1 (fr) 2020-06-08 2021-12-16 Curadev Pharma Pvt. Ltd., Procédé rapide de génotypage de variants sting chez des individus humains
WO2022253284A1 (fr) * 2021-06-02 2022-12-08 百奥泰生物制药股份有限公司 Conjugué de médicament et utilisation associée
WO2022262516A1 (fr) * 2021-06-18 2022-12-22 北京海步医药科技有限公司 Lieur et conjugué correspondant
US11571423B2 (en) 2017-06-22 2023-02-07 Curadev Pharma Limited Small molecule modulators of human sting
US11638716B2 (en) 2017-08-31 2023-05-02 F-star Therapeutics, Inc. Compounds, compositions, and methods for the treatment of disease
CN116178214A (zh) * 2022-12-08 2023-05-30 吉尔生化（上海）有限公司 一种n-(9-芴甲氧羰基)-谷氨酸-1-叔丁酯的制备方法
WO2023116911A1 (fr) * 2021-12-24 2023-06-29 百奥泰生物制药股份有限公司 ANTICORPS ANTI-FRα, CONJUGUÉ ANTICORPS-MÉDICAMENT ET SON UTILISATION
WO2023198079A1 (fr) * 2022-04-12 2023-10-19 百奥泰生物制药股份有限公司 Méthode de traitement d'une tumeur solide positive à her2
WO2024002042A1 (fr) * 2022-06-27 2024-01-04 百奥泰生物制药股份有限公司 Méthode de traitement de tumeur solide
US11939343B2 (en) 2019-08-02 2024-03-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
WO2024067816A1 (fr) * 2022-09-30 2024-04-04 厦门赛诺邦格生物科技股份有限公司 Lipide pégylé contenant un noyau de lysine
WO2024100449A1 (fr) * 2022-11-08 2024-05-16 Legochem Biosciences, Inc. Agonistes de sting

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US11571423B2 (en) 2017-06-22 2023-02-07 Curadev Pharma Limited Small molecule modulators of human sting
US11638716B2 (en) 2017-08-31 2023-05-02 F-star Therapeutics, Inc. Compounds, compositions, and methods for the treatment of disease
US11939343B2 (en) 2019-08-02 2024-03-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
CN115151304A (zh) * 2020-02-12 2022-10-04 库拉德夫制药私人有限公司 小分子干扰素基因刺激因子(sting)拮抗剂
WO2021161230A1 (fr) * 2020-02-12 2021-08-19 Curadev Pharma Pvt. Ltd. Antagonistes de sting à petites molécules
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CN116178214B (zh) * 2022-12-08 2024-03-26 吉尔生化（上海）有限公司 一种n-(9-芴甲氧羰基)-谷氨酸-1-叔丁酯的制备方法

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