Compound

Abstract

The present disclosure relates to compounds of formula (I), which are modulators of STING. Pharmaceutical compositions comprising the compounds of formula (I) and methods of using the compounds of formula (I) in the treatment or prevention of diseases ameliorated by modulation of STING are also disclosed. In one embodiment, the present invention provides compounds of the present invention for use in therapy. The present invention also provides compounds of formula I, or pharmaceutically acceptable salts thereof, for use in therapy. The present invention particularly provides compounds of formula I, or pharmaceutically acceptable salts thereof, for use in the treatment of STING-mediated diseases or disorders.

Description

[Technical Field]

[0001] This application claims priority to UK Provisional Application No. GB1918761.6, filed December 18, 2019, and UK Provisional Application No. GB2009944.6, filed June 30, 2020. The entire contents of each of GB1918761.6 and GB2009944.6 are incorporated herein by reference.

[0002] The present invention relates to substituted benzimidazole dimers and their use as pharmaceuticals, particularly in the treatment of diseases ameliorated by modulation of STING. [Background technology]

[0003] Background of the Invention Vertebrates are constantly threatened by microbial invasion and have evolved immune defense mechanisms to eliminate infectious pathogens. In mammals, this immune system comprises two branches: innate and adaptive immunity. The innate immune system is the first line of defense initiated by pattern recognition receptors (PRRs), which detect pathogen-derived ligands and damage-associated molecular patterns (Takeuchi 2010). An increasing number of these receptors have been identified, including Toll-like receptors (TLRs), C-type lectin receptors, retinoic acid-inducible gene I (RIG-I)-like receptors and NOD-like receptors (NLRs), and double-stranded DNA sensors. Activation of PRRs leads to the upregulation of genes involved in the inflammatory response, including type 1 interferons, pro-inflammatory cytokines, and chemokines, which suppress pathogen replication and facilitate adaptive immunity.

[0004] The adaptor protein STING (stimulator of interferon genes), also known as TMEM 173, MPYS, MITA, and ERIS, has been identified as a central signaling molecule in the innate immune response to cytoplasmic nucleic acids (Ishikawa 2008, WO2013 / 166000). Activation of STING leads to upregulation of the IRF3 and NFκB pathways, leading to the induction of type 1 interferons, including interferon-β, and other cytokines. STING is crucial for responses to cytoplasmic DNA of pathogen or host origin, as well as unusual nucleic acids called cyclic dinucleotides (CDNs).

[0005] CDNs were first identified as bacterial second messengers responsible for the regulation of numerous responses in prokaryotic cells. Bacterial CDNs, such as c-di-GMP, are symmetric molecules characterized by two 3',5' phosphodiester linkages. [ka]

[0006] Recently, direct activation of STING by bacterial CDNs was confirmed by X-ray crystallography (Burdette 2013), and as a result, bacterial CDNs and their analogs have attracted interest as potential vaccine adjuvants (Libanova 2012, WO2007 / 054279, WO2005 / 087238).

[0007] More recently, the response to cytoplasmic DNA has been elucidated and shown to involve the production of a novel mammalian CDN signaling molecule, identified as cGAMP, by an enzyme called cyclic GMP-AMP synthase (cGAS, previously known as C6orfl50 or MB21D1), which in turn activates STING. Unlike bacterial CDNs, cGAMP is an asymmetric molecule characterized by its mixed 2',5' and 3',5' phosphodiester linkages (Gao 2013A). The interaction of cGAMP(II) with STING has also been demonstrated by X-ray crystallography (Cai 2014).

[0008] Interferons were first described as substances capable of protecting cells from viral infection (Isaacs 1957). In humans, type I interferons are a family of related proteins encoded by a gene located on chromosome 9 that encodes at least 13 isoforms of interferon alpha (IFNα) and one isoform of interferon beta (IFNβ). Recombinant IFNα was the first approved biological therapeutic and has become an important treatment for viral infections and cancer. Interferons are known to have direct antiviral activity on cells as well as to be potent modulators of the immune response, acting on cells of the immune system.

[0009] The administration of small molecule compounds that can modulate innate immune responses, including activation or inhibition of type I interferon production and other cytokines, may be an important strategy for treating or preventing human diseases, including viral infections and autoimmune disorders. This type of immunomodulatory strategy has the potential to identify compounds that may be useful not only in infectious diseases but also in cancer (Zitvogel 2015), allergic diseases (Moisan 2006), neurodegenerative diseases such as amyotrophic lateral sclerosis and multiple sclerosis (Lemos 2014, Cirulli 2015, Freischmidt 2015), other inflammatory conditions such as irritable bowel disease (Rakoff-Nahoum 2004), and as vaccine adjuvants (Persing 2002, Dubensky 2013).

[0010] STING is essential for antimicrobial host defense, including protection against a range of DNA and RNA viruses and bacteria (reviewed in McNab 2015; Ma 2016). The Herpesviridae, Flaviviridae, Coronaviridae, Papillomaviridae, Adenoviridae, Hepadnaviridae, Orthomyxoviridae and Paramyxoviridae, and Rhabdoviridae families have evolved mechanisms to inhibit STING-mediated type I interferon production and evade host immune control (Holm 2016; Ma 2015; Wu 2015; Liu 2016; Chen 2014; Lau 2013; Ding 2013; Nitta 2013; Sun 2012; Aguirre 2012; Ishikawa 2009). Therefore, small molecule activation of STING may be beneficial for the treatment of these infectious diseases.

[0011] In contrast, increased and prolonged type I IFN production is associated with a variety of chronic infections, including mycobacteria (Collins 2015, Wassermann 2015, Watson 2015), Franciscella (Storek 2015, Jin 2011A), chlamydia (Prantner 2010), plasmodium (Sharma 2011), and HIV (Herzner 2015, Gao 2013B). Similarly, excessive type I interferon production is found in patients with complex autoimmune diseases. Genetic evidence in humans and support from studies in animal models support the hypothesis that STING inhibition results in a reduction of type I interferons, which drive autoimmune disease (Crow 2006, Stetson 2008). Therefore, STING inhibitors provide treatment for patients with chronic type I interferon and pro-inflammatory cytokine production associated with infectious diseases or combined autoimmune diseases. Allergic diseases are associated with a Th2-dominant immune response to allergens. Th2 responses are associated with elevated IgE levels, which, through their effects on mast cells, promote hypersensitivity to allergens, resulting in symptoms seen in, for example, allergic rhinitis and asthma. In healthy individuals, the immune response to allergens is more balanced, with a combination of Th2 / Th1 and regulatory T cell responses. Induction of type I interferon has been shown to reduce Th2-type cytokines in the local environment and promote Th1 / Treg responses. In this context, for example, induction of type I interferon by activation of STING may be beneficial in the treatment of allergic diseases, such as asthma and allergic rhinitis (Huber 2010).

[0012] Compounds that bind to STING and act as agonists have been shown to induce type 1 interferon and other cytokines when incubated with human PBMCs. Compounds that induce human interferon can be useful in the treatment of various disorders, such as allergic diseases and other inflammatory conditions, such as allergic rhinitis and asthma, infectious diseases, neurodegenerative diseases, precancerous syndromes and cancer, and can also be useful as immunogenic compositions or vaccine adjuvants. Compounds that bind to STING can act as antagonists and can be useful, for example, in the treatment of autoimmune diseases. It is anticipated that targeting STING with activators or inhibitors can be a promising approach for preventing and treating diseases and conditions, including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, and precancerous syndromes, in which modulation of the type 1 IFN pathway is beneficial, as well as for immunogenic compositions or vaccine adjuvants.

[0013] Skin cancer and various cutaneous viral infections are immunoprivileged environments, and activating local immune responses against these lesions could be a potential therapeutic approach. STING agonists can be used to treat viral warts, superficial skin cancer, and premalignant actinic keratoses. Through a dual mechanism of action, STING activation (e.g., via microneedle patch delivery or topical formulations) can be used to control HPV both directly through antiviral type I interferon production and indirectly by enhancing adaptive immune responses downstream of innate immune activation. STING agonists can activate innate immune responses in the lesions and promote anti-HPV T cell responses.

[0014] Recent evidence indicates that spontaneous activation of the STING pathway in tumor-resident dendritic cells leads to type I IFN production and adaptive immune responses against tumors. Furthermore, activation of this pathway in antigen-presenting cells (APCs) within the tumor microenvironment promotes subsequent T cell priming against tumor-associated antigens (Corrales 2015). International patent applications WO2014 / 093936, WO2014 / 189805, WO2013 / 185052, WO2015 / 077354, and WO2015 / 185565 disclose certain cyclic dinucleotides and their use in inducing immune responses via STING activation.

[0015] Additionally, non-CDN compounds have been described as active agonists of STING.

[0016] Applications WO2019 / 069269, WO2019 / 069270, WO2017 / 175156 and WO2017 / 175147, and Ramanjulu 2018 describe certain amido- and diamido-benzimidazole compounds and their use in modulating STING.

[0017] Applications WO2019 / 027858 and US2018 / 0093964 describe certain benzo[b]thiophene compounds and their use as STING agonists. WO2019 / 195063 describes aza-benzothiophene compounds, and WO2019 / 195124 describes benzothiophenes and related compounds and their use as STING agonists. WO2019 / 219820 describes benzothiophenes, thienopyridines, and thienopyrimidines as STING modulators.

[0018] Applications WO2018 / 234808, WO2018 / 234807, GB2563642A, and WO2018 / 234805 describe certain arylamide compounds and their use as modulators of STING.

[0019] Application WO2019 / 165032 describes certain imidazole-pyridazine compounds and their use as agonists of STING.

[0020] STING has known polymorphisms, including an allele encoding a histidine at position 232 that is refractory to bis-3',5' (canonical) CDNs but not 2',5'-3',5' (non-canonical, mixed-linkage) CDNs (Diner 2013; Jin 2011B). Single-nucleotide polymorphisms in the STING gene have been reported to affect responsiveness to bacterially derived canonical CDNs (Diner 2013; Gao 2013C; Conlon 2013). Five major haplotypes of STING have been reported (WT, R232H, HAQ, AQ, and Q alleles), which differ at amino acid positions 71, 230, 232, and 293 (Jin 2011B; Yi 2013).

[0021] The compounds of the present invention modulate the activity of STING and may therefore provide beneficial therapeutic impact in the prevention and treatment of diseases, disorders and / or conditions in which modulation of STING (stimulator of interferon genes) is beneficial, such as inflammation, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes, and also as vaccine adjuvants.

[0022] All publications, patents, and patent applications that may be cited herein are hereby incorporated by reference in their entirety.

[0023] Any discussion of documents, acts, materials, devices, articles or the like which has been included in this specification should not be construed as an admission that any or all of such matter, as existing prior to the priority date of each claim of this application, formed part of the prior art body or was common general knowledge in the field to which this disclosure pertains.

[0024] Unless otherwise specified, any embodiment herein should be deemed to apply mutatis mutandis to any other embodiment. The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended to be merely illustrative. Functionally equivalent products, compositions and methods are clearly included within the scope of the invention described herein. [Prior art documents] [Patent documents]

[0025] [Patent Document 1] International Publication No. 2013 / 166000 [Patent Document 2] International Publication No. 2007 / 054279 [Patent Document 3] International Publication No. 2005 / 087238 [Patent Document 4] International Publication No. 2014 / 093936 [Patent Document 5] International Publication No. 2014 / 189805 [Patent Document 6] International Publication No. 2013 / 185052 [Patent Document 7] International Publication No. 2015 / 077354 [Patent Document 8] International Publication No. 2015 / 185565 [Patent Document 9] International Publication No. 2019 / 069269 [Patent Document 10] International Publication No. 2019 / 069270 [Patent Document 11] International Publication No. 2017 / 175156 [Patent Document 12] International Publication No. 2017 / 175147 [Patent Document 13] International Publication No. 2019 / 027858 [Patent Document 14] US Patent Application Publication No. 2018 / 0093964 [Patent Document 15] International Publication No. 2019 / 195063 [Patent Document 16] International Publication No. 2019 / 195124 [Patent Document 17] International Publication No. 2019 / 219820 [Patent Document 18] International Publication No. 2018 / 234808 [Patent Document 19] International Publication No. 2018 / 234807 [Patent Document 20] GB Patent Application Publication No. 2563642 [Patent Document 21] International Publication No. 2018 / 234805 Summary of the Invention [Means for solving the problem]

[0026] Summary of the Invention A first aspect of the present invention is a compound of formula I: [ka] To provide a compound of [In the formula, Y is (CH2) n (where n is 2 to 4), or -CH2-CH=CH-CH2-, R 1 and R 11 are independently -C(=O)OH, -C(=O)OR P1 , Br, F, tetrazolyl, oxo-oxadiazolyl and [ka] (2H-triazol-4-yl), wherein R P1 is selected from methyl and ethyl; A 1 is CR A or N, A 2 is CR B or N, A 3 is CR C or N, A 4 is CR D or N, where A 1 , A 2 , A 3 , and A 4 can be N, R A , R B , R C and R D wherein one, two or three (when present) of are selected from H, F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH; R A , R B , R C and R D the remainder (if any) of is H, A 11 is CR AA or N, A 12 is CR BB or N, A 13 is CR CC or N, A 14 is CR DD or N, where A 11 , A 12 , A 13 and A 14 can be N, R AA , R BB , R CC and R DD wherein one, two or three (when present) of are selected from H, F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH; R AA , RBB , R CC and R DD the remainder (if any) of is H, R C1 , R C3 and R C4 are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 selected from alkenyl and C5 heterocyclyl; R C11 , R C13 and R C14 are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl].

[0027] A second aspect of the present invention provides a compound of the first aspect for use in a method of treatment. The second aspect also provides a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable excipient.

[0028] A third aspect of the present invention provides a method of treating or preventing a disease that is ameliorated by modulation of STING, the method comprising the step of administering to a patient in need of treatment a compound of the first aspect of the invention or a pharmaceutical composition of the second aspect of the invention. The third aspect of the present invention also provides the use of a compound of the first aspect of the invention in the manufacture of a medicament for treating or preventing a disease that is ameliorated by modulation of STING, and a compound of the first aspect of the invention or a pharmaceutical composition thereof for use in treating or preventing a disease that is ameliorated by modulation of STING. The present invention provides, for example, the following items. (Item 1) Formula I: [ka] Compounds of [In the formula, Y is (CH 2 ) n [wherein n is 2 to 4], or -CH 2 -CH=CH-CH 2 - either R 1 and R 11 are independently -C(=O)OH, -C(=O)OR P1 , Br, F, tetrazolyl, oxo-oxadiazolyl and

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[0029] definition C 3~6 Cycloalkyl: The term "C 3~6"Cycloalkyl," as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic hydrocarbon compound having 3 to 6 carbon atoms. 3~6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), and cyclohexyl (C6).

[0030] C 3~7 Heterocyclyl: The term "C 3~7 "Heterocyclyl," as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a monocyclic heterocyclic compound and having 3 to 7 ring atoms, of which 1 to 2 atoms are heteroatoms selected from oxygen, sulfur, or nitrogen. 3~7 Heterocyclyl groups can be non-aromatic or aromatic ring systems. 3~7 Heterocyclyl groups include C 3~7 It may be referred to as a heteroaryl group.

[0031] In this context, prefixes (e.g., C 3~7 ) indicates the number of ring atoms, whether carbon atoms or heteroatoms, or a range of the number of ring atoms. Thus, the prefixes can in some cases be interchanged with alternative prefixes that define the number of ring atoms, e.g., the prefix "C" 3~7 " can be interchanged with the prefix "3- to 7-membered." In some embodiments, the C 3~7 The heterocyclyl moiety may be a C3, C4, C5, C6 or C7 heterocyclyl, or any combination of these different sized rings / ring systems, e.g., C 3~6 , C 4~7 or C 5~6 It may be a heterocyclyl group, or the like.

[0032] C 3~7 Examples of heterocyclyl groups include, but are not limited to, N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), pyrrole (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), pyridine (C6), azepine (C7), azepane (C7); N2: Diazirine (C3) diazetidine (C4), imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), imidazole (C5), pyrazole (C5), piperazine (C6), pyrazine (C6), pyrimidine (C6), pyridazine (C6), diazepine (C7), diazepane (C7); O1: oxetane (C4), tetrahydrofuran (C5), oxane (C6); O2: dioxetane (C4), dioxolane (C5), dioxane (C6), dioxole (C5); N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), isoxazole (C5), oxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6); S1: thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiphene (C5), thiane (tetrahydrothiopyran) (C6), thiepane (C7); N1S1: thiazoline (C5), thiazolidine (C5), thiazole (C5), isothiazole (C5), thiomorpholine (C6), thiazine (C6); O1S1: Oxathiolidene (C5), isoxathiolidine (C5), oxathiol (C5), isoxathiol (C5) and oxathiane (thioxane) (C6) Examples of suitable groups include groups derived from

[0033] C1~4 Alkyl: The term "C 1~4 "Alkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having from 1 to 4 carbon atoms.

[0034] Examples of saturated alkyl groups include, but are not limited to, Me: methyl (C1), Et: ethyl (C2), Pr: propyl (C3), and Bu: butyl (C4).

[0035] Examples of saturated straight chain alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), nPr: n-propyl (C3), and nBu: n-butyl (C4).

[0036] Examples of saturated branched alkyl groups include, but are not limited to, iPr: iso-propyl (C3, -C(CH3)2), iBu: iso-butyl (C4), sBu: sec-butyl (C4), and tBu: tert-butyl (C4).

[0037] C 2~4 Alkenyl: The term "C 2~4 "Alkenyl," as used herein, pertains to an alkyl group having from 2 to 4 carbon atoms and having one or more carbon-carbon double bonds.

[0038] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (1-methylvinyl, -C(CH3)=CH2), and butenyl (C4).

[0039] C 1~4 Fluoroalkyl: The term "C 1~4 "Fluoroalkyl," as used herein, refers to a C substituted with one or more fluorine atoms. 1~4 Regarding alkyl groups.

[0040] Alkoxy: -OR (wherein R is C as defined above). 1~4 Alkoxy is an alkyl group. 1~4 Examples of alkoxy groups include, but are not limited to, methoxy (OMe, C1), ethoxy (OEt, C2), propyloxy (C3), and butyloxy (C4).

[0041] Alkylcarbamoyl: —NHC(═O)OR, where R is C as defined above. 1~4 Examples of alkylcarbamoyl groups include, but are not limited to, -N(H)C(=O)OCH3, -N(H)C(=O)OCH2CH3, and -N(H)C(=O)OC(CH3)3.

[0042] Alkylcarbamoyl ester: —OC(═O)NRR′, where R and R′ are independently H and C as defined above. 1~4 Examples of alkylcarbamoyl ester groups include, but are not limited to, —OC(═O)N(CH) and —OC(═O)N(H)CH.

[0043] Alkyl carboxyl ester: -OC(=O)OR (wherein R is C as defined above) 1~4 Examples of alkyl carboxyl ester groups include, but are not limited to, -OC(=O)OCH3, -OC(=O)OCH2CH3, -OC(=O)OC(CH3)3, and -OC(=O)OCH(CH3)2.

[0044] Amino: —N(R)R′, where R and R′ are independently H and C as defined above. 1~4 Examples of amino groups include, but are not limited to, -NH, -N(H)CH, -N(H)C(CH), -N(CH), and -N(CHCH).

[0045] Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamido, aminoacyl): —C(═O)N(R)R′, where R and R′ are independently H and C as defined above. 1~4 Examples of amido groups include, but are not limited to, -C(=O)NH, -C(=O)N(H)CH, -C(=O)N(CH), -C(=O)N(H)CHCH, and -C(=O)N(CHCH).

[0046] Acylamide: —N(R)C(═O)R′, where R and R′ are independently H and C as defined above. 1~4 Examples of acylamido groups include, but are not limited to, -N(H)C(=O)CH2CH3, -N(H)C(=O)CH3, and -N(CH3)C(=O)CH3.

[0047] Phenyl: -C6H5 (wherein phenyl itself can be one or more C 1~4 Alkyl groups, one or more C 1~4 Fluoroalkyl groups, one or more C 1~4 Optionally substituted with an alkoxy group, one or more halo substituents, and one or more cyano substituents).

[0048] Benzyl: -CH2-phenyl, where phenyl is as defined above.

[0049] Ester (carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR, where R is an ester substituent, e.g., C as defined above. 1~4 Alkyl group, C 3~7 heterocyclyl group, or phenyl group, preferably C 1~4 (An alkyl group.) Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh.

[0050] Acyloxy (reverse ester): —OC(═O)R, where R is an acyloxy substituent, e.g., C as defined above. 1~4 Alkyl group, C 3~7 heterocyclyl group, or phenyl group, preferably C 1~4 (An alkyl group.) Examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, and -OC(=O)Ph. Further examples of acyloxy groups include, but are not limited to, methyl ester (C1), ethyl ester (C2), propyl ester (C3), and butyl ester (C4).

[0051] Naturally occurring amino acid: The term "naturally occurring amino acid," as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from a carboxyl or amino group on one of the amino acid compounds commonly found in nature (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine). The amino acid is particularly selected from isoleucine, leucine, and valine, and most particularly valine.

[0052] In each of these groups, the carbon atom attached to both the carboxyl and amino groups is known as the α-carbon, and the carboxyl and amino groups attached thereto are the α-carboxyl and α-amino groups. Naturally occurring amino acids are optionally substituted with protecting groups on the α-amino or any other amino group on the moiety, including, but not limited to, acetyl, methyl, fluorenylmethoxycarbonyl (Fmoc), carboxybenzyl (Cbz; benzyloxycarbonyl), phthalimide, and tertbutylcarbamate (boc).

[0053] Phosphonate ester: -P(O)(OR)OR', where R and R' are independently C as defined above. 1~4 (Alkyl) Examples of phosphonate esters include, but are not limited to, -P(O)(OEt)2.

[0054] Cyano: -C≡N.

[0055] Pivaloyloxymethyl: Formula [ka] Based on.

[0056] Tetrazolyl: Formula [ka] Based on.

[0057] Oxo-oxadiazolyl: A five-membered heterocyclic compound having two nitrogen ring atoms, one oxygen ring atom, and one oxo substituent. Examples of oxo-oxadiazolyl groups include: [ka]

[0058] 2H-triazol-4-yl: Formula: [ka] Based on.

[0059] As used herein, unless the context requires otherwise, the term "comprise" and variations of this term such as "comprising", "comprises" and "comprised" do not exclude further additives, components, integers or steps.

[0060] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a salt" can include plural salts, reference to "at least one heteroatom" can include one or more heteroatoms, and so forth.

[0061] The term "and / or" can mean "and" or "or."

[0062] The term "(s)" after a noun contemplates either the singular or the plural, or both.

[0063] Various features of the present invention are described with reference to certain values ​​or ranges of values. These values ​​are intended to relate to the results of various appropriate measurement techniques and should therefore be interpreted as including the inherent error limits of any particular measurement technique. Some of the values ​​referred to herein are indicated by the term "about" to account, at least in part, for this variability. When used to describe a value, the term "about" can refer to an amount within ±10%, ±5%, ±1%, or ±0.1% of that value. Other forms included

[0064] Unless otherwise specified, the above includes well-known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO - ), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group also includes the protonated form (—N + HR 1 R 2 ), a salt or solvate of an amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group includes the anionic form (—O -), a salt or solvate thereof, as well as conventional protected forms. salt

[0065] It may be convenient or desirable to prepare, purify, and / or handle corresponding salts of the active compounds, e.g., pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0066] For example, if the compound is anionic or has a functional group that can be anionic (e.g., -COOH is -COO - In the case of a compound having a cation, such as methyl, ... + and K. + , alkaline earth cations, e.g., Ca 2+ and Mg 2+ , as well as other cations, e.g., Al +3 Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + Examples of some suitable substituted ammonium ions include ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + is.

[0067] The compound is cationic or has a functional group that can be cationic (e.g., -NH2 is -NH3 +(which may be a salt of a suitable inorganic anion.) Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

[0068] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, trifluoroacetic, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. solvate

[0069] It may be convenient or desirable to prepare, purify and / or handle the corresponding solvate of active compound.The term "solvate" is used herein in its conventional sense to refer to the complex of solute (e.g., active compound, salt of active compound) and solvent.When solvent is water, solvate can be conveniently called hydrate, for example, monohydrate, dihydrate, trihydrate, etc. Prodrug

[0070] Active compounds can be prepared as prodrugs. In particular, R 1 and R 11Carboxy groups, including: can exist as ester groups, amide (—C(═O)NH) groups, and substituted amide groups. In some embodiments, R 1 and R 11 is -C(=O)OR P , -C(=O)NH2 and -C(=O)NHR P where R P teeth, (I C 3~6 cycloalkyl, (ii) methyl, and ester C optionally substituted with a group selected from 3~7 heterocyclyl, and (iii) alkoxy, amino, amides, acyl amides, acyloxy, Alkyl carboxyl esters, alkylcarbamoyl, alkylcarbamoyl esters, phenyl, phosphonate esters, C optionally substituted with a group selected from methyl and oxo 3~7 heterocyclyl, and Naturally occurring amino acids optionally N-substituted with a group selected from methyl, acetyl and boc Straight or branched chain C optionally substituted with a group selected from 1~4 Alkyl is selected from.

[0071] In some embodiments, R 1 and R 11 is —C(═O)NH 2 . In these embodiments, the compound has formula Ic: [ka] wherein A 1 ~A 4 , A 11 ~A14 , R C1 , R C3 , R C4 , R C11 , R C13 , R C14 and Y is as defined above.

[0072] In some embodiments, R P is an optionally substituted straight-chain or branched C 1~4 In some embodiments, R P is the unsubstituted C 1~4 In some embodiments, R P is a substitution C 1~4 It is alkyl.

[0073] R P C 1~4 In some of these embodiments, when R is alkyl, P is methyl. In other of these embodiments, R P is ethyl. In other of these embodiments, R P is propyl (e.g., iso-propyl, n-propyl). In other of these embodiments, R P is butyl (e.g., iso-butyl, sec-butyl, tert-butyl).

[0074] In some embodiments, R P is C 3~6 In some of these embodiments, R is cycloalkyl. P is cyclopropyl. In other of these embodiments, R P is cyclobutyl. In other of these embodiments, R P is cyclopentyl. In other of these embodiments, R P is cyclohexyl.

[0075] In some embodiments, R P is C 3~7 In some of these embodiments, C is heterocyclyl. 3~7A heterocyclyl has a single nitrogen ring atom. In some of these embodiments, R P is azetidinyl, pyrrolidinyl, or piperidinyl. In some of these embodiments, R P is azetidinyl. In some of these embodiments, R P is piperidinyl. R P The above substituents

[0076] In some embodiments, R P is C 3~7 When R is heterocyclyl, it is substituted with a group selected from methyl and ester. P is C 3~7 When R is heterocyclyl, it is substituted with methyl. P is C 3~7 If it is heterocyclyl, it is substituted with an ester.

[0077] In some embodiments, R P is a linear or branched C 1~4 When it is alkyl, it is optionally substituted with a group selected from alkoxy, amino, amido, acylamido, acyloxy, alkylcarboxyl ester, alkylcarbamoyl, alkylcarbamoyl ester, phenyl, phosphonate ester, methyl, and oxo. 3~7 Heterocyclyl and substituted with a group selected from naturally occurring amino acids, optionally N-substituted with a group selected from methyl, acetyl and boc.

[0078] In some embodiments, R P is a linear or branched C 1~4 When R is alkyl, it is substituted with a group selected from acyloxy and phenyl. P is a linear or branched C substituted with acyloxy. 1~4 When it is alkyl, it has the formula: [ka] The group is pivaloyloxymethyl.

[0079] In some embodiments, R P is a linear or branched C substituted with acyloxy. 1~4 When it is alkyl, it has the formula: [ka] The group is propanoyloxyisobutyl.

[0080] In some embodiments, R P is a linear or branched C substituted with phenyl 1~4 When it is alkyl, it is benzyl.

[0081] In some embodiments, R P is a linear or branched C 1~4 If it is alkyl, it is substituted with a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl, and boc. P is substituted with a naturally occurring amino acid, 1~4 When R is alkyl, the naturally occurring amino acid is valine. P is substituted with a naturally occurring amino acid, 1~4 When R is alkyl, the naturally occurring amino acid is N-methylvaline. P is substituted with a naturally occurring amino acid, 1~4 When R is alkyl, the naturally occurring amino acid is N-acetylvaline. P is substituted with a naturally occurring amino acid, 1~4 When it is alkyl, the naturally occurring amino acid is N-boc valine.

[0082] In some embodiments, R P is a linear or branched C 1~4When R is alkyl, it is substituted with amino. P is a linear or branched C 1~4 When R is alkyl, it is substituted with an amide. P is a linear or branched C 1~4 When R is alkyl, it is substituted with acylamido. P is a linear or branched C 1~4 When R is alkyl, it is substituted with acyloxy. P is a linear or branched C 1~4 When R is alkyl, it is substituted with an alkyl carboxyl ester. P is a linear or branched C 1~4 When R is alkyl, it is substituted with alkylcarbamoyl. P is a linear or branched C 1~4 When R is alkyl, it is substituted with an alkyl carbamoyl ester. P is a linear or branched C 1~4 When R is alkyl, it is substituted with phenyl. P is a linear or branched C 1~4 If it is alkyl, it is substituted with a phosphonate ester.

[0083] In some embodiments, R P is a linear or branched C 1~4 When C is alkyl, it is optionally substituted with a group selected from methyl and oxo. 3~7 In some embodiments, R is substituted with heterocyclyl. P But C 3~7 Straight or branched C substituted with heterocyclyl 1~4 If alkyl, C 3~7 Heterocyclyl is dioxole optionally substituted with a group selected from methyl and oxo. Isomers

[0084] Certain compounds of the present invention may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-)-forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; M- and P-forms; Δ- and Λ-forms; R a -Type and S a -forms; as well as combinations thereof, which are hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0085] The term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0086] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0087] "Diastereomer" refers to a stereoisomer with two or more chiral centers whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures, such as electrophoresis and chromatography.

[0088] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0089] "Atropisomers" refers to two stereoisomers of a compound resulting from restricted rotation about a single bond, where rotation about said bond is sufficiently hindered that individual conformers can be isolated, and the conformers are either non-superimposable mirror images of one another (enantiomers) or stereoisomers that are not mirror images of one another (diastereomers).

[0090] The definitions and rules of stereochemistry used herein generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore can exist in different stereoisomeric forms. All stereoisomers of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, M and P, Δ and Λ, R, and R are used to denote the absolute configuration of the molecule about its chiral center(s). a and S aThe prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by a compound; (-) or l means the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, the (+)-stereoisomer and the (-)-stereoisomer are identical except that they are non-superimposable mirror images of each other. Each of these specific stereoisomers can also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0091] In particular, the compounds of the present invention are associated with atropisomerism, where rotation around the single bond between the two aromatic ring systems in each half of the dimer may be restricted, which can occur when A1 and / or A11 are of certain sizes.

[0092] It should be noted that, except as discussed below regarding tautomeric forms, structural (or constitutional) isomers (i.e., isomers that differ merely in the connectivity between atoms, rather than in the position of the atoms in space) are specifically excluded from the term "isomer" as used herein. For example, a reference to a methoxy group, -OCH3, should not be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may include structural isomeric forms that fall within that class as well (e.g., C 1~7 Alkyl includes n-propyl and iso-propyl, butyl includes n-, iso-, sec-, and tert-butyl, methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

[0093] The foregoing exclusion does not relate to tautomeric forms, e.g., keto-, enol-, and enolate forms, as found in, for example, the following tautomeric pairs: keto / enol (exemplified below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hyroxyazo, and nitro / aci-nitro. [ka]

[0094] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0095] It should be noted that the term "isomer" specifically includes compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 H(T), and C may be in any isotopic form, including 12 C. 13 C, and 14 C may be in any isotopic form, including 16 O and 18 It may be in any isotopic form, including O, etc.

[0096] Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, including, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F,31 P, 32 P, 35 S, 36 Cl, and 125 I. Various isotopically labeled compounds of the present invention, such as compounds containing radioactive isotopes, e.g. 3 H, 13 C, and 14 Those incorporating C. Such isotope-labeled compounds can be useful in metabolic studies, reaction kinetic studies, detection techniques or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in patient radiation treatment. The therapeutic compounds of the present invention labeled or substituted with deuterium can have improved DMPK (drug metabolism and pharmacokinetics) properties in terms of distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium can result in certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, resulting from increased metabolic stability. 18 F-labeled compounds may be useful for PET or SPECT studies. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. In addition, heavier isotopes, particularly deuterium (i.e., 2 Substitution with H or D) can result in certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. In this context, deuterium is understood to be considered a substituent. The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.

[0097] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (fully or partially) racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are known in the art or are readily obtained by adapting the methods taught herein or known methods in a known manner. polymorph

[0098] Compounds disclosed herein (in any of the various forms described herein) that form crystalline solids may demonstrate polymorphism. All polymorphic forms of the compounds are within the scope of the present disclosure. N-oxide

[0099] Nitrogen-containing groups can also be oxidized to form N-oxides. Treatment indications

[0100] The compounds disclosed herein can provide therapeutic benefit in a number of disorders, particularly in the treatment or prevention of diseases that are ameliorated by modulation of STING.

[0101] One aspect of the present invention provides a method for treating or preventing STING-mediated diseases and disorders that benefit from agonistic STING activity. Exemplary diseases / disorders include, but are not limited to, cancer and infectious diseases (e.g., diseases caused by viruses, such as HIV, HBV, HCV, HPV, influenza, and coronaviruses (including rhinovirus, SARS, MERS, and SARS-CoV-2), and bacteria). Another aspect of the present invention provides the use of STING agonists as vaccine adjuvants.

[0102] In one embodiment, the present invention provides a compound of the present invention for use in therapy.The present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in therapy.In particular, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of STING-mediated diseases or disorders.

[0103] The present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use as a vaccine adjuvant. Accordingly, an immunogenic composition or vaccine adjuvant comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, is also provided. In a further embodiment of the present invention, a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more immunostimulants is provided.

[0104] In another embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a STING-mediated disease or disorder and / or for use as an immunogenic composition or vaccine adjuvant. In another embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in ameliorating organ injury or damage sustained as a result of a STING-mediated disease or disorder.

[0105] The present invention further provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a STING-mediated disease or disorder.The present invention further provides the use of a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a STING-mediated disease or disorder, such as the diseases and disorders described herein.

[0106] The present invention further provides the use of a compound of formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a vaccine. Further provided is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of an immunogenic composition comprising an antigen or antigenic composition for the treatment or prevention of a disease. Further provided is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a vaccine composition comprising an antigen or antigenic composition for the treatment or prevention of a disease.

[0107] In another embodiment, the present invention is directed to a method of treating a STING-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound of the present invention to a human in need thereof.In another embodiment, the present invention is directed to a method of treating a STING-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt thereof, to a human in need thereof. infectious disease

[0108] The compounds of the present invention can be used to treat infectious diseases, which are any disease caused by or occurring simultaneously with infection from a pathogen. A pathogen is broadly defined as any organism that is foreign to the human tissue environment. Common pathogens that cause disease include bacteria (many such as TB), viruses (many such as HBV, HIV, influenza, and coronavirus), and parasitic protozoa (such as Plasmodium falciparum, which causes malaria). The compounds of the present invention can be used to treat infectious diseases of bacterial origin, such as TB infection (Mycobacterium tuberculosis), chlamydia, tularemia infection (Francisella tularensis), plasmodium infection, or infection by DNA or RNA viruses. The compounds of the present invention can be used to treat infectious diseases from the DNA virus families: Herpesviridae (herpes simplex virus type 1, Kaposi's sarcoma-associated virus, and Epstein-Barr virus), Papillomaviridae (human papillomavirus), Adenovirus, and Hepadnaviridae (hepatitis B virus). Examples of RNA virus families include Retroviridae (human immunodeficiency virus), Flaviviridae (dengue virus, hepatitis C virus), Orthomyxoviridae (influenza), and Coronaviridae (human coronaviruses and SARS coronaviruses, including SARS-CoV-2). cancer

[0109] As used herein, the terms "cancer," "neoplasm," and "tumor" are used interchangeably and refer to cells that have undergone malignant transformation, whether singular or plural, that render them pathological to the host organism. Primary cancer cells can be readily distinguished from noncancerous cells by well-established techniques, particularly histological examination. The definition of cancer cells, as used herein, includes not only primary cancer cells but also any cells derived from a cancer cell ancestor. Cancer cells include metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to types of cancer that typically manifest as solid tumors, a "clinically detectable" tumor is one that is detectable based on tumor burden, for example, by procedures such as computed tomography (CT) scans, magnetic resonance imaging (MRI), X-rays, ultrasound, or palpation during a physical examination, and / or by the expression of one or more cancer-specific antigens in samples obtainable from a patient. The tumor may be a hematopoietic (or hematologic or hematological or blood-related) cancer, such as a cancer derived from blood cells or immune cells, which may be referred to as a "liquid tumor." Specific examples of clinical conditions based on hematological tumors include leukemias, such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia; plasma cell malignancies, such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; lymphomas, such as non-Hodgkin's lymphoma, Hodgkin's lymphoma, etc.

[0110] The cancer may be any cancer in which there is an abnormal number of blast cells or unwanted cell proliferation, or which is diagnosed as a blood cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia, and megakaryocytic (or megakaryoblastic) leukemia. These leukemias can be collectively referred to as acute myeloid (or myelocytic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPDs), including, but not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which can be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT), and myelofibrosis with or without myeloid metaplasia of unknown cause (MFS).

[0111] Hematopoietic cancers also include lymphoid malignancies, which can affect lymph nodes, spleen, bone marrow, peripheral blood, and / or extra-lymphatic sites. Lymphoid cancers include B-cell malignancies, including, but not limited to, B-cell non-Hodgkin's lymphoma (B-NHL). B-NHL can be indolent (or low-grade), intermediate-grade (or aggressive), or high-grade (highly aggressive). Indolent B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL), including nodal MZL, extranodal MZL, splenic MZL, and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHL includes mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHL includes Burkitt lymphoma (BL), Burkitt-like lymphoma, small noncleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-associated (or AIDS-associated) lymphoma, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphocytic (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL can also include T-cell non-Hodgkin's lymphoma (T-NHL), including, but not limited to, T-cell non-Hodgkin's lymphoma, not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome.

[0112] Hematopoietic cancers also include Hodgkin lymphomas (or diseases), including classical Hodgkin lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cytology Hodgkin lymphoma, lymphocyte-predominant (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma, and lymphocytopenic Hodgkin lymphoma. Hematopoietic cancers also include plasma cell disorders or cancers, such as multiple myeloma (MM), including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers can also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes, and natural killer cells. Tissues containing hematopoietic cells, referred to herein as "hematopoietic cell tissues," include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as the spleen, lymph nodes, mucosa-associated lymphoid tissues (e.g., gut-associated lymphoid tissue), tonsils, Peyer's patches, and appendix, and other mucosa-associated lymphoid tissues, such as the bronchial lining.

[0113] Examples of cancer diseases and conditions in which the compounds of the invention may have potentially beneficial anti-tumor effects include, but are not limited to, cancer of the lung, bone, pancreas, skin, head, neck, uterus, ovary, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid, parathyroid, adrenal gland, urethra, prostate, penis, testicles, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinoma of the fallopian tube, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; soft tissue sarcoma; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatocellular carcinoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphoma; primary CNS lymphoma; CNS neoplasms; spinal axis tumors; squamous cell carcinoma; synovial sarcoma; malignant pleural mesothelioma; brain stem glioma; pituitary adenoma; bronchial adenoma; chondroitin hamartoma; mesothelioma; Hodgkin's disease, or a combination of one or more of the foregoing cancers.

[0114] Suitably, the present invention relates to the treatment of brain (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovary, pancreas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, islet cell adenoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastoma, The present invention relates to a method for treating or lessening the severity of cancer selected from the group consisting of: acute large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharangeal cancer, oral cavity cancer, mouth cancer, GIST (gastrointestinal stromal tumor), and testicular cancer.

[0115] In some embodiments, the compounds of the present invention can be used to treat solid tumors or liquid tumors.In some embodiments, the compounds of the present invention can be used to treat sarcoma, breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (RCC), lymphoma, squamous cell carcinoma of the head and neck (SCCHN), hepatocellular carcinoma (HCC), and / or non-Hodgkin's lymphoma (NHL).Suitably, the present invention relates to a method for treating or reducing the severity of pre-cancerous syndromes in mammals, including humans, wherein the pre-cancerous syndromes are selected from cervical intraepithelial neoplasia, monoclonal gammopathy of undetermined significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, cutaneous nevi (pre-melanoma), prostatic intraepithelial (intraductal) neoplasia (PIN), ductal carcinoma in situ (DCIS), colon polyps, and severe hepatitis or cirrhosis.

[0116] In one embodiment, the human has a solid tumor. In one embodiment, the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, ovarian cancer, and pancreatic cancer. In one embodiment, the human has one or more of colorectal cancer (CRC), esophageal, cervical, bladder, breast, head and neck, ovarian, melanoma, renal cell carcinoma (RCC), EC squamous cell, non-small cell lung cancer, mesothelioma, and prostate cancer. In another embodiment, the human has a liquid tumor, such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myelogenous leukemia.

[0117] In one embodiment, the compounds of the present invention may be useful in treating skin cancer (e.g., non-melanoma skin cancer, squamous cell carcinoma, basal cell carcinoma) or actinic keratosis. In addition to their field effect in clearing superficial skin cancers, the compounds of the present invention can prevent the development of secondary skin cancers and premalignant actinic keratosis in treated patients. autoimmune disease

[0118] Associated autoimmune diseases include, but are not limited to, STING-associated vasculitis of infancy (SAVI), Aicardi-Goutieres syndrome (AGS), lupus pernio, and ataxia-telangiectasia. telanogiectasia (also called Louis-Bar syndrome), retinal vasculopathy with cerebral leukodystrophy (RCVL), systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, psoriasis, diabetes mellitus including insulin-dependent diabetes mellitus (IDDM), dermatomyositis, human immunodeficiency virus (HIV), AIDS, polymyositis, systemic sclerosis (scleroderma), and Sjogren's syndrome (SS), rheumatoid arthritis, psoriatic arthritis, polyarthritis, myasthenia gravis, polyarteritis nodosa, vasculitis, cutaneous vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Henoch-Schönlein purpura, autoimmune hepatitis, primary sclerosing cholangitis, Wegener's granulomatosis, microscopic polyangiitis polyangiitis), Behçet's disease, spondylitis, giant cell arteritis, polymyalgia rheumatica, Raynaud's phenomenon, primary biliary cirrhosis, primary vasculitis of the central nervous system microscopic polyangiitis, neuromyelitis optica, and mixed connective tissue disease. inflammation

[0119] Inflammation refers to a group of vascular, cellular, and neural responses to trauma. Inflammation can be characterized as the migration of inflammatory cells, such as monocytes, neutrophils, and granulocytes, into tissues. This is usually associated with reduced endothelial barrier function and edema within the tissue. Inflammation can be classified as either acute or chronic. Acute inflammation is the body's initial response to harmful stimuli and is accompanied by increased migration of plasma and leukocytes from the blood into the injured tissue. A cascade of biochemical events propagates and develops an inflammatory response involving the local vasculature, immune system, and various cells within the injured tissue. Long-term inflammation, known as chronic inflammation, leads to a progressive migration of cell types present at the site of inflammation and is characterized by the simultaneous destruction and healing of tissue by the inflammatory process.

[0120] Inflammation can be beneficial when it occurs as part of an immune response to infection or as an acute response to trauma, and is usually self-limiting. However, inflammation can be harmful under various conditions. This includes the generation of excessive inflammation in response to infectious pathogens, which can lead to significant organ damage and death (e.g., in the setting of sepsis). Furthermore, chronic inflammation is generally harmful and underlies numerous chronic diseases, causing severe and irreversible damage to tissues. In such situations, the immune response is often directed against self-tissues (autoimmunity), although chronic responses to foreign entities can also lead to bystander damage to self-tissues.

[0121] Therefore, the goal of anti-inflammatory treatment is to reduce this inflammation, inhibit autoimmunity if present, and allow the physiological processes or healing and tissue repair to proceed.

[0122] The compounds of the present invention can be used to treat inflammation in any tissue or organ of the body, including musculoskeletal inflammation, vascular inflammation, neurogenic inflammation, gastrointestinal inflammation, ocular inflammation, reproductive system inflammation, and other inflammations, as exemplified below.

[0123] Musculoskeletal inflammation refers to any inflammatory condition of musculoskeletal system, especially the condition that affects skeletal joints, including the joints of hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knee, ankle and foot, and the condition that affects the tissue that connects muscle to bone, such as tendon.The example of musculoskeletal inflammation that can be treated with the compound of the present invention includes arthritis (including for example osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, gout and pseudogout-related arthritis and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibromyalgia, epicondylitis, myositis and osteitis (including for example Paget's disease, osteitis pubis and osteitis fibrosa cystic).

[0124] Ocular inflammation refers to inflammation of any structure of the eye, including eyelid.Examples of ocular inflammation that can be treated with the compound of the present invention include blepharitis, cutis laxa, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis and uveitis.

[0125] Examples of inflammation of the nervous system that may be treated with the compounds of the invention include encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, CNS vasculitis, and schizophrenia.

[0126] Examples of inflammation of the vasculature or lymphatic system that may be treated with the compounds of the invention include arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

[0127] Examples of inflammatory conditions of the digestive system that may be treated with the compounds of the invention include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), ileitis, and proctitis.

[0128] Examples of inflammatory conditions of the reproductive system that may be treated with the compounds of the invention include cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[0129] The compounds of the present invention can be used to treat autoimmune conditions with an inflammatory component, including acute universalis alopecia, Behçet's disease, Chagas' disease, STING-associated vasculitis of infancy (SAVI), Aicardi-Goutieres syndrome (AGS), pernio lupus erythematosus, ataxia-telangiectasia (also known as Louis-Barr syndrome), retinal vasculopathy with cerebral leukodystrophy (RCVL), ANCA-associated vasculitis, chronic fatigue syndrome, autonomic neuropathy, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes, giant cell arteritis, Goodpasture's disease, and others. Syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Henoch-Schönlein purpura, Kawasaki disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjögren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0130] The compounds of the present invention can be used to treat T cell-mediated hypersensitivity disorders with an inflammatory component, including contact hypersensitivity, contact dermatitis (including that caused by poison ivy), urticaria, skin allergies, respiratory allergies (seasonal nasal allergies, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0131] Other inflammatory conditions that may be treated with the compounds of the invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibromyalgia, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonitis, pharyngitis, pleuritis, pneumonia, prostatitis, pyelonephritis, and stomatitis, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small intestine, skin grafts, skin allografts, and heart valve xenografts, serum sickness, and graft-versus-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sézary syndrome, congenital adrenal hyperplasia, nonsuppurative thyroiditis, cancer-related hypercalcemia, and rheumatoid arthritis. These include: rheumatoid arthritis, pemphigus, bullous dermatitis herpes, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or generalized pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphoma in adults, acute leukemia of childhood, regional enterocolitis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, and sepsis. Preferred treatments include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic lung disease, and inflammation associated with infectious conditions (e.g., sepsis). In one embodiment, the compounds of the invention can be used to treat asthma. Cell proliferation

[0132] The compounds of the invention may also be useful in treating one or more diseases afflicting mammals that are characterized by cell proliferation in areas of disorders associated with angiogenesis and / or vascular permeability, including vascular proliferative disorders, including arthritis (rheumatoid arthritis) and restenosis; fibrotic disorders, including cirrhosis of the liver and atherosclerosis; mesangial cell proliferative disorders, including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, proliferative retinopathy, organ transplant rejection, and glomerulopathies; and metabolic disorders, including psoriasis, diabetes mellitus, chronic wound healing, inflammation, and neurodegenerative diseases. Neurodegenerative diseases

[0133] The compounds of the present invention can be used to treat neurodegenerative diseases. Exemplary neurodegenerative diseases include, but are not limited to, multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). combination

[0134] The compounds of the present invention can be employed alone or in combination with other therapeutic agents. As modulators of immune response, the compounds of the present invention can also be used as monotherapy or in combination with other therapeutic agents in the treatment of diseases and conditions in which modulation of STING is beneficial.

[0135] Thus, a combination therapy according to the present invention comprises the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof and at least one other therapeutically active agent. In one embodiment, a combination therapy according to the present invention comprises the administration of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent. The compound(s) of Formula I and its pharmaceutically acceptable salt(s) and the other therapeutic agent(s) can be administered together in a single pharmaceutical composition or separately, and when administered separately, can be administered simultaneously or sequentially in any order. The amounts of the compound(s) of Formula I and its pharmaceutically acceptable salt(s) and the other therapeutic agent(s), as well as the relative timing of administration, are selected to achieve a desired combination of therapeutic effects. Thus, in a further aspect, a combination comprising a compound of Formula I or a pharmaceutically acceptable salt thereof together with one or more other therapeutic agents is provided.

[0136] The compounds of Formula I and pharmaceutically acceptable salts thereof can be used in combination with one or more other therapeutic agents that may be useful in the prevention or treatment of allergic, inflammatory, or autoimmune diseases, such as antigen immunotherapy, antihistamines, steroids, NSAIDs, bronchodilators (e.g., beta 2 agonists, adrenergic agonists, anticholinergic agents, theophylline), methotrexate, leukotriene modulators, and similar agents; monoclonal antibody therapy, such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1, and similar agents; receptor therapy, such as etanercept and similar agents; antigen non-specific immunotherapy (e.g., interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists, and similar agents).

[0137] The compounds of formula I and their pharmaceutically acceptable salts can be used in combination with radiation therapy and / or surgery and / or at least one other therapeutic agent that may be useful in the treatment of cancer and precancerous syndromes. Any antineoplastic agent that has activity against the susceptible tumor being treated can be utilized in this combination. Exemplary useful antineoplastic agents include, but are not limited to, (a) anti-microtubule agents, such as diterpenoids (e.g., paclitaxel, docetaxel) and vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine); (b) platinum coordination complexes (e.g., oxaliplatin, cisplatin, and carboplatin); (c) alkylating agents, such as nitrogen mustards (e.g., cyclophosphamide, melphalan, and chlorambucil), oxazaphosphorines, alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine), and triazenes (e.g., dacarbazine); (d) antibiotic agents, such as anthracyclines (e.g., daunorubicin and doxorubicin), actinomycins (e.g., dactinomycin), and bleomycin; (e) topoisomerase II inhibitors, such as epipodophyllotoxins (e.g., (e.g., etoposide and teniposide), (f) antimetabolites, such as purine and pyrimidine analogs and antifolate compounds (e.g., fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine), (g) topoisomerase I inhibitors, such as camptothecin (e.g., irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin), (h) hormones and hormone analogs (e.g., corticosteroids, such as prednisone and prednisolone, which are useful in the treatment of malignant lymphomas and acute leukemias in children; aminoglutethimide and other aromatase inhibitors, such as anastrozole, letrozole, vorozole, and exemestane, which are useful in the treatment of adrenocortical carcinoma and hormone-dependent breast cancers that contain estrogen receptors;Progestins, such as megestrol acetate, useful in the treatment of hormone-dependent breast cancer and endometrial cancer; estrogens, and antiestrogens, such as fulvestrant, flutamide, nilutamide, bicalutamide, cyproterone acetate, and 5-reductase inhibitors, such as finasteride and dutasteride, useful in the treatment of prostate cancer and benign prostatic hyperplasia; antiestrogens, such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, and selective estrogen receptor modulators (SERMS), such as those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and 6,207,716, useful in the treatment of hormone-dependent breast cancer and other susceptible cancers; and gonadotropin release inhibitors, which stimulate the release of leutinizing hormone (LH) and / or follicle-stimulating hormone (FSH), for the treatment of prostate cancer. These include: (i) GnRH and its analogs, such as LHRH agonists and antagonists, e.g., goserelin acetate and leuprolide; (i) signal transduction pathway inhibitors; (j) non-receptor tyrosine angiogenesis inhibitors; (k) immunotherapeutics (e.g., ex-vivo and in-vivo approaches to increasing the immunogenicity of tumor cells in a patient, e.g., transfection with cytokines, e.g., interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor, approaches to reducing T cell energy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies); (l) pro-apoptotic agents (e.g., bcl-2 antisense oligonucleotides); (m) cell cycle signaling inhibitors; (n) cancer immunotherapy agents; and (o) immunostimulatory agents; Signal transduction pathway inhibitors

[0138] Signal transduction pathway inhibitors are inhibitors that block or inhibit chemical processes that induce intracellular changes. As used herein, this change is cell proliferation or cell differentiation. Signal transduction inhibitors useful in the present invention include receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidyl inositol-3 kinase, myo-inositol signaling, and Ras oncogene inhibitors.

[0139] Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor kinases or non-receptor kinases.

[0140] Receptor tyrosine kinases are transmembrane proteins that have an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain.Receptor tyrosine kinases are involved in the regulation of cell growth and are generally referred to as growth factor receptors.Inappropriate or uncontrolled activation of many of these kinases, i.e., abnormal kinase growth factor receptor activity, for example, due to overexpression or mutation, has been shown to result in uncontrolled cell growth.Therefore, the abnormal activity of such kinases has been linked to malignant tissue growth.As a result, inhibitors of such kinases could provide a method for treating cancer. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony-stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptor, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptor, and RET proto-oncogene. Several inhibitors of growth receptors are under development, including ligand antagonists, antibodies, tyrosine kinase inhibitors, and antisense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for example, in Kath 2000, Shawver 1997, and Lofts 1994.

[0141] Tyrosine kinases that are not growth factor receptor kinases are called non-receptor tyrosine kinases.Non-receptor tyrosine kinases that are useful in the present invention and are targets or potential targets of anti-cancer drugs include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Bruton's tyrosine kinase, and Bcr-Abl.These non-receptor kinases and drugs that inhibit non-receptor tyrosine kinase function are described in Sinh 1999 and Bolen 1997.

[0142] SH2 / SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins, including the PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2), and Ras-GAP. SH2 / SH3 domains as targets for anticancer drugs are discussed in Smithgall 1995.

[0143] Serine / threonine kinase inhibitors include MAP kinase cascade blockers, including blockers of Raf kinase (rafk), mitogen or extracellular-regulated kinase (MEK), and extracellular-regulated kinase (ERK); and protein kinase C family members blockers, including blockers of PKC (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, and TGF-beta receptor kinase. Such serine / threonine kinases and their inhibitors are described in Yamamoto 1999, Brodt 2000, Massague 1996, Philip 1995, Lackey 2000, U.S. Patent No. 6,268,391, and Martinez-Lacaci 2000.

[0144] Inhibitors of phosphatidylinositol-3 kinase family members, including blockers of Pekinese, ATM, DNA-PK, and Ku, are also useful in the present invention. Such kinases are discussed in Abraham 1996, Canman 1998, Jackson 1997, and Zhong 2000.

[0145] Myo-inositol signaling inhibitors, such as phospholipase C blockers and myo-inositol analogues, are also useful in the present invention. Such signaling inhibitors are described in Powis 1994.

[0146] Another group of signal transduction pathway inhibitors is the inhibitor of Ras oncogene.Such inhibitors include inhibitors of farnesyltransferase, geranylgeranyltransferase, and CAAX protease, as well as antisense oligonucleotides, ribozymes, and immunotherapy.Such inhibitors have been shown to block ras activation in cells containing wild-type mutant ras, thereby acting as antiproliferative agents.Ras oncogene inhibition is discussed in Scharovsky 2000, Ashby 1998, and Oliff 1999.

[0147] As mentioned above, antibody antagonists of receptor kinase ligand binding can also act as signal transduction inhibitors.This group of signal transduction pathway inhibitors includes the use of humanized antibodies against the extracellular ligand binding domain of receptor tyrosine kinase.For example, Imclone C225 EGFR-specific antibody (see Green 2000), Herceptin® erbB2 antibody (see Stern 2000), and 2CB VEGFR2-specific antibody (see Brekken 2000). Non-receptor tyrosine angiogenesis inhibitors

[0148] Antiangiogenic therapeutic agents, including non-MEK receptor angiogenesis inhibitors, may also be useful. Antiangiogenic drugs, such as those that block the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab [Avastin™]), and compounds that work by other mechanisms (e.g., linomide, inhibitors of integrin αvβ3 function, endostatin, and angiostatin). Cell cycle signaling inhibitors

[0149] Cell cycle signaling inhibitors inhibit molecules involved in cell cycle control. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins control the progression through the eukaryotic cell cycle. For normal progression through the cell cycle, the coordinated activation and inactivation of different cyclin / CDK complexes is required. Several inhibitors of cell cycle signaling are under development. For example, examples of cyclin-dependent kinases, including CDK2, CDK4, and CDK6, and their inhibitors are described, for example, in Rosania 2000. immune modulators

[0150] Additional examples of other therapeutic agents (eg, anti-neoplastic agents) for use in combination or co-administered with compounds of Formula I are immunomodulators.

[0151] As used herein, "immunomodulator" refers to any substance, including monoclonal antibodies, that affects the immune system. Immunomodulators can be used as anti-cancer agents for the treatment of cancer. For example, immunomodulators include, but are not limited to, anti-CTLA-4 antibodies, such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo / nivolumab and Keytruda / pembrolizumab). Other immunomodulators include, but are not limited to, ICOS antibodies, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies, and GITR antibodies. Anti-PD-L1 agents

[0152] Additional examples of other therapeutic agents (anti-neoplastic agents) for use in combination with or co-administered with the compounds of the present invention include anti-PD-L1 agents. Anti-PD-L1 antibodies and methods for producing them are known in the art. Such antibodies to PD-L1 may be polyclonal or monoclonal, and / or recombinant, and / or humanized. Exemplary PD-L1 antibodies are disclosed in U.S. Patent Nos. 8,217,149, 8,383,796, 8,552,154, 9,212,224, and 8,779,108, as well as U.S. Patent Application Publication Nos. 2011 / 0280877, 2014 / 0341902, and 2013 / 0045201. Additional exemplary antibodies to PD-L1 (also known as CD274 or B7-H1) and methods for use are disclosed in U.S. Patent Nos. 7,943,743, 8,168,179, and 7,595,048, WO 2014 / 055897, WO 2016 / 007235, and U.S. Patent Application Publication Nos. 2013 / 0034559 and 2015 / 0274835. PD-L1 antibodies are under development as immune modulators for the treatment of cancer.

[0153] In one embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. Patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. Patent No. 8,217,149. In another embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. Patent No. 8,779,108. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. Patent Application Publication No. 2013 / 0045201. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. Patent Application Publication No. 2013 / 0045201. In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105), described in WO2007 / 005874. In another embodiment, the anti-PD-L1 antibody is MPDL3280A

[0154] (RG7446). In another embodiment, the anti-PD-L1 antibody is MEDI4736, which is an anti-PD-L1 monoclonal antibody described in WO2011 / 066389 and US2013 / 034559. In another embodiment, the anti-PD-L1 antibody is TECENTRIQ™ (atezolizumab), which is an anti-PD-L1 cancer immunotherapy approved in the United States in May 2016 for certain types of bladder cancer. In another embodiment, the anti-PD-L1 antibody is YW243.55.S70, which is an anti-PD-L1 antibody described in WO2010 / 077634 and U.S. Patent No. 8,217,149. Examples of anti-PD-L1 antibodies useful in the methods of the invention, and methods for making them, are described in PCT patent applications WO2010 / 077634, WO2007 / 005874, WO2011 / 066389, U.S. Patent No. 8,217,149, and US2013 / 034559. PD-1 antagonist

[0155] Additional examples of other therapeutic agents (antineoplastic agents) for use in combination or co-administered with the compounds of the present invention are PD-1 antagonists.

[0156] "PD-1 antagonist" means any compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCDILI, PDL1, B7H1, B7-4, CD274, and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. In any of the aspects or embodiments of the invention in which a human individual is to be treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of both human PD-L1 and PD-L2 to human PD-1.

[0157] The human PD-1 amino acid sequence can be found at NCBI locus number: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI locus numbers: NP_054862 and NP_079515, respectively.

[0158] PD-1 antagonists useful in any of the aspects of the present invention include monoclonal antibodies (mAbs), or antigen-binding fragments thereof, which specifically bind to PD-1 or PD-L1, preferably specifically bind to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody and may comprise a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0159] Examples of mAbs that bind to human PD-1 and are useful in various aspects and embodiments of the present invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004 / 004771, WO2004 / 072286, WO2004 / 056875, and US2011 / 0271358. Specific anti-human PD-1 mAbs useful as PD-1 antagonists in any of the aspects and embodiments of the invention include MK-3475, a humanized IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and comprising the heavy and light chain amino acid sequences shown in Figure 6; nivolumab, a human IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013) and comprising the heavy and light chain amino acid sequences shown in Figure 7; humanized antibodies h409All, h409A16, and h409A17, described in WO2008 / 156712, and AMP-514, being developed by Mediimmune.

[0160] Other PD-1 antagonists useful in any of the aspects and embodiments of the invention include immunoadhesins that specifically bind to PD-1, preferably human PD-1, such as fusion proteins containing the extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region, of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010 / 027827 and WO2011 / 066342. Particular fusion proteins useful as PD-1 antagonists in the treatment methods, medicaments, and uses of the invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1.

[0161] Other examples of mAbs that bind to human PD-L1 and are useful in the methods of treatment, medicaments, and uses of the present invention are described in WO2013 / 019906, WO2010 / 077634, and US8383796. Particular anti-human PD-L1 mAbs useful as PD-1 antagonists in the methods of treatment, medicaments, and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, and MSB0010718C.

[0162] Keytruda / pembrolizumab is an anti-PD-1 antibody marketed by Merck for the treatment of lung cancer. The amino acid sequence and method of use of pembrolizumab are disclosed in U.S. Patent No. 8,168,757.

[0163] Opdivo / nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1 / PCD-1) with immune-enhancing activity. Nivolumab binds to PD-1, an Ig superfamily transmembrane protein, and blocks activation by its ligands PD-L1 and PD-L2, resulting in T cell activation and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T cell activation and effector function by suppressing activation of the PI3k / Akt pathway. Other names for nivolumab include BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence and methods for use and production of nivolumab are disclosed in U.S. Patent No. 8,008,449. Antibodies against ICOS

[0164] Additional examples of other therapeutic agents (antineoplastic agents) for use in combination with or co-administered with compounds of Formula I are antibodies against ICOS.

[0165] ICOS is a costimulatory T cell receptor with a structural and functional relationship to the CD28 / CTLA-4-Ig superfamily (Hutloff 1999). ICOS activation occurs through binding to ICOS-L (B7RP-1 / B7-H2). Neither B7-1 nor B7-2 (ligands for CD28 and CTLA-4) binds to or activates ICOS. However, ICOS-L has been shown to weakly bind to both CD28 and CTLA-4 (Yao 2011). ICOS expression appears to be restricted to T cells. ICOS expression levels vary among different T cell subsets and depending on the T cell activation state. ICOS expression has been demonstrated on resting T17, follicular helper T cells (TFH), and regulatory T cells (Treg), but unlike CD28, it is not highly expressed on naive T1 and T2 effector T cell populations (Paulos 2010). ICOS expression is highly induced on CD4+ and CD8+ effector T cells after activation via TCR engagement (Wakamatsu 2013).

[0166] CDRs for murine antibodies against human ICOS with agonistic activity are shown in PCT / EP2012 / 055735 (WO2012 / 131004). Antibodies against ICOS are also disclosed in WO2008 / 137915, WO2010 / 056804, EP1374902, EP1374901, and EP1125585.

[0167] Agonistic antibodies or ICOS binding proteins against ICOS are disclosed in WO2012 / 131004, WO2014 / 033327, WO2016 / 120789, US20160215059, and US20160304610. In one embodiment, the agonistic antibody against ICOS includes an ICOS binding protein or antigen-binding portion thereof comprising one or more of the CDRH1 set forth in SEQ ID NO: 1, the CDRH2 set forth in SEQ ID NO: 2, the CDRH3 set forth in SEQ ID NO: 3, the CDRL1 set forth in SEQ ID NO: 4, the CDRL2 set forth in SEQ ID NO: 5, and / or the CDRL3 set forth in SEQ ID NO: 6, or direct equivalents of each CDR, wherein the direct equivalents have no more than two amino acid substitutions in said CDRs as disclosed in WO2016 / 120789, which is incorporated herein by reference in its entirety. In one embodiment, the ICOS binding protein or antigen-binding portion thereof is an agonist antibody against ICOS, as described in WO2016 / 120789, comprising a VH domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7, and / or a VL domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:8, wherein said ICOS binding protein specifically binds to human ICOS. In one embodiment, the ICOS binding protein is an agonist antibody against ICOS, as described in WO2016 / 120789, comprising a VH domain comprising the amino acid sequence set forth in SEQ ID NO:7, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO:8.

[0168] Yervoy (ipilimumab) is a fully human CTLA-4 antibody sold by Bristol Myers Squibb. The protein structure and methods of use of ipilimumab are described in U.S. Patent Nos. 6,984,720 and 7,605,238.

[0169] CD134, also known as OX40, is a member of the TNFR superfamily of receptors that, unlike CD28, is not constitutively expressed on resting naive T cells. OX40 is a secondary costimulatory molecule expressed 24 to 72 hours after activation. Its ligand, OX40L, is also not expressed on resting antigen-presenting cells (APCs), but is expressed after their activation. OX40 expression is dependent on full T cell activation; without CD28, OX40 expression is delayed and 4-fold lower. OX-40 antibodies, OX-40 fusion proteins, and methods for their use are disclosed in U.S. Patent Nos. 7,504,101, 7,758,852, 7,858,765, 7,550,140, ​​7,960,515, WO 2012 / 027328, and WO 2013 / 028231.

[0170] In one embodiment, the OX40 antigen binding protein is one disclosed in WO2012 / 027328 (PCT / US2011 / 048752), international filing date August 23, 2011. In another embodiment, the antigen binding protein comprises the CDRs of an antibody disclosed in WO2012 / 027328 (PCT / US2011 / 048752), international filing date August 23, 2011, or CDRs which are 90% identical to the disclosed CDR sequences. In a further embodiment, the antigen binding protein comprises the VH, VL, or both, of an antibody disclosed in WO2012 / 027328 (PCT / US2011 / 048752), international filing date August 23, 2011, or a VH or VL which is 90% identical to the disclosed VH or VL sequences.

[0171] In another embodiment, the OX40 antigen binding protein is disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international filing date February 9, 2012, which is incorporated herein by reference in its entirety. In another embodiment, the antigen binding protein comprises the CDRs of an antibody disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international filing date February 9, 2012, or CDRs which are 90% identical to the disclosed CDR sequences. In a further embodiment, the antigen binding protein comprises the VH, VL, or both, of an antibody disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international filing date February 9, 2012, or a VH or VL which is 90% identical to the disclosed VH or VL sequences. In one embodiment, the OX40 antigen binding protein is an isolated agonist antibody to OX40, comprising a light chain variable region having a sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 10 as described in WO2013 / 028231, and a heavy chain variable region having a sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 4 as described in WO2013 / 028231. In one embodiment, the OX40 antigen binding protein is an isolated antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10 as described in WO2013 / 028231, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 as described in WO2013 / 028231. immune stimulants

[0172] Additional examples of other therapeutic agents for use in combination with or co-administered with a compound of Formula I, or a salt thereof, are immunostimulants.

[0173] As used herein, "immunostimulatory agent" refers to any agent that can stimulate the immune system. As used herein, immunostimulatory agents include, but are not limited to, vaccine adjuvants such as Toll-like receptor agonists, T cell checkpoint blockers such as mAbs against PD-1 and CTL4, and T cell checkpoint agonists such as agonist mAbs against OX-40 and ICOS. As used herein, "immunostimulatory agent" refers to any agent that can stimulate the immune system. As used herein, immunostimulatory agents include, but are not limited to, vaccine adjuvants.

[0174] The term "Toll-like receptor" (or "TLR"), as used herein, refers to a member of the Toll-like receptor family of proteins or fragments thereof that sense microbial products and / or initiate adaptive immune responses. In one embodiment, a TLR activates dendritic cells (DCs). Toll-like receptors (TLRs) are a family of pattern recognition receptors that were initially identified as sensors of the innate immune system that recognize microbial pathogens. TLRs recognize distinctive structures on microorganisms, often referred to as "PAMPs" (pathogen-associated molecular patterns). Ligand binding to a TLR triggers a cascade of intracellular signaling pathways that induce the production of factors involved in inflammation and immunity. Ten TLRs have been identified in humans. TLRs expressed on the cell surface include TLR-1, -2, -4, -5, and -6, while TLR-3, -7 / 8, and -9 are expressed by the ER compartment. Human DC subsets can be identified based on characteristic TLR expression patterns. For example, myeloid or "conventional" DC subsets (mDCs) express TLR1-8 upon stimulation, resulting in the production of activation markers (e.g., CD80, CD86, MHC class I and II, CCR7), proinflammatory cytokines, and a cascade of chemokines. The result of this stimulation and resulting expression is antigen-specific CD4+ and CD8+ T cell priming. These DCs acquire an enhanced ability to internalize antigens and present them to T cells in an appropriate format. In contrast, the plasmacytoid subset of DCs (pDCs) express only TLR7 and TLR9 upon activation, resulting in the activation of NK cells and T cells. Because dying tumor cells can adversely affect DC function, it has been suggested that activation of DCs with TLR agonists may be beneficial for priming antitumor immunity in immunotherapy approaches for cancer treatment. It has also been suggested that TLR4 activation is required for successful treatment of breast cancer using radiation and chemotherapy.

[0175] TLR agonists known in the art and that find use in the present invention include, but are not limited to, the following: Pam3Cys, a TLR1 / 2 agonist; CFA, a TLR2 agonist; MALP2, a TLR2 agonist; Pam2Cys, a TLR2 agonist; FSL-I, a TLR-2 agonist; Hib-OMPC, a TLR-2 agonist; polyinosinic:polycytidylic acid (poly I:C), a TLR3 agonist; polyadenosinic-polyuridylic acid (poly AU), a TLR3 agonist; polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (Hiltonol), a TLR3 agonist; bacterial flagellin These include TLR5 agonists; imiquimod, a TLR7 agonist; resiquimod, a TLR7 / 8 agonist; loxoribine, a TLR7 / 8 agonist; and unmethylated CpG dinucleotides (CpG-ODN), a TLR9 agonist.

[0176] Additional TLR agonists known in the art and found use in the present invention further include, but are not limited to, aminoalkyl glucosaminide phosphates (AGPs) that bind to TLR4 receptors, which are known to be useful as vaccine adjuvants and immunostimulants for stimulating cytokine production, activating macrophages, promoting innate immune responses, and increasing antibody production in immunized animals.An example of a naturally occurring TLR4 agonist is bacterial LPS.An example of a semi-synthetic TLR4 agonist is monophosphoryl lipid A (MPL).AGPs and their immunomodulatory effects via TLR4 have been disclosed in patent publications such as WO2006 / 016997, WO2001 / 090129, and / or U.S. Patent No. 6,113,918, and have been reported in the literature. Additional AGP derivatives are disclosed in U.S. Patent No. 7,129,219, U.S. Patent No. 6,525,028, and U.S. Patent No. 6,911,434. Certain AGPs act as agonists of TLR4, while others are recognized as TLR4 antagonists.

[0177] In addition to the aforementioned immunostimulatory agents, the compositions of the present invention can further contain other therapeutic agents that, due to their adjuvant properties, can stimulate the immune system to respond to cancer antigens present on inactivated tumor cell(s). Such adjuvants include, but are not limited to, lipids, liposomes, inactivated bacteria that induce innate immunity (e.g., inactivated or attenuated Listeria monocytogenes), and compositions that mediate innate immune activation via NOD-like receptors (NLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), and / or C-type lectin receptors (CLRs). Examples of PAMPs include lipoproteins, lipopolypeptides, peptidoglycans, zymosan, lipopolysaccharides, neisseriaporins, flagellins, profilins, galactoceramides, and muramyl dipeptides. Peptidoglycan, lipoproteins, and lipoteichoic acid are cell wall components of Gram-positive bacteria. Lipopolysaccharides are expressed by most bacteria, and MPL is one example. Flagellin refers to a structural component of bacterial flagella secreted by pathogenic and commensal bacteria. rt-Galactosylceramide (rt.-GalCer) is an activator of natural killer T (NKT) cells. Muramyl dipeptide is a bioactive peptidoglycan motif common to all bacteria.

[0178] Due to their adjuvant qualities, TLR agonists are preferably used in combination with other vaccines, adjuvants, and / or immunomodulators, and can be combined in various combinations. Thus, in certain embodiments, compounds of Formula I described herein that bind to STING and induce inactivated tumor cells that express and secrete one or more cytokines that stimulate STING-dependent TBKI activation and DC induction, recruitment, and / or maturation can be administered together with one or more TLR agonists for therapeutic purposes, as described herein.

[0179] Indoleamine 2,3-dioxygenase 1 (IDO1) is a critically important immunosuppressive enzyme that modulates antitumor immune responses by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to evade immune surveillance (Lemos 2016, Munn 2016). Additional active ingredients (antineoplastic agents) for use in combination with or co-administered with the compounds of Formula I of the present invention are IDO inhibitors. Epacadostat ((Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboxamidine) is a highly potent, selective, oral inhibitor of the IDO1 enzyme that reverses tumor-associated immunosuppression and restores effective antitumor immune responses. Epacadostat is disclosed in U.S. Patent No. 8,034,953.

[0180] Additional examples of other therapeutic agents (antineoplastic agents) for use in combination with or co-administered with compounds of Formula I are CD73 inhibitors, and A2a and A2b adenosine antagonists.

[0181] The compound of formula I and its pharmaceutically acceptable salts can be used in combination with at least one other therapeutic agent that is useful for preventing or treating bacterial infection and viral infection.The examples of such agents include but are not limited to polymerase inhibitors, such as those disclosed in WO2004 / 037818, and those disclosed in WO2004 / 037818 and WO2006 / 045613; JTK-003, JTK-019, NM-283, HCV-796, R-803, R1728, R1626, and WO2006 / 018725, WO2004 / 074270, WO2003 / 095441, those disclosed in US2005 / 0176701, WO2006 / 020082, WO2005 / 080388, WO2004 / 064925, WO2004 / 065367, WO2003 / 007945, WO02 / 04425, WO2005 / 014543, WO2003 / 000254, EP1065213, WO01 / 47883, WO2002 / 057287, WO2002 / 057245 and similar agents; replication inhibitors, e.g., aciclovir; protease inhibitors, such as the HIV protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, parinavir, lasinavir, and the HCV protease inhibitors BILN2061, VX-950, SCH503034; and similar agents. nucleoside and nucleotide reverse transcriptase inhibitors, such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, tenofovir disproxil fumarate, tenofovir alafenamide fumarate / hemifumarate, and similar agents;Non-nucleoside reverse transcriptase inhibitors (including drugs with antioxidant activity, such as immunocal, oltipraz, etc.), such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, rilpivirine and similar drugs; entry inhibitors, such as enfuvirtide (T-20), T-1249, PRO -542, PRO-140, TNX-355, BMS-806, 5-Helix and similar agents; integrase inhibitors, such as dolutegravir, elvitegravir, raltegravir L-870,180 and similar agents; budding inhibitors, such as PA-344 and PA-457, and similar agents; chemokine receptor inhibitors, such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-427,85 7), TAK449, and those disclosed in WO02 / 74769, WO2004 / 054974, WO2004 / 055012, WO2004 / 055010, WO2004 / 055016, WO2004 / 055011 and WO2004 / 054581, and similar agents; pharmacokinetic enhancers, such as cobicistat; neuraminidase inhibitors, such as CS-8958, zanamivir, oseltamivir, peramivir, Mivir and similar agents; ion channel blockers such as amantadine or rimantadine and similar agents; and interfering RNA and antisense oligonucleotides such as ISIS-14803 and similar agents; antiviral agents with an unknown mechanism of action such as those disclosed in WO2005 / 105761, WO2003 / 085375, WO2006 / 122011, ribavirin and similar agents.

[0182] The compounds of Formula I and pharmaceutically acceptable salts thereof can also be used in combination with other therapeutic agents that may be useful in the treatment of Kaposi's sarcoma-associated herpesvirus infections (KSHV and KSHV-related), including, but not limited to, chemotherapeutic agents such as bleomycin, vinblastine, vincristine, cyclophosphamide, prednisone, alitretinoin and liposomal anthracyclines such as doxorubicin, daunorubicin, immunotherapeutic agents such as rituximab, tocilizumab, siltuximab, and others such as paclitaxel and rapamycin.

[0183] In one embodiment of the invention, the at least one other therapeutic agent is an antimycobacterial agent or a bactericidal antibiotic. The compounds of Formula I and pharmaceutically acceptable salts thereof may also be used in combination with at least one other therapeutic agent that may be useful in the treatment of TB infection (Mycobacterium tuberculosis) and tularemia (Franciseiia tularensis), including, but not limited to, first-line oral agents isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, rifabutin; injectable agents including kanamycin, amikacin, capreomycin, streptomycin; fluoroquinolones including levofloxacin, moxifloxacin, and ofloxacin; oral bacteriostatic agents para-aminosalicylic acid, cycloserine, terizidone, thionamide, and prothionamide; SQ-109, PNU-100480, rifapentine, linezolid, PA-824, AZD5847, and gatifloxacin. These include moxifloxacin, saturo (bedaquiline) delamanid (OPC-67683), and drugs with an undefined mechanism of action in the treatment of drug-resistant TB, including clofazimine, linezolid, amoxicillin / clavulanate thioacetazone imipenem / cilastatin high-dose isoniazid clarithromycin, and ciprofloxacin.The compounds of Formula I and pharmaceutically acceptable salts thereof may be used in the treatment of various conditions, including but not limited to, antimycobacterial agents (e.g., isoniazid (INH), ethambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)), bactericidal antibiotics (e.g., rifabutin (Mycobutin®) or rifapentine (Priftin®)), aminoglycosides (Capreomycin®), fluoroquinolones (levofloxacin, moxifloxicin, ofloxacin), thioamides (ehionamide), cyclosporine (Sandimmune®), para-aminosalicyclic acid) (Paser®), cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®), bedaquiline fumarate (Sirturo®), oxazolidinone (Sutezolid®), PNU-100480, or delamanid (OPC-67683).

[0184] The compounds of Formula I and pharmaceutically acceptable salts thereof may also be used in combination with at least one other therapeutic agent that may be useful in the treatment of chlamydia, including, but not limited to, azithromycin, doxycycline, erythromycin, levofloxacin, and ofloxacin.

[0185] The compounds of the present invention may also be used in combination with at least one other therapeutic agent that may be useful in the treatment of Plasmodium infections, including, but not limited to, chloroquine, atovaquone-proguanil, artemeter-lumefantrine, mefloquine, quinine, quinidine, doxocycline, clindamycin, artesunate, primaquine.

[0186] In the treatment of amyotrophic lateral sclerosis (ALS), the compound of formula I or a pharmaceutically acceptable salt thereof may be used in combination with a glutamate blocker (riluzole (Rilutek®)), quinidine (Nuedexta®), an anticholinergic (amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)), a sympathomimetic (pseudoephedrine), a mucolytic (guaifenesin) or an analgesic (tramadol (Ultram®), ketorolac (Toradol®), morphine, fentanyl patch (Duragesic®)).

[0187] In the treatment of multiple sclerosis, the compound of formula I or a pharmaceutically acceptable salt thereof may be used in combination with corticosteroids (prednisone, methylprednisolone), interferon beta 1-A (Avonex®, Extavia®, Rebif®, Betaseron®), pegylated interferon beta-1A (Plegridy®), glatiramer acetate (Copaxone®), glatiramer acetate (Glatopa®), It can be used in combination with fluticasone (a generic equivalent of copaxone), dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), teriflunomide (Aubagio®), dalfampridine (Ampyra®), daclizumab (Zinbryta), alemtuzumab (Lemtrada®), natalizumab (Tysabri®), or mitoxantrone hydrochloride (Novantron®).

[0188] The compounds of the invention can also be used as adjuvants to improve the immune response generated against any given antigen and / or to reduce reactogenicity / toxicity in patients, particularly humans, in need thereof. Thus, the compounds of the invention can be used in combination with vaccine compositions to modify, and especially enhance, the immune response, for example by increasing the level or duration of protection and / or allowing for a reduction in antigen dose.

[0189] The compounds of Formula I and their pharmaceutically acceptable salts can be used in combination with one or more vaccines or immunogenic antigens useful in preventing or treating viral infections. Such vaccines or immunogenic antigens include, but are not limited to, proteins or particles derived from pathogens that are typically used as immunogenic substances, such as attenuated viruses, virus particles, and viral proteins. Examples of viruses and viral antigens include, but are not limited to, poliovirus, coronaviruses and coronaviruses, rhinoviruses (all subtypes), adenoviruses (all subtypes), hepatitis A, hepatitis B, hepatitis C, hepatitis D, human papillomaviruses (including all subtypes), rabies virus, human T-cell lymphotropic viruses (all subtypes), rubella virus, mumps virus, Coxsackievirus A (all subtypes), Coxsackievirus B (all subtypes), human enteroviruses, herpesviruses including cytomegalovirus, Epstein-Barr virus, human herpesviruses, and the like.ruses (all subtypes), herpes simplex virus, varicella-zoster virus, human immunodeficiency virus (HIV) (all subtypes), Epstein-Barr virus, reovirus (all subtypes), filoviruses (all strains) including Marburg virus and Ebola virus, lymphocytic choriomeningitis virus, arenaviruses including Lassa virus, Junin virus, and Machupo virus, arboviruses (all serotypes) including West Nile virus, dengue virus, Zika virus, Colorado tick fever virus, Sindh virus, Poxviruses, including bisvirus, Togaviraidae, Flaviviridae, Bunyaviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, orthopoxviruses (variola virus, monkeypox virus, vaccinia virus, cowpox virus), Yatapoxviruses (tanapox virus, Yaba monkey tumor virus), parapoxvirus, morsipoxvirus, yellow fever, Hantan, Seoul, Dobrava, Sin Nombre virus, Nombre, Puumala, and Dobrava-like Saaremaa; human parainfluenza viruses and influenza viruses (all types); H1N1 influenza and swine influenza viruses; respiratory syncytial viruses (all subgroups); rotaviruses, including human rotaviruses A-E, bovine rotavirus, and rhesus rotavirus; polyomaviruses, including simian virus 40, JC virus, BK virus, coltivirus, eyach virus, calcivirus; and parvoviridae, including dependovirus, parvovirus, and erythrovirus.

[0190] Accordingly, the present invention provides an immunogenic composition comprising an antigen or antigenic composition and a compound of Formula I, or a pharmaceutically acceptable salt thereof. Additionally, a vaccine composition is provided comprising an antigen or antigenic composition and a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0191] The compounds of Formula I and pharmaceutically acceptable salts thereof may also be used in combination with at least one other therapeutic agent that may be useful in the prevention or treatment of viral infections, such as immunotherapeutic agents (e.g., interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists and similar agents), as well as therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs (nonsteroidal anti-inflammatory drugs) and similar agents.

[0192] STING-modulating compounds, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, can be administered in combination with other anti-inflammatory agents, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicylic acid and mesalamine preparations, hydroxychloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors; anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics and other cytokine inhibitors or biologics directed against T-cell or B-cell receptors or interleukins.

[0193] For example, in the treatment of systemic lupus erythematosus and related lupus disorders, compounds that modulate STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, may be used in combination with corticosteroids (e.g., prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred)), immunosuppressants (e.g., methotrexate (Rhuematrex®, Trexall®), dexamethasone (Decadron®, Solurex®), mycophenolate mofetil (Cellcept®), tacrolimus®, Sirolimus®), B-cell therapy (belimumab (Benlysta®)), B-cell inhibitors (Atacice®), and the like). pt®, Apratuzumab® (anti-CD22), SBI-087 (anti-CD20), anti-BAFF antibodies (LY2127399, A623), Velcade®), azathioprine (Azasan®, Imuran®), triamcinolone (Clinacort®, Kenalog-10®), hydroxychloroquine (Plaquenil®), thalidomide (Immunoprin®, Contergan®), immune globulin therapy (HyQiva®, Flebogamma®, Gamunex®, Privigen®, GammaGuard®), anti-interferon-alpha therapy (Rontalizumab®, Sifalimumab®, AGS-009®, IFNKinoid), TLR7 and TLR9 blockers (IMO-3100), anti-cytokine therapy (anti-IL6 (CNTO-136), anti-interferon-gamma (AMG811), immunomodulatory therapy (Lupuzor™, Abatacept, Orencia®, AMG557, Laquinimod, Paquinimod, Leflunomide, anti-ICOS (Medi-570), anti-CD40 ligand antibody (CDP7657)), and / or platelet aggregation inhibitors (aspirin).

[0194] In the treatment of vasculitis and diseases involving inflammation of small or medium-sized blood vessels, STING-modulating compounds, particularly compounds of Formula I, or pharmaceutically acceptable salts thereof, can be administered in combination with alkylating agents (cyclophosphamide, Cytoxan®), anti-rheumatic anti-CD20 antibodies (Rituxan®, Rituximab®), and anti-TNF inhibitors (Etanrcept®).

[0195] In the treatment of psoriasis, a compound that modulates STING, particularly a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be administered in combination with ixekizumab, tildrakizumab (MK-3222), or secukinumab (AIN457).

[0196] In one embodiment of the invention, the at least one other therapeutic agent is selected from an inhaled corticosteroid, a long-acting beta-agonist, a combination of an inhaled corticosteroid and a long-acting beta-agonist, a short-acting beta-agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. For example, in the treatment of asthma, compounds that inhibit STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, may be used in combination with inhaled corticosteroids (ICS), such as fluticasone proprionate (Flovent®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort), triamcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone furoate (Asmanex®, Twisthaler®), or ciclesonide (Alvesco®)), long-acting beta-agonists (LABA), such as formoterol fumarate (Foradil®), salmeterol xinafoate (Serevent®), combinations of ICS and LABA (e.g., fluticasone furoate and vilanterol (Breo®)), Ellipta®), formoterol / budesonide inhalation (Symbicort®), beclomethasone dipropionate / formoterol (Inuvair®), and fluticasone propionate / salmeterol (Advair®), short-acting beta agonists (SABAs), such as albuterol sulfate (ProAir®, Proventil HFA®, Ventolin®),HFA®, AccuNeb® Inhalation Solution), levalbuterol tartrate (Xopenex® HFA), ipratropium bromide / albuterol (Combivent® Respimat®), ipratropium bromide (Atrovent® HFA), leukotriene modifiers (e.g., montelukast sodium (Singulair®), zafirlukast (Accolate®), or zileuton (Zyflo®), and and anti-IgE (e.g., omalizumab (Xolair®)), methylxanthine bronchodilators (e.g., theophylline (Accurbron®, Aerolate®, Aquaphyllin®, Asbron®, Bronkodyl®, Duraphyl®, Elixicon®, Elixomin®, Elixophyllin®, Labid®, Lanophyllin®), ®), Quibron-T®, Slo-Bid®, Slo-Phyllin®, Somophyllin®, Sustaire®, Synophylate®, T-Phyll®, Theo-24®, Theo-Dur®, Theobid®, Theochron®, Theoclear®, Theolair®, Theolixir®, Theophyl®, Theovent®, Uni-dur®, Unifil®), mast cell inhibitors (e.g., cromulyn sodium (Nasalcrom®) and nedocromil sodium (Tilade®)), long-acting muscarinic antagonists (LAMAs, e.g., mometasone furoate / formoterol fumarate dihydrate (Dulera®)).

[0197] Other agents that may be suitable for use in combination therapy in the treatment of asthma include protein tyrosine kinase inhibitors (masitinib), CRTH2 / D-prostanoid receptor antagonist (AMG853), indacaterol (Arcapta® Neohaler®), epinephrine inhalation aerosol (E004), fluticasone furoate / fluticasone propionate, vinanterol inhalation / fluticasone furoate powder (Relovair™), fluticasone propionate / formoterol fumarate dehydrate (eformoterol fumarate dehydrate), and fluticasone propionate / formoterol fumarate dehydrate. dehydrate) (Flutiform®), reslizumab, salbutamol dry powder inhaler, tiotropium bromide (Spiriva® HandiHaler®), formoterol / budesonide (Symbicort® SMART®), fluticasone furoate (Veramyst®), VR506 manufactured by Vectura, lebrikizumab (RG3637), and a combination phosphodiesterase (PDE)-3 and (PDE)-4 inhibitor (RPL554).

[0198] In one embodiment of the invention, the at least one other therapeutic agent is selected from a long-acting beta-agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, an inhaled corticosteroid long-acting beta-agonist combination, a short-acting beta-agonist, and an inhaled corticosteroid.For example, in the treatment of COPD, compounds that modulate STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, are used in combination with LABAs (e.g., salmeterol xinafoate (Serevent), umeclidinium / vilanterol (Anoro Ellipta®), umeclidinium (Incruse Ellipta®), formoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta®, Neohaler®) or fluticasone propionate / formoterol fumarate dehydrate (Flutiform®), long-acting inhaled anticholinergics (or muscarinic antagonists, e.g., tiotropium bromide (Spiriva®), and aclidinium bromide (Tudorza®, Pressair®), phosphodiesterase (PDE-r) inhibitors (e.g., roflumilast, Daliresp®), combination ICS / LABAs (e.g., fluticasone furoate and vilanterol (Breo It may be administered in combination with other antihistamines, such as Ellipta®, fluticasone propionate / salmeterol (Advair®), budesonide / formoterol (Symbicort®), mometasone / formoterol (Dulera®), ipratropium bromide / albuterol sulfate (Duoneb®, Atrovent®), albuterol / ipratropium (Combivent Respimat®)), SABAs (e.g., ipratropium bromide (Atrovent®), and albuterol sulfate (ProAir®, Proventil®)), and ICS (e.g., budesonide (Pulmicort®) and fluticasone propionate (Flovent®), beclomethasone dipropionate (QVAR®).

[0199] Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (CXCR2 antagonist), glycopyrronium bromide ((NVA237) Seebri® Breezhaler®), glycopyrronium bromide and indacaterol maleate ((QVA149) Ultibro® Breezhaler®), glycopyrrolate and formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol (Striverdi® Respimat®), tiotropium (Spiriva®) / olodaterol (Striverdi® Respimat®), and aclidinium / formoterol inhalation.

[0200] In one embodiment of the present invention, the at least one other therapeutic agent is selected from oral corticosteroids, antithymocyte globulin, thalidomide, chlorambucil, calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin-1 receptor inhibitors, antifibrotic agents, proton pump inhibitors or imatinib, ARG201, and tocilizumab. For example, in the treatment of systemic sclerosis, compounds that modulate STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, may be used in combination with oral corticosteroids (e.g., prednisolone (Delatsone®, Olapred, Millipred, Omnipred, Econopred, Furopred), immunosuppressants (e.g., methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), antithymocyte globulin (Atgam®), mycophenolate mofetil (Cellcept®), cyclophosphamide (Cytoxan®), etc.). trademark), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Leukeran®), azathioprine (Imuran®, Azasan®), calcium channel blockers (e.g., nifedipine (Procardia®, Adalat®) or nicardipine (Cardene®), topical emollients (nitroglycerin ointment), ACE inhibitors (e.g., lisinopril (Zestril®, Prinivil®), diltiazem (Cardizem®, Cardizem®), SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®), serotonin reuptake inhibitors (e.g., fluoxetine (Prozac®)), endothelin-1 receptor inhibitors (e.g., bosentan (Tracleer®) or epoprostenol (Floran®, Veletri®, Prostacyclin®))It may be administered in combination with antifibrotic agents (e.g., colchicine (Colcrys®), para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO), and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gamma (INF-g)), proton pump inhibitors (e.g., omeprazole (Prilosec®), metoclopramide (Reglan®), lansoprazole (Prevacid®), esomeprazole (Nexium®), pantoprazole (Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®), ARG201 (arGentis Pharmaceuticals), belimumab (Benlysta®), tocilizumab (Actema®).

[0201] In the treatment of Sjogren's syndrome, STING-modulating compounds, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, can be administered in combination with antirheumatic agents (hydroxychloroquine and Plaquenil®, Ridora®, Kineret®), cholinergic agonists (Salagen®, Evozac®), JAK inhibitors (Xelijanz®), and anti-TNF treatments (Remicade®, Humira®, Enbrel®, Cimzia®, Simponi®).

[0202] In one embodiment of the present invention, at least one other therapeutic agent is ciliary neurotrophic growth factor or gene transfer agent.For example, in the treatment of retinitis pigmentosa, the compound that modulates STING, particularly the compound of formula I or its pharmaceutically acceptable salt, can be administered in combination with ciliary neurotrophic growth factor (NT-501-CNTF) or gene transfer agent, UshStat (registered trademark).

[0203] In one embodiment of the present invention, the at least one other therapeutic agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a tetravalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a tetravalent live-attenuated influenza vaccine, an antiviral agent, or an inactivated influenza vaccine. For example, in the treatment of influenza, a STING-modulating compound, particularly a compound of Formula I or a pharmaceutically acceptable salt thereof, can be used in combination with a trivalent (IIV3) inactivated influenza vaccine (e.g., Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®), a tetravalent (IIV4) inactivated influenza vaccine (e.g., Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), or a tetravalent (IIV4) inactivated influenza vaccine (e.g., Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent). , trivalent recombinant influenza vaccines (e.g., FluBlok®), tetravalent live attenuated influenza vaccines (e.g., FluMist® Quadrivalent), antiviral agents (e.g., oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®), or amantadine (Symmetrel®)), or Fluad®, Fludase, FluNhance®, Preflucel, or VaxiGrip®.

[0204] In the treatment of staphylococcal infections, STING-modulating compounds, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, can be administered in combination with antibiotics (e.g., β-lactam cephalosporins (Duricef®, Kefzol®, Ancef®, Biocef®, etc.), nafcillin (Unipen®), sulfonamides (sulfamethoxazole and trimethoprim (Bacrim®, Septra®), sulfasalazine (Azulfidine®), acetylsulfisoxazole (Gantrisin®), etc.), or vancomycin (Vancocin®)).

[0205] In one embodiment of the invention, the at least one other therapeutic agent is selected from a topical immune modulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, interferon gamma, an antihistamine, or an antibiotic.For example, in the treatment of atopic dermatitis, compounds that modulate STING, particularly compounds of Formula I, or pharmaceutically acceptable salts thereof, are used in combination with topical immunomodulators or calcineurin inhibitors (e.g., pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), topical corticosteroids (e.g., hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), and the like). (R), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)), oral corticosteroids (e.g., hydrocortisone (Cortef®), methylprednisolone (Medrol®) or prednisolone (Pediapred®, Prelone®), immunosuppressants (e.g., cyclosporine (Neoral®) or interferon gamma (Alferon®)), N®, Infergen®, Intron A, Roferon-A®), antihistamines (for pruritus, e.g., Atarax®, Vistaril®, Benadryl®), antibiotics (e.g., penicillin derivatives flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm®, etc.)), non-steroidal immunosuppressants (e.g., azathioprine (Imuran®, Azasan®), methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®) or mycophenolate mofetil (Cellcept®)).

[0206] The compounds of the present invention can also be formulated with vaccines as adjuvants to modulate their activity. Such compositions can contain one or more components with adjuvant activity, including but not limited to, aluminum salts, oil and water emulsions, heat shock proteins, lipid A preparations and derivatives, glycolipids, other TLR agonists, such as CpG DNA or similar agents, cytokines, such as GM-CSF or IL-12 or similar agents, together with antigenic components, including but not limited to, antibodies (several) or antibody fragments (several), proteins, DNA, live or killed bacteria and / or viruses or virus-like particles.

[0207] In a further aspect of the invention, there is provided a vaccine adjuvant comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. Additionally, there is provided a vaccine composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and an antigen or antigen composition. Treatment method

[0208] The compounds of the present invention can be used in therapeutic methods. Also provided is a treatment method comprising administering a therapeutically effective amount of the compounds of the present invention to a subject in need of treatment. The term "therapeutically effective amount" refers to an amount sufficient to provide benefit to the patient. Such benefit may be at least the improvement of at least one symptom. The actual amount administered, as well as the rate and time course of administration, will vary depending on the nature and severity of the condition being treated. Prescribing treatment, for example, determining dosage, is the responsibility of general medical practitioners and other physicians. Administration

[0209] The active compound or a pharmaceutical composition comprising the active compound can be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the desired site of action, including, but not limited to, oral (e.g., by ingestion); topical (including, e.g., transdermal, intranasal, ophthalmic, buccal, and sublingual); pulmonary (e.g., using an aerosol, e.g., through the mouth or nose, e.g., by inhalation or insufflation therapy); rectal; intravaginal; parenteral by injection, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intravitreal, and intrasternal; e.g., by implantation of a depot subcutaneously, intravitreal, or intramuscularly. The subject can be a eukaryote, an animal, a vertebrate, a mammal, a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, a chimpanzee, an orangutan, a gibbon), or a human.

[0210] In one embodiment for treating tumors, intratumoral injection can be used. formulation

[0211] While it is possible for an active compound or combination of compounds to be administered alone, it is preferable to present them as a pharmaceutical composition (e.g., a formulation) comprising at least one active compound as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants or other materials well known to those of skill in the art, and, if desired, other therapeutic or prophylactic agents.

[0212] Thus, the present invention further provides a pharmaceutical composition as defined above, and a method of making a pharmaceutical composition comprising the step of mixing at least one active compound as defined above together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials as described herein.

[0213] The term "pharmaceutically acceptable," as used herein, refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0214] Suitable carriers, excipients, etc. can be found in standard medical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.

[0215] Preparation can be conveniently presented in unit dosage form, and can be prepared by any method well known in the field of pharmacy.This method comprises the step of combining active compound with the carrier that constitutes one or more auxiliary components.Generally, preparation is prepared by mixing active compound with liquid carrier or finely divided solid carrier or both uniformly and thoroughly, and then optionally shaping product.

[0216] The formulation may be in the form of a liquid, solution, suspension, emulsion, elixir, syrup, tablet, lozenge, granule, powder, capsule, cachet, pill, ampoule, suppository, pessary, ointment, gel, paste, cream, spray, mist, foam, lotion, oil, bolus, electuary, or aerosol.

[0217] Formulations suitable for oral administration (e.g., by ingestion) may be presented as discrete units each containing a predetermined amount of the active compound, such as capsules, cachets, or tablets; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion; as a bolus; as a electuary; or as a paste.

[0218] Tablets can be prepared by conventional means, such as compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active compound in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose), fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate), and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be coated or scored as needed and can be formulated to provide a sustained or controlled release of the active compound therein using, for example, various percentages of hydroxypropyl methylcellulose to provide the desired release profile. Tablets can optionally be provided with an enteric coating, for release in parts of the gut other than the stomach.

[0219] Formulations suitable for topical administration (e.g., transdermal, intranasal, ophthalmic, buccal, and sublingual) can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. Alternatively, a formulation can comprise a patch or dressing, such as a bandage or adhesive plaster, impregnated with active compounds and optionally one or more excipients or diluents.

[0220] Formulations suitable for topical administration in the mouth include lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.

[0221] Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

[0222] Formulations suitable for nasal administration wherein the carrier is a solid include, for example, a coarse powder having a particle size in the range from about 20 to about 500 microns, which may be administered in the manner of a sniff, i.e., by rapid inhalation through the nostrils from a container of the powder held close to the nose. Suitable formulations wherein the carrier is a liquid, for administration as, for example, a nasal spray, nasal drops, or by aerosol administration by nebulizer, include aqueous or oily solutions of the active compound.

[0223] Formulations suitable for administration by inhalation include those presented as an aerosol spray from pressurized packs using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gas.

[0224] Formulations suitable for topical administration via the skin include ointments, creams, and emulsions. When formulated into an ointment, the active compound can be optionally employed with either a paraffinic or water-miscible ointment base. Alternatively, the active compound can be formulated into a cream using an oil-in-water cream base. Optionally, the aqueous phase of the cream base can contain, for example, at least about 30 wt% of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations can desirably contain a compound that enhances the absorption or penetration of the active compound through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0225] When formulated as a topical emulsion, the oil phase can optionally contain only an emulsifier (otherwise known as an emulgent), or it can contain a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. Overall, the emulsifier(s), with or without stabilizer(s), constitute the so-called emulsifying wax, which, together with the oil and / or fat, constitutes the so-called emulsifying ointment base, which forms the dispersed oil phase of the cream formulation.

[0226] Suitable emulsifiers and emulsion stabilizers include Tween® 60, Span® 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Because the solubility of active compounds in most oils likely to be used in pharmaceutical emulsion formulations can be very low, the selection of an appropriate oil or fat for the formulation is based on achieving the desired cosmetic properties. Therefore, creams should preferably be non-greasy, non-staining, washable products with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of the branched ester known as Crodamol CAP, can be used, with the last three being preferred esters. These can be used alone or in combination depending on the properties required.

[0227] Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0228] Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0229] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active compound, such carriers as are known in the art to be appropriate.

[0230] Suitable formulations for parenteral administration (e.g., via injection, including cutaneous, subcutaneous, intramuscular, intravenous, and intradermal) include aqueous and non-aqueous isotonic, pyrogen-free sterile injection solutions, which may contain antioxidants, buffers, preservatives, stabilizers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents, and liposomes or exosomes or other microparticle systems that are designed to target the compound to blood components or one or more organs.Examples of suitable isotonic vehicles for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection.Typically, the concentration of the active compound in the solution is about 1 ng / mL to about 10 μg / mL, for example, about 10 ng / mL to about 1 μg / mL. The formulations can be presented in single-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Injectable solutions and suspensions for immediate use can be prepared from sterile powders, granules, and tablets. The formulations can also be in the form of liposomes, exosomes, or other microparticulate systems designed to target the active compound to blood components or one or more organs. Dosage

[0231] Those skilled in the art will recognize that the appropriate dosage of compounds and compositions containing compounds may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dosage level will depend on various factors, including, but not limited to, the activity of the specific compound, the route of administration, the timing of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds and / or materials used in combination, the severity of the condition, and the patient's species, sex, age, weight, condition, overall health, and past medical history. The amount of the compound and the route of administration are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dosage is selected to achieve a local concentration at the site of action that achieves the desired effect without causing significant harm or adverse side effects.

[0232] Administration can be in one dose, continuously, or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those skilled in the art and will vary with the formulation used for therapy, the therapeutic purpose, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out, with the dose level or pattern being selected by the treating physician, veterinarian, or clinician.

[0233] Generally, a suitable dose of the active compound is in the range of about 100 ng to about 25 mg (more typically about 1 μg to about 10 mg) per kilogram of subject body weight per day. Where the active compound is a salt, ester, amide, prodrug, or the like, the amount administered is calculated based on the parent compound, and therefore the actual weight to be used will be increased proportionately.

[0234] In one embodiment, the active compound is administered to a human patient according to a dosing regimen of about 100 mg three times daily.

[0235] In one embodiment, the active compound is administered to a human patient according to a dosing regimen of about 150 mg twice daily.

[0236] In one embodiment, the active compound is administered to a human patient according to a dosing regimen of about 200 mg twice daily.

[0237] However, in one embodiment, the active compound is administered to a human patient according to a dosing regimen of about 50 mg or about 75 mg three or four times daily.

[0238] In one embodiment, the active compound is administered to a human patient according to a dosing regimen of about 100 mg or about 125 mg twice daily. treatment

[0239] The term "treatment," as used herein in the context of treating a condition, generally relates to treatment and therapy, whether in humans or animals (e.g., veterinary applications), in which some desired therapeutic effect is achieved, such as inhibiting the progression of the condition, including reducing the rate of progression, halting the rate of progression, regressing the condition, ameliorating the condition, and curing the condition. Preventative treatment (i.e., prevention, prophylaxis) is also included.

[0240] The term "therapeutically effective amount," as used herein, relates to an amount of an active compound or material, composition, or dosage form containing an active compound, commensurate with a reasonable benefit / risk ratio, effective to provide some desired therapeutic effect when administered in accordance with a desired treatment regimen.

[0241] Similarly, the term "prophylactically effective amount," as used herein, relates to an amount of an active compound or material, composition, or dosage form containing an active compound, commensurate with a reasonable benefit / risk ratio, effective to provide some desired prophylactic effect when administered in accordance with a desired treatment regimen. Subjects / patients

[0242] The subject / patient may be an animal, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), monotreme (e.g., platypus), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human.

[0243] Furthermore, the subject / patient may be in any of its forms of development, for example, a fetus. In a preferred embodiment, the subject / patient is a human. General synthesis method

[0244] The compounds of the present invention can be prepared by employing the following general methods and using the procedures detailed in the Examples. The reaction conditions mentioned are exemplary and non-limiting, for example, a person skilled in the art can use a variety of synthetic methods to synthesize the desired compounds, such as, but not limited to, those described in the literature (for example, but not limited to, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition or Larock's Comprehensive Organic Transformations: Comprehensive Organic Transformations: A Guide to Functional Group Preparations).

[0245] The compounds of formula I above can be prepared by the synthetic strategies outlined below, where the above definitions apply. Thus, in any of the following general synthetic schemes, A 1 , A 2 , A3 , A 4 , A 11 , A 12 , A 13 , A 14 , R 1 , R 11 , R C1 , R C2 , R C3 , R C4 , R C13 , R C14 , R P and Y are as defined for any compound of the invention described herein, including formula (I) and any embodiment thereof. General synthesis 1 [ka]

[0246] Scheme 1a illustrates the synthesis of compounds having structure G4. 1 , A 1 , A 2 , A 3 and A 4

[0047] One equivalent of aldehyde G1 having substituent R is reacted with one equivalent of aldehyde G2 having substituent R in the presence of either (a) a suitable acid, such as, but not limited to, acetic acid, or (b) sodium bisulfite, or (c) sodium metabisulfite, or (d) Oxone®. 11 , A 11 , A 12 , A 13 and A 14 and 1 equivalent of tetra-aniline G3 to give compounds of type G4. In some cases, two equivalents of the same aldehyde (i.e., G1=G2, R 1 =R 11 , A 1 =A 11 , A 2 =A 12 , A 3 =A 13 , A 4 =A 14 ) is reacted with one equivalent of tetra-aniline G3 to give compounds of type G4. The tetra-aniline may also be symmetrical (RC1 =R C11 , R C3 =R C13 , R C4 =R C14 In other cases, aldehydes G1 and G2 can be reacted with one equivalent of di-nitro / di-aniline compound G5 using conditions such as, but not limited to, heating with sodium dithionite as shown in Scheme 1b. [ka]

[0247] As illustrated in Schemes 1a and 1b, the substituent R on compounds G1-G5 A (A 1 =CR A ), R B (A 2 =CR B ), R C (A 3 =CR C ), and R D (A 4 =CR D ), R AA (A 11 =CR AA ), R BB (A 12 =CR BB ), R CC (A 13 =CR CC ) and R DD (A 14 =CR DD ), R C1 , R C3 and R C4 , R C11 , R C13 and R C14Those skilled in the art will recognize that may be a halogen atom or other suitable leaving group (e.g., boronic acid or ester, —OH, —O-triflyl, —OC(O)allyl, etc.) that allows for transition metal catalyzed transformations, such as Ullmann, Negishi, Stille, Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig couplings, or SnAr displacement to generate additional examples of the type of compound I. General synthesis 2 [ka]

[0248] Compounds of structure G1 can be obtained by treating an appropriately substituted arene or heteroarene G6 with either an alkyllithium, such as, but not limited to, n-butyllithium, or a lithium amide base, such as, but not limited to, lithium diisopropylamide, followed by quenching the resulting lithiated species with N,N-dimethylformamide. Compounds of structure G1 can also be obtained by brominating intermediate G7 in the presence of an initiator, such as, but not limited to, benzoyl peroxide, using a suitable bromine source, such as, but not limited to, N-bromosuccinimide, to form alkyl bromide G8. Oxidation of G8 can be carried out using a suitable oxidizing agent, such as, but not limited to, N-methylmorpholine N-oxide, to provide compounds of type G1. Aldehydes of type G1 can also be prepared by numerous other methods well known to those skilled in the art, such as, but not limited to, oxidation of benzyl alcohol, reaction with organolithium compounds, and reduction of acids / esters / nitriles. General synthesis 3 [ka]

[0249] Scheme 3 illustrates how compounds of formula G3 can be made where "X" is a suitable leaving group, such as, but not limited to, a halogen atom, or an activated leaving group, such as, but not limited to, a triflate, mesylate, or tosylate. In Scheme 3, "W" represents a primary amide C(=O)NH2 or a group that can be converted to a primary amide using conditions known to those skilled in the art, such as, but not limited to, an ester -C(=O)OR P , a carboxylic acid -CO2H, an activated acid (e.g., an acid halide or mixed anhydride), or a nitrile -CN.

[0250] The first step to obtain compounds of formula G3 is to react a phenyl compound G9 substituted with a suitable leaving group with a diamine of type G10 and one equivalent of another phenyl compound G11 substituted with a suitable leaving group to obtain a bis-nitro species G12. In some cases, the bis-nitro compound G12 will be symmetrical, where R C1 =R C11 , R C3 =R C13 , R C4 =R C14 Alternatively, compounds of type G12 can be obtained by first reacting phenyl compound G9, substituted with a suitable leaving group, with diamine G13, monoprotected with a suitable protecting group, such as, but not limited to, a Boc group, to give intermediate G14. Deprotection of the amine, for example, using acidic conditions, gives intermediates of type G15, which can then be reacted with phenyl compound G11, substituted with a suitable leaving group, to give di-nitro intermediate G12. Reduction of the aromatic nitro group of compound G12 can be achieved by methods well known to those skilled in the art, including, but not limited to, catalytic hydrogenation using 10% Pd / C or Raney nickel in a hydrogen atmosphere, iron or zinc in acidic medium, or sodium dithionite, to give tetra-aniline compounds of type G3.

[0251] Substituent R on compounds G3, G9, G11, G12, G143 and G15 C1 , R C3 and R C4 , R C11 , R C13 and R C14 Those skilled in the art will recognize that may be a halogen atom or other suitable leaving group (e.g., boronic acid or ester, —OH, —O-triflyl, —OC(O)allyl, etc.) that allows for transition metal catalyzed transformations, such as Ullmann, Negishi, Stille, Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig couplings, or SnAr displacement to generate further examples of the type of compound I. General synthesis 4 [ka]

[0252] Conditions for converting diacid G16 to diester G18 will be apparent to those skilled in the art and include an excess of the appropriate nucleophile G17 and a catalyst, such as concentrated sulfuric acid (for ester formation), as shown in Scheme 4a. Alternatively, G16 can first be activated with a coupling agent, such as, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, or N,N'-dicyclohexylcarbodiimide, followed by reaction with nucleophile G17 in the presence of a catalyst, such as, but not limited to, 4-dimethylaminopyridine. Diamide analogs of diester G16 can be prepared by converting diacid G16 using an appropriately functionalized nucleophile in place of nucleophile G17 under conditions apparent to those skilled in the art, including conditions similar to those described in Scheme 4a.

[0253] Diesters G18 can also be obtained by reacting diacids G16 with appropriate alkyl halides G19 in the presence of a suitable base, such as, but not limited to, cesium carbonate, as shown in Scheme 4b. [ka] General synthesis 5 [ka]

[0254] Scheme 5 illustrates a method for preparing a hydroxyl group in which "W" is a primary amide C(=O)NH or a group that can be converted to a primary amide using conditions known to one of skill in the art, such as, but not limited to, an ester -C(=O)OR PThis illustrates an alternative route for the synthesis of compounds having structure G4 defined as carboxylic acid -COH, activated acid (e.g., acid halide or mixed anhydride), or nitrile -CN. Nitro intermediate G14 can be reduced to a di-aniline intermediate using conditions such as, but not limited to, stirring over a heterogeneous catalyst, such as Pd / C, under a hydrogen atmosphere to afford G190. Condensation of this di-aniline with aldehyde intermediate G1 in the presence of either (a) a suitable acid, such as, but not limited to, acetic acid, or (b) sodium bisulfite, or (c) sodium metabisulfite, or (d) Oxone®, can afford intermediates of type G20. Treatment of the Boc-monoprotected material under acidic conditions liberates the primary amine to afford compounds of type G21. A second nucleophilic aromatic substitution can be carried out with a phenyl compound of type G11 substituted with an appropriate leaving group in the presence of a base, such as, but not limited to, triethylamine, to afford G22. A reduction step of the nitro compound G22 can be carried out using conditions, such as, but not limited to, stirring over a heterogeneous catalyst, such as Pd / C, under a hydrogen atmosphere to afford G23. The di-aniline intermediate G23 can be condensed with one equivalent of an aldehyde of type G2 in the presence of either (a) a suitable acid, such as, but not limited to, acetic acid, or (b) sodium bisulfite, or (c) sodium metabisulfite, or (d) Oxone®, to afford bis-benzimidazole compounds of type G4. General synthesis 6 [ka]

[0255] Compounds of formula G26 or G27 can be obtained via the common nitrile intermediate G24 (Scheme 6a). Compounds of type G24 can be obtained using the chemical reactions described in General Synthesis 1 and General Synthesis 5, where R1 / R11 are replaced by nitrile-CN groups. Treatment of the appropriately substituted nitrile G24 with hydroxylamine hydrochloride can provide N-hydroxyamidine intermediates of type G25. Subsequent treatment of intermediate G25 with a reagent that provides a carbonyl (C=O) equivalent, such as, but not limited to, carbonyldiimidazole, provides 5-oxo-4H-1,2,4-oxadiazol-3-yl derivatives of type G26. Alternatively, nitrile G24 can be employed to form tetrazole compound G27 in one step in the presence of a base, such as, but not limited to, triethylamine, and an azide source, such as sodium azide. [ka]

[0256] Compounds of type G30 are positional isomers of G26 and can be prepared from acid G16. Coupling of acid G16 with hydrazine substituted on one nitrogen atom with a suitable protecting group ("PG"), such as, but not limited to, tert-butyloxycarbonyl (Boc), using coupling agents such as, but not limited to, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole in the presence of a base, such as, but not limited to, N,N-diisopropylethylamine, can provide protected intermediates of type G28. Removal of the protecting group using conditions well known to those skilled in the art provides compounds of type G29, which can be reacted with a reagent that provides a carbonyl (C=O) equivalent, such as, but not limited to, carbonyldiimidazole, to provide 2-oxo-3H-1,3,4-oxadiazol-5-yl derivatives of type G30. Further embodiments

[0257] In some embodiments, the two moieties attached to Y are the same, i.e., A 11 =A 1 , A 12 =A 2 , A 13 =A 3 , A 14 =A 4 , R C11 =R C1 , R C13 =R C3 , R C14 =R C4 , R 11 =R 1 is. A 1 ~A 4 and A 11 ~A 14

[0258] In some embodiments, A 1 is CR A is.

[0259] In other embodiments, A 1 is N.

[0260] In some embodiments, A 2 is CR B is.

[0261] In other embodiments, A 2 is N.

[0262] In some embodiments, A 3 is CR C is.

[0263] In other embodiments, A 3 is N.

[0264] In some embodiments, A 4 is CR D is.

[0265] In other embodiments, A 4 is N.

[0266] In some embodiments, A 1 , A 2 , A 3 and A 4 Two of them are N.

[0267] In other embodiments, A 1 , A 2 , A 3 and A 4 One of them is N.

[0268] In other embodiments, A 1 , A 2 , A 3 and A 4 None of the above is N, i.e. A 1 , A 2 , A 3 and A 4 are CR A , C.R. B , C.R. C , and C.R. D is.

[0269] In some embodiments, A 11 is CR AA is.

[0270] In other embodiments, A 11 is N.

[0271] In some embodiments, A 12 is CR BB is.

[0272] In other embodiments, A 12 is N.

[0273] In some embodiments, A 13 is CR CC is.

[0274] In other embodiments, A 13 is N.

[0275] In some embodiments, A 14 is CR DD is.

[0276] In other embodiments, A 14 is N.

[0277] In some embodiments, A 11 , A 12 , A 13 and A 14 Two of them are N.

[0278] In other embodiments, A 11 , A 12 , A 13 and A 14 One of them is N.

[0279] In other embodiments, A 11 , A 12 , A 13 and A 14 None of the above is N, i.e. A 11 , A 12 , A 13 and A 14 are CR AA , C.R. BB , C.R. CC , and C.R. DD is.

[0280] In some embodiments, the compound of Formula I has the formula (IIIa)-(IIIe): [ka] [ka] The compound is selected from the group consisting of: R A , R B , R C , R D , R AA , R BB , R CC and R DD (if present)

[0281] In some embodiments, R A , R B , R C , R D , R AA , R BB , R CC and R DD (when present) is selected from H, F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe, and OH. In some embodiments, R A , R B , R C , R D , R AA , R BB , R CC and R DD (when present) are independently selected from H, F, Cl and Br, preferably H, Cl and F.

[0282] In some embodiments, R A , R B , R C and R D (if present), and R AA , R BB , R CC and R DD one of (if present) is selected from H, F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe, and OH, and the rest (if present) are H.

[0283] In other embodiments, R A , R B , R C and R D Two of them (if they exist), and R A , R B , R C , R D , R AA , R BB , R CC and R DDtwo of (if present) are selected from H, F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH, and the remaining (if present) is H.

[0284] In a further embodiment, R A , R B , R C and R D three of them (if they exist), and R A , R B , R C , R D , R AA , R BB , R CC and R DD Three of (if present) are selected from H, F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe, and OH, and the remainder (if present) is H.

[0285] In some embodiments, R A , R B , R C and R D One, two, or three (if present) of the AA , R BB , R CC and R DD One, two, or three (if present) of R are selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, and OMe. The remainder (if present) are H. In some of these embodiments, R A , R B , R C and R D One, two, or three (if present) of the AA , R BB , R CC and R DD One, two, or three (if present) of R are selected from H, F, Cl, Br, Me, CF, and cyclopropyl and OMe. The remainder (if present) are H. In some of these embodiments, RA , R B , R C and R D One, two, or three (if present) of the AA , R BB , R CC and R DD where one, two or three (if present) of are selected from H, F, Cl, Br, Me, and CF3 and OMe.

[0286] In some embodiments, R A , R B , R C and R D (if present), and R AA , R BB , R CC and R DD are selected from F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe, and OH, and the remainder, if present, are H.

[0287] In other embodiments, R A , R B , R C and R D Two of them (if they exist), and R A , R B , R C , R D , R AA , R BB , R CC and R DD are selected from F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe, and OH, and the remainder, if present, are H.

[0288] In a further embodiment, R A , R B , R C and R D three of them (if they exist), and R A , RB , R C , R D , R AA , R BB , R CC and R DD are selected from F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe, and OH, and the remainder, if present, are H.

[0289] In some embodiments, R A , R B , R C and R D One, two, or three (if present) of the AA , R BB , R CC and R DD one of (if present) is selected from F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe, and OH, and the rest (if present) are H.

[0290] In other embodiments, R A , R B , R C and R D One, two, or three (if present) of the A , R B , R C , R D , R AA , R BB , R CC and R DD two of (if present) are selected from F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH, and the remaining (if present) is H.

[0291] In a further embodiment, R A , R B , R C and R D One, two, or three (if present) of theA , R B , R C , R D , R AA , R BB , R CC and R DD Three of (if present) are selected from F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe, and OH, and the remainder (if present) is H.

[0292] In some embodiments, R A and R AA is selected from H, Br and F, preferably H and F. In some embodiments, R A is H. In some embodiments, R AA is H. In some embodiments, R A and R AA is H. In some embodiments, R A is F. In some embodiments, R AA is F. In some embodiments, R A and R AA is F.

[0293] In some embodiments, R B is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. BB is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. B and R BB is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. B and / or R BB is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, and OMe. B and / or R BBis selected from H, F, Br, and Cl. In some embodiments, R B and / or R BB is selected from H, F, and Cl. In some embodiments, R B and / or R BB is selected from H and Cl. In some embodiments, R B and / or R BB is H. In some embodiments, R B and / or R BB is F. In some embodiments, R B and / or R BB is Cl.

[0294] In some embodiments, R C is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. CC is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. C and R CC is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. C and / or R CC is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, and OMe. C and / or R CC is selected from H, F, Br, and Cl. In some embodiments, R C and / or R CC is selected from H, F, and Cl. In some embodiments, R C and / or R CC is H. In some embodiments, R C and / or R CC is F. In some embodiments, R C and / or R CC is Cl.

[0295] In some embodiments, R D is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. DD is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. D and R DD is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. D and / or R DD is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, and OMe. D and / or R DD is selected from H, F, Br and Cl. In some embodiments, R D and / or R DD is selected from H, F, and Cl. In some embodiments, R D and / or R DD is H. In some embodiments, R D and / or R DD is F. In some embodiments, R D and / or R DD is Cl.

[0296] In some embodiments, R A , R B , R C and R D One or two (if present) of R are halo and the remainder are H. In these embodiments, preferred halo atoms are Cl, Br and F, more preferably Cl and F, most preferably F. In these embodiments, R A and R C One or two of the groups are halo and R B and R D is H.

[0297] In some embodiments, R AA , R BB , R CC and R DD One or two (if present) of R are halo and the remainder are H. In these embodiments, preferred halo atoms are Cl, Br and F, more preferably Cl and F, most preferably F. In these embodiments, R AA and R CC One or two of the groups are halo and R B and R D is H.

[0298] In some embodiments, A 1 , A 2 , A 3 and A 4 The combinations in the table below are 1.1 to 1.30: [Table 1] is selected from.

[0299] In some embodiments, A 11 , A 12 , A 13 and A 14 The combinations 2.1 to 2.30 in the table below: [Table 2] is selected from.

[0300] In some embodiments, A 1 , A 2 , A 3 , A 4 , A 11 , A 12 , A 13 and A 14 Combinations 3.1 to 3.8 in the table below: [Table 3] is selected from.

[0301] Of these, combinations 1, 3, 4, 6 and 7 may be preferred.

[0302] In a further embodiment, A 1 , A 2 , A 3 , A 4 , A 11 , A 12 , A 13 and A 14 is the combination 9 to 28 in the table below: [Table 4] is selected from.

[0303] Of these, combinations 9 and 10 may be preferred.

[0304] In some embodiments, combinations 1, 3, 6 and 9 may be preferred.

[0305] In some embodiments, combinations 1 and 10 may be preferred.

[0306] In some embodiments, combination 10 may be preferred.

[0307] In some embodiments, combination 1 may be preferred. Y

[0308] In some embodiments, Y is (CH) n wherein n is 2 to 3. In some embodiments, Y is (CH2)2. In some embodiments, Y is (CH2)3. In some embodiments, Y is (CH2)4.

[0309] In other embodiments, Y is -CH2-CH=CH-CH2-. R C1 , R C3 , R C4、 R C11 , R C13 and R C14

[0310] In some embodiments, R C1 , R C3 , R C4 , R C11 , R C13 and R C14 are all H.

[0311] In other embodiments, R C1 , R C3 and R C4 Two of the R C11 , R C13 and R C14 Two of are H and the others are selected from the defined groups (excluding H).

[0312] In other embodiments, R C1 , R C3 and R C4 One of the following, as well as R C11 , R C13 and R C14 is H and the others are independently selected from the defined groups (excluding H).

[0313] In some embodiments, R C1 , R C3 and R C4 is independently selected from H, Cl, F, Br, Me, OMe, cyano, CF3, and CH2OH. In some of these embodiments, R C1 , R C3 and R C4 is independently selected from H, Cl, F, CF, OMe, and CHOH. In further of these embodiments, R C1 , R C3 and R C4 is independently selected from H, Cl, and OMe. In other embodiments, R C1 , R C3 and R C4 is independently selected from H, F, and OMe. In further of these embodiments, R C1 , R C3 and R C4 is independently selected from H and OMe.

[0314] In some embodiments, R C11 , R C13 and R C14 is independently selected from H, Cl, F, Br, Me, OMe, cyano, CF3, and CH2OH. In some of these embodiments, R C11 , R C13 and R C14 is independently selected from H, Cl, F, CF, OMe, and CHOH. In further of these embodiments, R C11 , R C13 and R C14 is independently selected from H, Cl, and OMe. In other embodiments, R C1 , R C3 and R C4 is independently selected from H, F, and OMe. In further of these embodiments, R C11 , R C13 and R C14 is independently selected from H and OMe.

[0315] In some embodiments, R C1 is OMe.

[0316] In some embodiments, R C11 is OMe.

[0317] In some embodiments, R C3 is H.

[0318] In some embodiments, R C13 is H.

[0319] In some embodiments, R C4 is H or F, preferably H.

[0320] In some embodiments, R C14 is H or F, preferably H.

[0321] In some embodiments, R C1 and RC11 is OMe and R C3 and R C13 is H and R C4 and R C14 are both either H or F, preferably H.

[0322] In some embodiments, R C1 , R C3 and R C4 is the following combination 1-4: [ka] is selected from.

[0323] In some embodiments, combinations 3 and 4 may be preferred.

[0324] In some embodiments, combination 3 may be preferred.

[0325] In some embodiments, R C11 , R C13 and R C14 is the following combination 1-4: [ka] is selected from.

[0326] In some embodiments, combinations 3 and 4 may be preferred.

[0327] In some embodiments, combination 3 may be preferred.

[0328] In some embodiments, R C1 , R C3 , R C4 , R C11 , R C13 and R C14 is the following combination 1-4: [ka] is selected from.

[0329] In some embodiments, combinations 3 and 4 may be preferred.

[0330] In some embodiments, combination 3 may be preferred. R 1 and R 11

[0331] In some embodiments, R 1 and R 11 is selected from C(=O)OH, C(=O)OCH3, F, Br, tetrazolyl and oxo-oxadiazolyl.

[0332] In some embodiments, R 1 and R 11 is selected from C(=O)OH, tetrazolyl and oxo-oxadiazolyl.

[0333] In some embodiments, R 1 and R 11 is -C(=O)OH.

[0334] In other embodiments, R 1 and R 11 is tetrazolyl.

[0335] In other embodiments, R 1 and R 11 is oxo-oxadiazolyl, such as 5-oxo-4H-1,2,4-oxadiazol-3-yl and 2-oxo-3H-1,3,4-oxadiazol-5-yl.

[0336] In other embodiments, R 1 and R 11 is triazoyl.

[0337] In other embodiments, R 1 and R 11 is Br or F.

[0338] In some embodiments, R 1 and R11 are not the same. In these embodiments, R C1 is R C11 may be the same as R C3 is R C13 may be the same as R C4 is R C14 and A 1 , A 2 , A 3 and A 4 are A 11 , A 12 , A 13 and A 14 In some embodiments, R 1 is tetrazolyl and R 11 is C(=O)OH.

[0339] In some embodiments, R 1 and R 11 is C(=O)OR P1 In these embodiments, R P1 is preferably methyl.

[0340] Other embodiments In some embodiments, the compound has formula (II): [ka] It is of [In the formula, Y is (CH2) n where n is 2 to 4; R 1 and R 11 is selected from —C(═O)OH and tetrazolyl; A 1 is CR A or N, A 2 is CR B or N, A 3 is CR C or N, A 4 is CR Dor N, where A 1 , A 2 , A 3 , and A 4 can be N, R A , R B , R C and R D wherein one, two or three (when present) of are selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH; R A , R B , R C and R D the remainder (if any) of is H, A 11 is CR AA or N, A 12 is CR BB or N, A 13 is CR CC or N, A 14 is CR DD or N, where A 11 , A 12 , A 13 and A 14 can be N, R AA , R BB , R CC and R DD wherein one, two or three (when present) of are selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH; R AA , R BB , R CC and R DD the remainder (if any) of is H, R C1 , R C3 and R C4are independently H, Cl, F, Br, Me, OMe, cyano, CF3, CH2OH, CHOMe, C 2~4 selected from alkenyl and C5 heterocyclyl; R C11 , R C13 and R C14 are independently H, Cl, F, Br, Me, OMe, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl]. Example

[0341] The following examples are provided merely to illustrate the present invention and are not intended to limit the scope of the invention described herein. acronym

[0342] For convenience, many chemical moieties are represented using well-known abbreviations, including, but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), tert-butyl (tBu), phenyl (Ph), benzyl (Bn), methoxy (MeO), ethoxy (EtO), trimethylsilyl (TMS), and acetyl (Ac).

[0343] For convenience, many compounds may be used, including but not limited to, methanol (MeOH), deuterated methanol (MeOD-d4 or CD3OD), ethanol (EtOH), isopropanol (i-PrOH), ether or diethyl ether (Et2O), ethyl acetate (EtOAc), acetic acid (AcOH), acetonitrile (MeCN or ACN), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), deuterated chloroform (CDCl3), diethylamine (DEA), deuterium oxide (DEA), and methyl methyl ether (MME). Dimethyl sulfoxide (DMSO-d6), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl), meta-chloroperoxybenzoic acid (mCPBA), 1,1'-bis(diphenylphosphino)ferrocene (dppf), tert-butyloxycarbonyl (Boc, BOC), 2-(trimethylsilyl)ethoxymethyl (SEM), triethylamine (Et3N or TEA), 2-(1H-7-azabenzoxazole), Triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA or DIEA), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (PdCl2(dppf)), trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2), tris(di benzylideneacetone)dipalladium(0) (Pd2(dba)3), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), propylphosphonic anhydride (T3P), hexamethylphosphoramide (HMPA), 1,2-dichloroethane (DCE), chromium(VI) oxide (CrO3), n-bromosuccinimide (NBS), potassium hydroxide (KOH), benzoyl peroxide (BPO), carbon tetrachloride (CCl4), petroleum ether (Pet.These compounds are represented using well-known abbreviations, including methyl ether, potassium carbonate (K2CO3), sodium sulfate (Na2SO4), lithium diisopropylamine (LDA), azobisisobutyronitrile (AIBN), N-methylmorpholine N-oxide (NMO), benzoyl peroxide (BPO), 1,1'-carbonyldiimidazole (CDI), and 1-hydroxybenzotriazole (HOBt).

[0344] Additionally, TLC refers to thin layer chromatography. General Experimental Details

[0345] Unless otherwise stated, the following generalizations apply: 1 H NMR spectra were recorded on a Bruker AVANCE III (400 MHz). Signal multiplicities are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; td, triplet of doublets; ddd, doublet of doublet of doublets; br, broad; m, multiplet. All observed coupling constants, J, are reported in Hertz. Exchangeable protons are not always observed.

[0346] LCMS data was generated using the following conditions: Chlorine isotopes: 35 Bromine isotopes reported as Cl are 79 Br or 81 Either Br or 79 Br / 81 Report as both Br.

[0347] LC-MS method A (LCMS-A): Device information LC model: Agilent 1200 (Pump type: binary pump, detector type: DAD) MS model: Agilent G6110A Quadrupole LCMS parameters LC: Column: Xbridge-C18, 2.5 μm, 2.1 × 30 mm Column temperature: 30℃ Wavelength acquisition: 214nm, 254nm Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH MS: Ion source: ES+ (or ES-) MS range: 50-900 m / z Fragmenter: 60 Drying gas flow: 10 L / min Nebulizer pressure: 35 psi Drying gas temperature: 350°C Vcap: 3.5kV Gradient table: [Table 5]

[0348] Sample preparation Samples were dissolved in methanol at a concentration of approximately 0.11–1 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1–10 μL).

[0349] LC-MS method B (LCMS-B): Device information LC model: Agilent 1200 (Pump type: binary pump, detector type: DAD) MS model: Agilent G6110A Quadrupole LCMS parameters LC: Column: Xbridge-C18, 2.5 μm, 2.1 × 30 mm Column temperature: 30℃ Wavelength acquisition: 214nm, 254nm Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH MS: Ion source: ES+ (or ES-) MS range: 50-900 m / z Fragmenter: 60 Drying gas flow: 10 L / min Nebulizer pressure: 35 psi Drying gas temperature: 350°C Vcap: 3.5kV Gradient table: [Table 6] Sample preparation Samples were dissolved in methanol at a concentration of approximately 0.11–1 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1–10 μL).

[0350] LC-MS method C (LCMS-C): Device information LC model: Waters 2695 Alliance (Pump type: Quaternary pump, Detector: 2996 Photodiode Array Detector) MS model: Micromass ZQ LCMS parameters LC: Column: Xbridge-C18, 3.5 μm, 2.1 × 50 mm Column temperature: 30℃ Wavelength acquisition: 214nm, 254nm Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH MS: Ion source: ES+ (or ES-) MS range: 50-900 m / z Capillary: 3kV Cone: 3V Extractor: 3V Drying gas flow: 600L / hour Cone: 50L / hour Desolvation temperature: 300℃ Source temperature: 100℃ Gradient table: [Table 7]

[0351] Sample preparation Samples were dissolved in methanol at a concentration of approximately 0.11–1 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1–10 μL). Other Chromatography

[0352] Analytical thin layer chromatography was performed on Merck silica gel 60 F254 aluminum-backed plates, which were visualized using fluorescence quenching under UV light or by adding basic KMnO4 or ninhydrin.

[0353] Preparative thin-layer chromatography (preparative TLC) was performed using Tklst (China), top grade: (HPTLC): 8±2 μm > 80%; (TLC): 10-40 μm, type: GF254. Compounds were visualized by UV (254 nm).

[0354] Column chromatography was performed using Tklst (China), top grade, 100-200 mesh silica gel.

[0355] Where necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods. Solutions of inorganic acids or bases were made up as aqueous solutions unless otherwise stated.

[0356] Solutions of hydrogen chloride, sodium hydroxide, potassium carbonate and sodium bicarbonate are aqueous solutions unless otherwise stated. Preparation of intermediates (i) 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) (I4) [ka] (a) tert-Butyl (2-((4-carbamoyl-2-nitrophenyl)amino)ethyl)carbamate (I1)

[0357] A suspension of 4-chloro-3-nitrobenzamide (8.0 g, 39.9 mmol), tert-butyl (2-aminoethyl)carbamate (6.40 g, 39.9 mmol), and EtN (8.1 g, 79.8 mmol) in NMP (80 mL) was heated at 150 °C under N overnight. Water (500 mL) was added, followed by pet. ether / EtOAc (5:1, 300 mL), and the resulting precipitate was collected by filtration to give the title compound (12.0 g, 92%) as a yellow solid. LCMS-B: rt 3.2 min, m / z 347.1 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.44 (t, J = 5.8 Hz, 1H), 8.05 - 7.92 (m, 2H), 7.27 (s, 1H), 7.14 (d, J = 9.1 Hz, 1H), 7.04 (t, J = 5.8 Hz, 1H), 3.46 - 3.45 (m, 2H), 3.20 - 3.19 (m, 2H), 1.35 (s, 9H). (b) 4-((2-aminoethyl)amino)-3-nitrobenzamide hydrochloride (I2)

[0358] A mixture of tert-butyl (2-((4-carbamoyl-2-nitrophenyl)amino)ethyl)carbamate (I1) (12.0 g, 37.0 mmol) and 5.5 M HCl in dioxane solution (200 mL) was stirred at room temperature overnight. The solvent was then removed under reduced pressure to give the title compound (8.0 g, 96%) as a yellow solid. LCMS-B: rt 1.2 min, m / z 225.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.1 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 2H), 8.05 (dd, J = 9.0, 2.2 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 5.62 (br s, 3H), 3.76 - 3.74 (m, 2H), 3.01 - 2.97 (m, 2H). (c) 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-nitrobenzamide) (I3)

[0359] A suspension of 4-((2-aminoethyl)amino)-3-nitrobenzamide hydrochloride (I2) (7.6 g, 33.9 mmol), 4-chloro-3-nitrobenzamide (6.80 g, 33.9 mmol), and EtN (20.6 g, 203 mmol) in NMP (80 mL) was heated at 150 °C under N overnight. Additional 4-((2-aminoethyl)amino)-3-nitrobenzamide hydrochloride (I2) (800 mg, 3.57 mmol) and EtN (3.0 g, 29.6 mmol) were added, and the mixture was heated at 150 °C under N overnight. The mixture was allowed to cool to room temperature, diluted with pet. ether / EtOAc (1:1, v / v, 500 mL), and the resulting precipitate was collected by filtration to give the title compound (12.0 g, 91%) as a yellow solid. LCMS-B:rt 1.3 min, m / z 389.0[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 4H), 7.99 - 7.95 (m, 4H), 7.30 - 7.28 (m, 4H), 3.70 - 3.64 (m, 4H). (d) 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) (I4)

[0360] A suspension of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-nitrobenzamide) (I3) (12 g, 30.9 mmol) and 10% Pd / C (2.0 g) in DMF (200 mL) was heated at 100 °C under an atmosphere of H2 overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (9.0 g, 90%) as a black solid. LCMS-B: rt 0.3 min, m / z 329.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.11 (s, 2H), 6.74 (s, 2H), 6.46 (d, J = 8.0 Hz, 2H), 5.05 (s, 2H), 4.58 (s, 4H), 3.41 - 3.36 (m, 4H). (ii) 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) I [ka] (a) Methyl 4-fluoro-2-hydroxybenzoate (I5)

[0361] A mixture of 4-fluoro-2-hydroxybenzoic acid (50.0 g, 320.3 mmol) and concentrated HSO (40 mL, 672.7 mmol) in MeOH (600 mL) was heated to reflux under N for 16 h. The mixture was poured into water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic extracts were washed with water (500 mL × 2), brine (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1 to 20:1) to give the title compound (50.0 g, 91%) as a white solid. LCMS-A (ES-API): rt 1.80 min, m / z 171.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 7.83 (dd, J = 8.9, 6.8 Hz, 1H), 6.90 - 6.70 (m, 2H), 3.88 (s, 3H). (b) Methyl 4-fluoro-2-hydroxy-3-nitrobenzoate (I6)

[0362] To a solution of methyl 4-fluoro-2-hydroxybenzoate I5 (50.0 g, 294.0 mmol) in concentrated H2SO4 (100 mL) was added concentrated HNO3 (20 mL, 382.1 mmol) dropwise at 0 °C under N2, and the mixture was warmed to room temperature and stirred for 16 h. The mixture was slowly poured into water (2.0 L) and extracted with EtOAc (1.5 L × 3). The combined organic extracts were washed with water (1.5 L × 2), brine (1.5 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% pet. ether) to give a mixture of the title compound and an unidentified regioisomer (50 g, approximately 3.75:1 unidentified regioisomer / title compound). The mixture was used in the next step without further purification or characterization. LCMS-A(ES-API): rt 1.57 min (small amount) m / z 216.0[M+H] + and rt 1.68 min (major) m / z 216.1 [M+H] + . (c) Methyl 4-fluoro-2-methoxy-3-nitrobenzoate (I7)

[0363] A mixture of methyl 4-fluoro-2-hydroxy-3-nitrobenzoate (containing a major unidentified regioisomer) I6 (50.0 g), CHI (99.0 g, 697 mmol), and KCO (64.1 g, 465 mml) in DMF (200 mL) was stirred at room temperature under N2 for 16 h. The mixture was poured into water (1.0 L) and extracted with EtOAc (1.0 L × 3). The combined organic extracts were washed with water (1.0 L × 2), brine (1.0 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1 to 40:1). Fractions containing minor components were collected to give the title compound (14.0 g, 21% over two steps) as a white solid. LCMS-C(ES-API): rt 3.53 min, m / z 230.0[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J = 9.1, 6.5 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 3.93(s, 3H), 3.91 (s, 3H). (d) Methyl 4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methoxy-3-nitrobenzoate (I8)

[0364] A mixture of methyl 4-fluoro-2-methoxy-3-nitrobenzoate I7 ​​(6.0 g, 26.2 mmol), tert-butyl (2-aminoethyl)carbamate (4.2 g, 26.2 mmol), and EtN (5.3 g, 52.4 mmol) in NMP (100 mL) was heated at 80 °C under N for 16 h. The mixture was poured into water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic extracts were washed with water (500 mL × 2), brine (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1 to 10:1) to afford the title compound (9.5 g, 98%) as a yellow solid. LCMS-C(ES-API): rt 4.43 min, m / z 392.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 9.2 Hz, 1H), 6.96 (t, J = 5.5 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 6.70 (t, J = 5.7 Hz, 1H), 3.79 (s, 6H), 3.27 - 3.21 (m, 2H), 3.11 - 3.06 (m, 2H), 1.37 (s, 9H). (e) Methyl 4-((2-aminoethyl)amino)-2-methoxy-3-nitrobenzoate hydrochloride (I9)

[0365] A mixture of methyl 4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methoxy-3-nitrobenzoate I8 (9.5 g, 25.7 mmol) and 3 M HCl in dioxane solution (200 mL) was stirred at room temperature under N for 16 h. The mixture was concentrated under reduced pressure to give the title compound (6.0 g, 87%) as a white solid. LCMS-C (ES-API): rt 0.82 min, m / z 270.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 9.2, 3.8 Hz, 1H), 6.82 - 6.71 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.31 - 3.28 (m, 4H). (f) Dimethyl 4,4'-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzoate) (I10)

[0366] A mixture of methyl 4-((2-aminoethyl)amino)-2-methoxy-3-nitrobenzoate hydrochloride I9 (5.5 g, 18.0 mmol), methyl 4-fluoro-2-methoxy-3-nitrobenzoate I7 ​​(4.68 g, 20.4 mmol), and EtN (6.2 g, 61.3 mmol) in NMP (100 mL) was heated at 80 °C under N for 16 h. The mixture was poured into water (600 mL), and the resulting precipitate was collected by filtration to afford the title compound (8.0 g, 82%) as a yellow solid. LCMS-C (ES-API): rt 4.75 min, m / z 477.1 [M−H] - . 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 9.2 Hz, 2H), 6.77 - 6.74 (m, 4H), 3.78 (s, 6H), 3.77 (s, 6H), 3.40 (br s, 4H). (g) 4,4'-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzoic acid) (I11)

[0367] A mixture of dimethyl 4,4'-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzoate) I10 (4.0 g, 8.4 mmol) and NaOH (2.0 g, 50.2 mmol) in EtOH / water (50 mL / 50 mL) was heated at 80 °C for 16 h. Most of the EtOH was removed under reduced pressure, and the residue was diluted with water (50 mL) and acidified to pH 4-5 with 2 M aqueous HCl. The resulting precipitate was collected by filtration to give the title compound (3.5 g, 93%) as a yellow solid. LCMS-C (ES-API): rt 3.45 min, m / z 473.1 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.6 (br s, 2H), 7.77 (d, J = 9.1 Hz, 2H), 6.74 (d, J = 9.3 Hz, 2H), 6.69 (t, J = 5.5 Hz, 2H), 3.78 (s, 6H), 3.44 (br s, 4H). (h) 4,4'-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzamide) (I12)

[0368] A mixture of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzoic acid) I11 (3.4 g, 7.6 mmol), NH4Cl (2.4 g, 45.3 mmol), HOBt (3.1 g, 22.7 mmol), EDCI.HCl (4.3 g, 22.7 mmol), and DIPEA (5.9 g, 45.3 mmol) in DMF (300 mL) was stirred at room temperature under N2 for 16 h. The mixture was poured into water (600 mL), and the resulting precipitate was collected by filtration to give the title compound (2.4 g, 71%) as a yellow solid. LCMS-C (ES-API): rt 3.02 min, m / z 471.1 [M+Na] + . 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 9.0 Hz, 2H), 7.42 (br s, 4H), 6.77 (d, J = 9.1 Hz, 2H), 6.60 (t, J = 4.8 Hz, 2H), 3.77 (s, 6H), 3.39 - 3.36 (m, 4H). (i) 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13)

[0369] A mixture of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(2-methoxy-3-nitrobenzamide) I12 (1.0 g, 2.3 mmol) and 10% Pd / C (200 mg) in MeOH (150 mL) was stirred at room temperature under a H2 atmosphere (3 MPa) for 3 days. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (120 mg). The filter cake was washed with DMSO, and the filtrate was freeze-dried to give additional title compound (680 mg). The isolated solids were combined to give the title compound (800 mg, 92%) as a brown solid. LCMS-B (ES-API): rt 1.09 min, m / z 388.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (br s, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.10 (br s, 2H), 6.37 (d, J = 8.5 Hz, 2H), 5.23 (br s, 2H), 4.42 (br s, 4H), 3.66 (s, 6H), 3.35 (br s, 4H). [Example]

[0370] Example 1 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) [ka] (a) Methyl 2-(bromomethyl)-5-chlorobenzoate (A1)

[0371] To a solution of methyl 5-chloro-2-methylbenzoate (5.0 g, 27.1 mmol) in CCl (50 mL) was added NBS (5.3 g, 29.8 mmol) and AIBN (2.2 g, 13.5 mmol), and the mixture was heated to reflux under N for 4 hours. The mixture was poured into water and extracted with EtOAc, and the combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (pet. ether) to give the title compound (3.0 g, 34%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 2.2 Hz, 1H), 7.69 - 7.62 (m, 2H), 4.99 (s, 2H), 3.88 (s, 3H). (b) Methyl 5-chloro-2-formylbenzoate (A2)

[0372] To a solution of methyl 2-(bromomethyl)-5-chlorobenzoate A1 (480 mg, 1.83 mmol) in THF (7.0 mL) was added NMO (429 mg, 3.66 mmol), and the mixture was heated at 100 °C under N for 16 h. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether / EtOAc = 1:0 to 250:1) to give the title compound (170 mg, 47%) as a white solid. LCMS-B (ES-API): rt 3.68 min, m / z 198.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 7.93 - 7.83 (m, 3H), 3.92 (s, 3H). (c) Dimethyl 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoate) (A3)

[0373] A mixture of methyl 5-chloro-2-formylbenzoate A2 (83 mg, 0.42 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) I13 (80 mg, 0.21 mmol), and NaHSO3 (44 mg, 0.42 mmol) in DMF (4 mL) was heated at 100 °C under N2 for 16 h. The mixture was diluted with water until a precipitate formed, which was collected by filtration to give the title compound (130 mg, 83%) as a brown solid. LCMS-B (ES-API): rt 3.95 min, m / z 745.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 2.3 Hz, 2H), 7.71 (s, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.45 (s, 2H), 7.28 (dd, J = 8.2, 2.3 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H), 4.36 (s, 6H), 4.25 (s, 4H), 3.61 (s, 6H). (d) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (1)

[0374] A mixture of dimethyl 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoate) A3 (120 mg, 0.16 mmol) and NaOH (39 mg, 0.96 mmol) in EtOH / HO (5 mL / 5 mL) was heated at 80 °C for 3 h. Most of the EtOH was removed under reduced pressure, and the residue was adjusted to pH 4-5 with 1 M aqueous HCl. The resulting precipitate was collected by filtration and purified by trituration with DCM / MeOH (10:1) to give the title compound (44 mg, 38%) as a brown solid. LCMS-B (ES-API): rt 2.66 min, m / z 717.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 2.3 Hz, 2H), 7.71 (s, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.44 (s, 2H), 7.14 (dd, J = 8.4, 1.2 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.2 Hz, 2H), 4.39 (s, 6H), 4.27 (s, 4H). Example 2 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazol-1,2-diyl))dibenzoic acid (2) [ka] (a) Dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoate (A4)

[0375] A solution of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) I4 (500 mg, 1.52 mmol), methyl 2-formylbenzoate (499 mg, 3.04 mmol), and NaHSO3 (316 mg, 3.04 mmol) in DMF (30 mL) was heated at 120 °C under N2 overnight. The resulting precipitate was collected by filtration, washed with water and DCM, and dried under reduced pressure to give the title compound (100 mg, 26%) as a grey solid. LCMS-B (ES-API): rt 2.59 min; m / z 617.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 1.0 Hz, 2H), 8.01 (br s, 2H), 7.89 (dd, J = 7.9, 1.3 Hz, 2H), 7.65 (dd, J = 8.5, 1.6 Hz, 2H), 7.54 - 7.43 (m, 2H), 7.28 (br s, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.21 - 7.16 (m, 2H), 6.52 (d, J = 7.5 Hz, 2H), 4.26 (s, 4H), 3.53 (m, 6H). (b) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (2)

[0376] A mixture of 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl)) dibenzoate A4 (120 mg, 0.19 mmol) and NaOH (47 mg, 1.17 mmol) in EtOH / water (10 mL / 2 mL) was heated at 50 °C under N overnight. The solvent was removed under reduced pressure, and the residue was diluted with water (3 mL) and acidified to pH 4-5 with 1 M aqueous HCl. The resulting precipitate was collected by filtration, washed with water, and dried at 60 °C to give the title compound (25 mg, 22%) as a black solid. LCMS-B (ES-API): rt 0.33 min; m / z 589.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 2H), 8.08 (br s, 2H), 7.91 (d, J = 7.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.52 (t, J = 7.4 Hz, 2H), 7.41 (br s, 2H), 7.36 - 7.28 (m, 2H), 7.21 - 7.28 (m, 2H), 6.74 - 6.59 (m, 2H), 4.42 (s, 4H). Example 3 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoic acid) (3) [ka] (a) Methyl 4-bromo-2-formylbenzoate (A5)

[0377] To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (2.0 g, 6.5 mmol) in acetonitrile (31 mL) was added NMO (50% aqueous solution, 4.6 g, 19.7 mmol) at 0 °C, and the mixture was stirred at 0 °C overnight. The mixture was diluted with water and extracted with EtOAc, and the organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 50:1) to give the title compound (622 mg, 39%) as a white solid. LCMS-B (ES-API): rt 3.93 min, m / z 242.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.4 (s, 1H), 8.01 - 7.95 (m, 2H), 7.85 (d, J = 8.2 Hz, 1H), 3.90 (s, 3H). (b) Dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoate) (A6)

[0378] To a solution of methyl 4-bromo-2-formylbenzoate A5 (200 mg, 0.82 mmol) and 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) I4 (135 mg, 0.41 mmol) in DMF (9 mL) was added NaHSO3 (85 mg, 0.82 mmol), and the mixture was heated at 120 °C under N2 overnight. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (165 mg, 52%) as a yellow solid. LCMS-B (ES-API): rt 2.99 min, m / z 773.0 / 775.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 2H), 7.97 (br s, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.76 - 7.73 (m, 4H), 7.32 (d, J = 8.5 Hz, 2H), 7.27 (br s, 2H), 6.82 (s, 2H), 4.31 (s, 4H), 3.58 (s, 6H). (c) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoic acid) (3)

[0379] To a solution of dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoate) A6 (100 mg, 0.13 mmol) in EtOH (6 mL) was added a solution of NaOH (31 mg, 0.78 mmol) in water (4 mL), and the mixture was stirred at room temperature overnight. Most of the EtOH was removed under reduced pressure, and the residue was diluted with water and acidified to pH 3-4 with 2 M aqueous HCl. The resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (17 mg, 18%) as a yellow solid. LCMS-B (ES-API): rt 2.48 min, m / z 745.0 / 747.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 2H), 8.00 (br s, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.75 - 7.65 (m, 4H), 7.37 - 7.21 (m, 4H), 6.79 (br s, 2H), 4.39 (s, 4H). Example 4 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazol-1,2-diyl))dibenzoic acid (4) [ka] (a) Dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoate (A7)

[0380] A mixture of methyl 2-formylbenzoate (197 mg, 1.20 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) I13, and NaHSO3 (52 mg, 0.50 mmol) in DMF (20 mL) was heated at 120 °C under a N2 atmosphere overnight. The mixture was diluted with water and partitioned against EtOAc, resulting in the formation of a precipitate. The precipitate was collected by filtration, triturated with DCM / MeOH = 20 / 1, and then dried under reduced pressure to give the title compound (115 mg, 14%) as a white solid. LCMS-C (ES-API): rt 3.1 min, m / z 677.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 7.9 Hz, 2H), 7.70 (br s, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.56 - 7.51 (m, 2H), 7.46 (br s, 2H), 7.34 (t, J = 8.4 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 7.2 Hz, 2H), 4.36 (s, 6H), 4.22 (s, 4H), 3.56 (s, 6H). (b) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazol-1,2-diyl))dibenzoic acid (4)

[0381] A mixture of dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazol-1,2-diyl))dibenzoate A7 (70 mg, 0.10 mmol) and NaOH (40.0 mg, 1.00 mmol) in MeOH / water (10 mL / 1 mL) was stirred at room temperature overnight. Most of the MeOH was removed under reduced pressure, and the residue was acidified to pH 5 with 1 M aqueous HCl. The resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (16 mg, 25%) as a gray solid. LCMS-C (ES-API): rt 2.3 min, m / z 649.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.9 Hz, 2H), 7.70 (br s, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.45 (br s, 2H), 7.27 (t, J = 7.5 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 7.6 Hz, 2H), 4.37 (s, 6H), 4.18 (s, 4H). Example 5 2-(2-(1H-tetrazol-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazol-5-yl)phenyl)-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (5) [ka] (a) 2-(1H-tetrazol-5-yl)benzaldehyde (A8)

[0382] To a solution of 5-phenyl-1H-tetrazole (5.0 g, 34.2 mmol) in THF (100 mL) at −78 °C under nitrogen, s-butyllithium (1.3 M, 54.0 mL, 69.0 mmol) was added dropwise, and the mixture was stirred at −78 °C for 30 min. DMF (20 mL, 300 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 10 min. The reaction was quenched with 1 M aqueous HCl (100 mL), and the mixture was extracted with EtOAc (300 mL × 3). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 5:1 to 4:1) to afford the title compound (4.0 g, 67%) as a white solid. LCMS-B(ES-API):rt 1.03min;m / z 175.0[M+H] + . (b) 2-(2-(1H-tetrazol-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazol-5-yl)phenyl)-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (5)

[0383] A mixture of 2-(1H-tetrazol-5-yl)benzaldehyde A8 (500 mg, 2.88 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzamide) I4 (472 mg, 1.44 mmol), and NaHSO3 (299 mg, 2.88 mmol) in DMF (10 mL) was heated at 125 °C overnight. The mixture was poured into water (10 mL), and the resulting precipitate was collected by filtration, washed with water, and then triturated with MeOH to give the title compound (300 mg, 17%) as a brown solid. LCMS-C (ES-API): rt 0.59 min; m / z 635.2 [M−H] - . 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 1.6 Hz, 2H), 7.97 (br s, 2H), 7.91 (d, J = 7.8 Hz, 2H), 7.66 (dd, J = 8.4, 1.7 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.28 (br s, 2H), 7.14 - 7.12 (m, 4H), 6.63 (d, J = 7.4 Hz, 2H), 4.20 (s, 4H). Example 6 1,1'-(ethane-1,2-diyl)bis(2-(2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (6) [ka]

[0384] A mixture of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) I13 (50 mg, 0.13 mmol), 2-(2H-tetrazol-5-yl)benzaldehyde A8 (45 mg, 0.26 mmol), and NaHSO3 (40 mg, 0.39 mmol) in DMF (5 mL) was heated at 120 °C under nitrogen overnight. The mixture was cooled to room temperature, poured into water (50 mL), and EtOAc (50 mL) was added. The resulting precipitate was collected by filtration and purified by preparative HPLC (Varian-940-LC; BOSTON, 10 μm, 250 × 2.12 mm column, eluted with a gradient of ACN in water containing 0.1% HCOH at a flow rate of 15 mL / min) to give the title compound (4 mg, 4%) as a white solid. LCMS-C(ES-API):rt 2.36min;m / z 697.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 7.6 Hz, 2H), 7.69 (br s, 2H), 7.59 - 7.55 (m, 4H), 7.44 (br s, 2H), 7.25 (t, J = 7.6 Hz, 2H), 6.76 (d, J = 7.6 Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 4.28 (s, 6H), 4.08 (s, 4H). Example 7 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoic acid) (7) [ka] (a) Methyl 2-(bromomethyl)-4-chlorobenzoate (A9)

[0385] To a solution of methyl 4-chloro-2-methylbenzoate (2.0 g, 10.8 mmol) in CCl (40 mL) was added NBS (2.0 g, 11.9 mmol) and AIBN (1.0 g, 5.42 mmol), and the mixture was heated at 80 °C under N overnight. The mixture was poured into water and extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1) to give the title compound (2.3 g, 82%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 2.2 Hz, 1H), 7.69 - 7.62 (m, 2H), 4.99 (s, 2H), 3.88 (s, 3H). (b) Methyl 4-chloro-2-formylbenzoate (A10)

[0386] To a solution of methyl 2-(bromomethyl)-4-chlorobenzoate (A9) (2.3 g, 8.73 mmol) in THF (30 mL) was added NMO (2.0 g, 17.5 mmol), and the mixture was heated to reflux under N for 16 h. Additional NMO (1.0 g, 8.73 mmol) and THF (15 mL) were added, and the mixture was heated to reflux under N for an additional 4 h. The mixture was poured into water (40 mL) and extracted with EtOAc (40 mL × 3). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 200:1 to 150:1 to 120:1) to afford the title compound (380 mg, 22%) as a yellow solid. LCMS-B (ES-API): rt 3.71 min, m / z 199.0, 201.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.4 (s, 1H), 7.94 - 7.81 (m, 3H), 3.91 (s, 3H). (c) Dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoate) (A11)

[0387] A mixture of methyl 4-chloro-2-formylbenzoate (A10) (0.100 g, 0.50 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (0.098 g, 0.25 mmol), and NaHSO (0.052 g, 0.50 mml) in DMF (4 mL) was heated at 100 °C under N for 16 h. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3), and the combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with MeOH to afford the title compound (66 mg, 35%) as a white solid. LCMS-B (ES-API): rt 3.15 min, m / z 745.2, 747.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.5 Hz, 2H), 7.68 - 7.66 (m, 4H), 7.58 (dd, J = 8.5, 2.1 Hz, 2H), 7.45 (d, J = 1.9 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.80 (br s, 2H), 4.38 (s, 6H), 4.29 (s, 4H), 3.60 (s, 6H). (d) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoic acid) (7)

[0388] A mixture of dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoate) (A11) (66 mg, 0.09 mmol) and NaOH (21 mg, 0.53 mmol) in EtOH / HO (5 mL / 5 mL) was stirred overnight at room temperature. The mixture was poured into water (10 mL) and washed with EtOAc (10 mL x 3). The aqueous phase was adjusted to pH 4-5 with 1 M aqueous HCl, and the resulting precipitate was collected by filtration and triturated with 10:1 DCM / MeOH to give the title compound (7.4 mg, 11%) as a white solid. LCMS-B (ES-API): rt 2.75 min, m / z 717.1, 719.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.2 (br s, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 2.0 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.52 (dd, J = 8.5, 1.8 Hz, 2H), 7.43 (d, J = 2.0 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.56 (br s, 2H), 4.41 (s, 6H), 4.27 (s, 4H). Example 8 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-dichlorobenzoic acid) (8) [ka] (a) 4,5-Dichloro-2-(methoxycarbonyl)benzoic acid (A12)

[0389] A solution of 5,6-dichloroisobenzofuran-1,3-dione (5 g, 23 mmol) in methanol (50 mL) was heated to reflux for 5 hours. The mixture was concentrated under reduced pressure to give the title compound (5.7 g, 100%) as a white solid. LCMS-B (ES-API): rt 3.45 min; m / z 249.0 / 251.0 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.96 (s, 1H), 3.81 (s, 3H). (b) 5,6-Dichloroisobenzofuran-1(3H)-one (A13)

[0390] To a solution of 4,5-dichloro-2-(methoxycarbonyl)benzoic acid (A12) (1.0 g, 4.0 mmol) and EtN (1.1 mL, 8.0 mmol) in dry THF (20 mL) was added dropwise ClCOEt (654 mg, 6.0 mmol) at 0 °C. The mixture was stirred for 40 min and then filtered. The filtrate was diluted with dry THF (10 mL), water (0.36 mL) was added, followed by portionwise addition of NaBH (303 mg, 8.0 mmol), and the mixture was stirred until TLC analysis showed all starting material was consumed. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (812 mg, 87%) as a white solid. LCMS-B (ES-API): rt 3.61 min, m / z 202.9, 205.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.05 (s, 1H), 5.41 (s, 2H). (c) 3-Bromo-5,6-dichloroisobenzofuran-1(3H)-one (A14)

[0391] A mixture of 5,6-dichloroisobenzofuran-1(3H)-one (A13) (580 mg, 2.86 mmol), NBS (610 mg, 3.43 mmol), and AIBN (46.9 mg, 0.286 mmol) in benzene (20 mL) was heated to reflux overnight under N. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Pet. ether / Et0Ac = 100:1 to 50:1) to give the title compound (545 mg, 68%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H). (d) 4,5-Dichloro-2-formylbenzoic acid (A15)

[0392] A mixture of 3-bromo-5,6-dichloroisobenzofuran-1(3H)-one (A14) (547 mg, 1.95 mmol) in water (10 mL) was heated to reflux for 90 min. The water was then removed by freeze-drying to give the title compound (410 mg, 96%) as a white solid. LCMS-B (ES-API): rt 3.29 min, m / z 218.9, 220.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.1 (br s, 2H), 8.09 (s, 1H), 7.96 (s, 1H). (e) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-dichlorobenzoic acid) (8)

[0393] A mixture of 4,5-dichloro-2-formylbenzoic acid (A15) (0.100 g, 0.459 mmol), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (0.089 g, 0.23 mmol), and NaHSO (0.119 g, 1.15 mmol) in DMF (3 mL) was heated at 80° C. under N overnight. The mixture was concentrated by freeze-drying, and the residue was purified by preparative HPLC (Agilent, YMC-C18, 150 × 20 mm, 5 μm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to give the title compound (13.7 mg, 8%) as a white solid. LCMS-B (ES-API): rt 2.90 min, m / z 785.3, 787.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 2H), 7.66 (s, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.43 (br s, 2H), 6.94 (d, J = 8.6 Hz, 2H), 6.88 (br s, 2H), 4.41 (s, 6H), 4.31 (s, 4H). Example 9 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (9) [ka] (a) 5-chloro-2-(dimethoxymethyl)benzonitrile (A16)

[0394] To a solution of 5-chloro-2-formylbenzonitrile (2.0 g, 12.1 mmol) in MeOH (60 mL) were added trimethoxymethane (2.51 g, 24.2 mmol) and TsOH (0.21 g, 1.21 mmol), and the mixture was heated at 80 °C under N overnight. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc, washed with saturated aqueous NaHCO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1 to 60:1) to give the title compound (1.7 g, 66%) as a yellow oil. LCMS-A (ES-API): rt 3.86 min, m / z 234.0, 236.0 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 8.4, 2.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 5.50 (s, 1H), 3.26 (s, 6H). (b) 5-(5-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A17)

[0395] To a solution of 5-chloro-2-(dimethoxymethyl)benzonitrile (A16) (1.0 g, 4.73 mmol) in NMP (20 mL) was added EtN.HCl (1.95 g, 14.2 mmol) and NaN (1.54 g, 23.6 mmol), and the mixture was heated at 110 °C under N for 3 h. Most of the NMP was removed by lyophilization, and the residue was dissolved in DCM / MeOH (10:1) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM / MeOH = 50:1 to 10:1) to give the title compound (1.1 g, containing some NMP) as a yellow oil, which was used in the next step without further purification. LCMS-B (ES-API): rt 3.2 min, m / z 277.1, 279.1 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.4, 2.2 Hz, 1H), 6.07 (s, 1H), 3.22 (s, 6H). (c) 4-chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A18)

[0396] A mixture of 5-(5-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A17) (1.1 g) and 2M aqueous HSO (21.0 mL, 42.0 mmol) in acetone (30 mL) was stirred at room temperature for 3 h. The mixture was extracted with EtOAc, and the combined organic extracts were washed with water, brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=5:1) to give the title compound (0.66 g, 67% over two steps) as a white solid. LCMS-B (ES-API): rt 2.83 min, m / z 209.0, 211.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4, 2.1 Hz, 1H). (d) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (9)

[0397] To a solution of 4-chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A18) (0.100 g, 0.481 mmol) in DMF (6 mL) were added 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (0.093 mg, 0.240 mmol) and NaHSO (0.050 mg, 0.481 mmol), and the mixture was heated at 80 °C under N overnight. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Varian-940-LC, YMC-C18, 5 μm, 150 × 20 mm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15 mL / min) to give the title compound (50 mg, 27%) as a white solid. LCMS-A (ES-API): rt 2.57 min, m / z 765.2, 767.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 2H), 7.73 (s, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.41 (s, 2H), 6.98 (d, J = 7.7 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.0 Hz, 2H), 4.38 (s, 6H), 3.88 (s, 4H). Example 10 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (10) [ka] (a) Ethyl 3-fluoro-2-methylbenzoate (A19)

[0398] To a solution of 3-fluoro-2-methylbenzoic acid (5.0 g, 32.5 mmol) in DMF (80 mL) was added K2CO3 (13.5 g, 97.5 mmol) and EtI (7.6 g, 48.8 mmol), and the mixture was stirred at room temperature under N2 for 3 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1:0 to 100:1) to give the title compound (5.4 g, 91%) as a yellow oil. LCMS-B (ES-API): rt 4.12 min, m / z 183.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 7.2 Hz, 1H), 7.43 - 7.30 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.39 (d, J = 2.3 Hz, 3H), 1.31 (t, J = 7.1Hz, 3H). (b) Ethyl 2-(bromomethyl)-3-fluorobenzoate (A20)

[0399] To a solution of ethyl 3-fluoro-2-methylbenzoate (A19) (5.4 g, 29.7 mmol) in CCl (100 mL) was added NBS (6.33 g, 35.6 mmol) and AIBN (2.43 g, 14.8 mmol), and the mixture was heated at 80 °C overnight. The mixture was diluted with water and extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1:0 to 100:1) to give the title compound (6.2 g, 86%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.75 - 7.71 (m, 1H), 7.57 - 7.49 (m, 2H), 4.95 (d, J = 1.7 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). (c) Ethyl 3-fluoro-2-formylbenzoate (A21)

[0400] To a solution of ethyl 2-(bromomethyl)-3-fluorobenzoate (A20) (6.2 g, 23.8 mmol) in THF (20 mL) was added NMO (11.2 g, 95.4 mmol), and the mixture was heated to reflux overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1:0 to 50:1) to give the title compound (3.6 g, 77%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 7.79 - 7.72 (m, 1H), 7.69 - 7.57 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). (d) Diethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoate) (A22)

[0401] To a solution of ethyl 3-fluoro-2-formylbenzoate (A21) (0.800 g, 4.49 mmol) in DMF (15 mL) was added 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide (I13) (0.872 g, 2.25 mmol) and NaHSO (0.930 g, 8.98 mmol), and the mixture was heated at 100 °C overnight. Additional ethyl 3-fluoro-2-formylbenzoate (A21) was added. The benzoate (A21) (0.100 g, 0.51 mmol) was added, and the mixture was heated at 100° C. overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The solid gray residue was rinsed with pet. ether / EtOAc = 10:1 (50 mL × 2) to give the title compound (1.1 g, 75%) as a gray solid. LCMS-B (ES-API): rt 3.12 min, m / z 741.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.6 Hz, 2H), 7.80 - 7.60 (m, 6H), 7.56 - 7.36 (m, 6H), 4.80 (br s, 2H), 4.30 (s, 6H), 4.11 (br s, 2H), 3.99 - 3.85 (m, 4H), 0.77 (t, J = 6.4 Hz, 6H). (e) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (10)

[0402] To a solution of diethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoate) (A22) (1.1 g, 1.49 mmol) in 5:1 EtOH / water (6 mL) was added NaOH (0.600 g, 14.9 mmol), and the mixture was stirred at room temperature for 16 hours. Most of the EtOH was removed under reduced pressure, and the aqueous residue was adjusted to pH 5 with 1 M aqueous HCl. The resulting precipitate was collected by filtration and purified by preparative HPLC (Varian-940-LC, YMC-C18, 150 × 20 mm, 5 μm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to afford the title compound (17 mg, 2%) as a white solid. LCMS-B(ES-API): rt 2.49 min, m / z 685.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.2 (s, 2H), 7.80 - 7.61 (m, 8H), 7.46 (s, 2H), 7.29 - 7.21 (m, 4H), 4.49 (br s, 2H), 4.31 (s, 6H), 4.17 (br s, 2H). Example 11 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chloro-3-fluorobenzoic acid) (11) [ka] (a) 2-Amino-5-chloro-3-fluorobenzoic acid (A23)

[0403] A mixture of 2-amino-3-fluorobenzoic acid (5.0 g, 0.03 mol) and NCS (5.6 g, 0.04 mmol) in DMF (80 mL) was stirred overnight at room temperature under N2. DCM (60 mL) was added and the mixture was washed with water (2 x 60 mL). A precipitate formed during the second wash, which was collected by filtration, washed with water, and then dried under vacuum to give the title compound (4.0 g, 71%) as a brown solid. LCMS-B (ES-API): rt 3.3 min, m / z 189.9, 191.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.50 (m, 1H), 7.44 (dd, J = 11.2, 2.5 Hz, 1H). (b) 2-Bromo-5-chloro-3-fluorobenzoic acid (A24)

[0404] To a solution of 2-amino-5-chloro-3-fluorobenzoic acid (A23) (4.0 g, 0.021 mol) in ACN (100 mL) at 0 °C was added 40% aqueous HBr (16.9 g, 0.083 mol) dropwise over 10 min. Next, a solution of NaNO (1.6 g, 0.023 mol) in water (20 mL) was added dropwise over 1 h, and the mixture was stirred at 0 °C for 5 min. Next, CuBr (3.6 g, 0.025 mol) was added portionwise over 30 min, and the mixture was heated at 70 °C for 1 h. Water (80 mL) was added, and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (2.0 g, 41%) as a brown solid. LCMS-B (ES-API): rt 3.4 min, m / z 252.9, 254.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.0 (br s, 1H), 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.66 (dd, J = 2.4, 1.4 Hz, 1H). (c) 5-chloro-3-fluoro-2-formylbenzoic acid (A25)

[0405] To a solution of 2-bromo-5-chloro-3-fluorobenzoic acid (A24) (2.0 g, 0.008 mol) in anhydrous THF (50 mL) was added i-PrMgCl (2 M solution in THF, 16.0 mL, 0.032 mol) dropwise at −30° C., and the mixture was stirred for 2 h. DMF (6 mL) was then added, and the mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under reduced pressure, and the residue was diluted with 1 M aqueous HCl and extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine and concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography (Biotage) eluting with a water / MeOH gradient to give the title compound (1.1 g, 69%) as a brown solid. 1 H NMR analysis showed the lactol form of the product. LCMS-B (ES-API): rt 2.90 min, m / z 202.9, 204.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (br s, 1H), 7.91 (dd, J = 8.8, 1.5 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 6.85 (br s, 1H). (d) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chloro-3-fluorobenzoic acid) (11)

[0406] A mixture of 5-chloro-3-fluoro-2-formylbenzoic acid (A25) (0.800 g, 3.95 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (0.767 g, 1.97 mmol), and NaHSO (0.205 g, 1.97 mmol) in DMF (20 mL) was heated at 60 °C under N overnight. Water (30 mL) was added, and the resulting precipitate was collected by filtration and purified by preparative HPLC (Agilent, YMC-C18, 150 × 20 mm, 5 μm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to afford the title compound (301 mg, 20%) as a gray solid. LCMS-B (ES-API): rt 2.75 min, m / z 753.3, 755.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.63 (m, 6H), 7.47 (s, 2H), 7.42 - 7.24 (m, 4H), 4.68 - 4.43 (m, 2H), 4.31 (s, 6H), 4.25 - 4.05 (m, 2H). Example 12 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chloro-3-fluorobenzoic acid) (12) [ka] (a) 4-chloro-3-fluoro-2-formylbenzoic acid (A26)

[0407] To a solution of diisopropylamine (695 mg, 6.87 mmol) in THF (20 mL) at −78 °C under N was added n-BuLi (2.5 M in hexane, 3.0 mL, 7.5 mmol), and the mixture was stirred at −78 °C for 1 h. 4-Chloro-3-fluorobenzoic acid (1.0 g, 5.73 mmol) was then added, and stirring was continued for another 1 h. DMF (1.3 g, 17.2 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and washed with EtOAc. The aqueous phase was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (pet. ether to pet. ether / EtOAc = 1:1 to DCM / MeOH = 10:1) to give the title compound (1.0 g) as a white solid. LCMS analysis showed this to be a 1:5 mixture of the title compound / unreacted 4-chloro-3-fluorobenzoic acid, which was used directly in the next step without further purification. LCMS-B (ES-API): rt, 2.99 min, m / z 203.0, 205.0 [M+H] for the title compound. + . (b) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chloro-3-fluorobenzoic acid) (12)

[0408] To a solution of 104 mg of a 1:5 mixture of 4-chloro-3-fluoro-2-formylbenzoic acid / 4-chloro-3-fluorobenzoic acid (A26) and 100 mg, 0.26 mmol of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) in 8 mL of DMF was added 107 mg of NaHSO (1.03 mmol), and the mixture was heated at 120 °C under N overnight. The mixture was purified by preparative HPLC (Agilent, YMC-C18, 150 × 20 mm, 5 μm column, eluting with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to give the title compound (5 mg) as a white solid. LCMS-B (ES-API): rt 2.66 min, m / z 753.1, 755.1 [M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 3.0 Hz, 2H), 7.63 - 7.59 (m, 4H), 7.42 (br s, 2H), 7.03 (d, J = 8.5 Hz, 2H), 4.50 - 4.47 (m, 2H), 4.37 (s, 6H), 4.24 - 4.21 (m, 2H). Example 13 Dimethyl 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoate) (13) and 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoate) (14) [ka] (a) Methyl 5-bromo-2-(bromomethyl)benzoate (A27)

[0409] A mixture of methyl 5-bromo-2-methylbenzoate (1.0 g, 4.4 mmol), NBS (0.56 g, 4.4 mmol), and AIBN (0.36 g, 2.2 mmol) in CCl (20 mL) was heated at 80 °C under N for 2 h. Additional NBS (56.3 mg, 0.44 mmol) was added, and heating at 80 °C was continued for 1 h. Additional NBS (56.3 mg, 0.44 mmol) was added, and heating at 80 °C was continued for 1 h. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 120:1 to 80:1) to give the title compound (1.01 g, 75%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.3, 2.2 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 4.98 (s, 2H), 3.88 (s, 3H). (b) Methyl 5-bromo-2-formylbenzoate (A28)

[0410] A solution of methyl 5-bromo-2-(bromomethyl)benzoate (A27) (1.01 g, 3.3 mmol) and NMO (1.55 g, 13.2 mmol) in THF (20 mL) was heated to reflux overnight under N. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1 to 70:1) to give the title compound (217 mg, 26%) as a yellow solid. LCMS-B (ES-API): rt 3.7 min, m / z 243.0, 245.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.00 (dd, J = 8.5, 2.2 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H). (c) Dimethyl 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoate) (13)

[0411] A mixture of methyl 5-bromo-2-formylbenzoate (A28) (100 mg, 0.41 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (81.6 mg, 0.21 mmol), and NaHSO (21.9 mg, 0.21 mmol) in DMF (5 mL) was heated at 120 °C under N overnight. Water (20 mL) was added, and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (66 mg, 38%) as a black solid. LCMS-B (ES-API): rt 3.17 min, m / z 833.1, 835.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 2.1 Hz, 2H), 7.72 - 7.69 (m, 4H), 7.46 - 7.41 (m, 4H), 7.11 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 8.0 Hz, 2H), 4.36 (s, 6H), 4.25 (s, 4H), 3.61 (s, 6H). (d) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid) (14)

[0412] To a solution of dimethyl 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoate) (13) (60 mg, 0.07 mmol) in 9:1 EtOH / water (5.5 mL) was added NaOH (28 mg, 0.7 mmol), and the mixture was stirred at room temperature overnight. Most of the EtOH was removed under reduced pressure, and the aqueous residue was adjusted to pH 5 with 2 M aqueous HCl. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (35 mg, 62%) as a black solid. LCMS-B (ES-API): rt 2.66 min, m / z 805.1, 807.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 2.0 Hz, 2H), 7.72 (br s, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.45 (br s, 2H), 7.33 (dd, J = 8.0, 1.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.2 Hz, 2H), 4.37 (s, 6H), 4.25 (s, 4H). Example 15 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-difluorobenzoic acid) (15) [ka] (a) 4,5-Difluoro-2-formylbenzoic acid (A29)

[0413] To a solution of 2-bromo-4,5-difluorobenzoic acid (500 mg, 2.11 mmol) in THF (5 mL) at −78° C. under N2, n-BuLi (2.5 M solution in hexane, 1.70 mL, 4.22 mmol) was added dropwise, and the mixture was stirred at −78° C. for 45 min. DMF (0.20 mL, 2.53 mmol) was then added, and stirring was continued at −78° C. for 2 h. The reaction was quenched with saturated aqueous NH4Cl, and the mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous phase was freeze-dried. The residue was purified by preparative TLC (DCM / MeOH=10:1) to give the title compound (16 mg, 4%) as a white solid. LCMS-B (ES-API): rt 2.50 min; m / z 187.0 [M+H] + . (b) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-difluorobenzoic acid) (15)

[0414] A mixture of 4,5-difluoro-2-formylbenzoic acid (A29) (16 mg, 0.086 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (23 mg, 0.07 mmol), and NaHSO (14 mg, 0.13 mml) in DMF (1 mL) was heated at 120 °C overnight. The mixture was partitioned between EtOAc and water, the layers were separated, and the aqueous layer was freeze-dried. The residue was purified by preparative HPLC (Agilent, YMC-C18, 150 × 20 mm, 5 μm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to give the title compound (10 mg, 32%) as a white solid. LCMS-B(ES-API): rt 2.54 min; m / z 721.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 8.3, 4.9 Hz, 2H), 7.68 (d, J = 2.0 Hz, 2H), 7.60 (d, J = 7.9 Hz, 2H), 7.49 - 7.38 (m, 4H), 7.08 (d, J = 7.7 Hz, 2H), 4.48 - 4.46 (m, 2H), 4.34 (s, 6H), 4.23 - 4.22 (m, 2H). Example 16 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (16) [ka] (a) 3,5-Difluoro-2-formylbenzoic acid (A30)

[0415] To a solution of 2-bromo-3,5-difluorobenzoic acid (500 mg, 2.11 mmol) in anhydrous THF (10 mL) was added i-PrMgCl (2 M solution in THF, 2.2 mL, 4.4 mmol) at −30° C., and the mixture was stirred at −30° C. for 3 h. DMF (1.5 mL) was added, and the mixture was warmed to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with 0.5 M aqueous HCl and extracted with DCM. The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:0 to 100:1) to afford the title compound (130 mg, 33%) as a yellow solid. 1 H NMR analysis showed the lactol form of the product. LCMS-B (ES-API): rt 2.69 min, m / z 186.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (br s, 1H), 7.75 (td, J = 9.3, 2.1 Hz, 1H), 7.62 (dd, J = 7.0, 2.1 Hz, 1H), 6.82 (br s, 1H). (b) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (16)

[0416] A mixture of 3,5-difluoro-2-formylbenzoic acid (A30) (130 mg, 0.70 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (136 mg, 0.35 mmol), and NaHSO (73 mg, 0.70 mmol) in DMF (8 mL) was heated at 120 °C under N for 16 h. The mixture was concentrated under reduced pressure until a precipitate formed, which was collected by filtration and purified by preparative HPLC (Agilent, YMC-C18, 150 × 20 mm, 5 μm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to give the title compound (2.5 mg, 1%) as a white solid. LCMS-B(ES-API): rt 2.55 min, m / z 721.3[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.62 (m, 4H), 7.60 - 7.50 (m, 2H), 7.47 (d, J = 2.8 Hz, 2H), 7.30 - 7.06 (m, 2H), 7.26 (d, J = 8.6 Hz, 2H), 4.63 - 4.42 (m, 2H), 4.32 (s, 6H), 4.24 - 4.08 (m, 2H). 1 H NMR (400 MHz, 60 °C, DMSO-d6) δ7.75 (d, J = 8.6 Hz, 2H), 7.66 - 7.51 (m, 4H), 7.38 - 7.16 (m, 4H), 7.20 (d, J = 8.6 Hz, 2H), 4.43 - 4.24 (m, 10H). Example 17 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (17) [ka] (a) Di-tert-butyl 2,2'-(2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chlorobenzoyl))bis(hydrazine-1-carboxylate) (A31)

[0417] A mixture of 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (1) (0.300 g, 0.42 mmol), tert-butyl hydrazine carboxylate (0.332 g, 2.52 mmol), EDCI.HCl (0.240 g, 1.26 mmol), HOBt (0.169 g, 1.26 mmol), and DIPEA (0.324 g, 2.52 mmol) in DMF (12 mL) was stirred at room temperature under N for 16 h. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with water (30 × 2 mL), brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to afford the title compound (410 mg, >100%) as a yellow oil, which was used directly in the next step without further purification. (b) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) dihydrochloride (A32)

[0418] A mixture of 2,2'-(2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chlorobenzoyl))bis(hydrazine-1-carboxylate) (A31) (410 mg, assumed yield from the previous step, 0.42 mmol) and a 3 M solution of HCl in dioxane (6 mL) was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to give the title compound (400 mg, >100%) as a gray solid, which was used directly in the next step without further purification. LCMS-B (ES-API): rt 1.67 min, m / z 745.3, 747.3 [M+H]+ . (c) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (17)

[0419] A mixture of 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) dihydrochloride (A32) (90 mg, assumed yield from the previous step, 0.095 mmol), CDI (59 mg, 0.36 mmol), and EtN (37 mg, 0.36 mmol) in DMF (4 mL) was heated at 40 °C under N for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (15 mL × 3), and the combined organic extracts were washed with water (15 × 2 mL), brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Agilent, BOSTON, 250 x 2.12 mm, 10 μm column, eluting with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 20.0 mL / min) to give the title compound (5 mg, 7%) as a gray solid. LCMS-B (ES-API): rt 2.75 min, m / z 797.4, 799.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.6 (br s, 2H), 7.71 (br s, 2H), 7.66 (d, J = 1.8 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.46 (br s, 2H), 7.05 (d, J = 6.8 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.3 Hz, 2H), 4.38 (s, 6H), 4.21 (s, 4H). Example 18 2,2'-(ethane-1,2-diylbis(5-carbamoyl-7-fluoro-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (18) [ka] (a) 4,5-Difluoro-2-methoxybenzoic acid (A33)

[0420] Prepared from 2,4,5-trifluorobenzoic acid according to the procedure described in Bioorg. Med. Chem. Lett. 2016, 26, 2455. LCMS-B (ES-API): rt 2.98 min, m / z 189.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 10.5, 9.1 Hz, 1H), 6.90 (dd, J = 11.2, 6.0 Hz, 1H), 4.05 (s, 3H). (b) 4,5-Difluoro-2-methoxybenzamide (A34)

[0421] To a solution of 4,5-difluoro-2-methoxybenzoic acid (A33) (16.5 g, 85 mmol) in dry DCM (300 mL) at 0 °C, DMF (10 drops) and (COCl) (15 mL, 17 mmol) were added, and the mixture was warmed to room temperature and stirred for 3 h. The solvent was removed under reduced pressure, and the residue was dissolved in dry DCM (30 mL) and cooled to 0 °C. Concentrated aqueous NHOH (26-28% in water, 70 mL) was added, and the mixture was stirred at room temperature overnight. Most of the DCM was removed under reduced pressure, and the resulting precipitate was collected by filtration and dried at 50 °C overnight to give the title compound (15.5 g, 97%) as a white solid. LCMS-B (ES-API): rt 2.76 min, m / z 188.0. [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 11.5, 9.6 Hz, 1H), 7.70 (br s, 1H), 7.66 (br s, 1H), 7.32 (dd, J = 12.7, 6.5 Hz, 1H), 3.89 (s, 3H). (c) 4,5-Difluoro-2-methoxy-3-nitrobenzamide (A35)

[0422] To a solution of 4,5-difluoro-2-methoxybenzamide (A34) (12.0 g, 64.2 mmol) in concentrated HSO (150 mL) was added a mixture of KNO (9.74 g, 96.3 mmol) in concentrated HSO (5 mL) dropwise over 30 min, maintaining the reaction temperature at 0 °C. After complete addition, TLC analysis indicated that the starting material had been consumed. The mixture was diluted with water and extracted with EtOAc, and the combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 1:0 to 200:1 to 100:1) to afford the title compound (4.5 g, 30%) as a white solid. LCMS-B (ES-API): rt 3.12 min, m / z 232.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (br s, 1H), 7.96 (dd, J = 10.4, 8.8 Hz, 1H), 7.92 (br s, 1H), 3.89 (s, 3H). (d) 4,4'-(ethane-1,2-diylbis(azanediyl))bis(5-fluoro-2-methoxy-3-nitrobenzamide) (A36)

[0423] To a solution of 4,5-difluoro-2-methoxy-3-nitrobenzamide (A35) (2.5 g, 10.8 mmol) in DMF (13 mL) was added KCO (4.48 g, 32.4 mmol) and ethylenediamine (324 mg, 5.4 mmol), and the mixture was stirred at room temperature overnight. The mixture was carefully poured into ice water with stirring, and the resulting precipitate was collected by filtration, washed with water (10 mL), and dried at 50 °C overnight to give the title compound (1.91 g, 73%) as a yellow solid. LCMS-B (ES-API): rt 3.07 min, m / z 485.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (br s, 2H), 7.54 (br s, 2H), 7.47 (d, J = 13.9 Hz, 2H), 6.27 - 6.20 (m, 2H), 3.75 (s, 6H), 3.34 - 3.33 (m, 4H). (e) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-7-fluoro-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (18)

[0424] To a solution of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(5-fluoro-2-methoxy-3-nitrobenzamide) (A36) (0.200 g, 0.41 mmol) in 1:1 DMSO / MeOH (8 mL) was added 3,5-difluoro-2-formylbenzoic acid (A30) (0.152 g, 0.82 mmol) and NaSO (0.214 g, 1.23 mmol). The flask was fitted with a condenser and the mixture was heated at 120 °C for 6 h. The mixture was concentrated under reduced pressure to remove most of the solvent, and the residue was diluted with water (20 mL) and adjusted to pH 5 with 1 M aqueous HCl. The resulting precipitate was collected by filtration, dried under vacuum at 50° C. overnight, and then purified by preparative HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, eluted with a gradient of ACN in water containing 0.1% TFA at a flow rate of 15.0 mL / min) to give the title compound (20.7 mg, 7%) as a white solid. LCMS-B (ES-API): rt 2.71 min, m / z 757.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 2H), 7.71 - 7.61 (m, 4H), 7.40 - 7.30 (m, 2H), 7.15 (br s, 2H), 4.50 - 4.36 (m, 4H), 4.24 (s, 6H). Example 19 1,1'-(ethane-1,2-diyl)bis(2-(5-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (42) [ka] (a) 4-chloro-2-(dibromomethyl)benzonitrile (A37)

[0425] A solution of 4-chloro-2-methylbenzonitrile (10.0 g, 66.0 mmol), NBS (35.2 g, 198 mmol), and BPO (1.60 g, 6.60 mmol) in CCl (200 mL) was heated to reflux under N for 24 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Pet. ether / Et0Ac=500:1 to 200:1) to give the title compound (13.0 g, 64%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 8.3, 2.1 Hz, 1H), 7.40 (s, 1H). (b) 4-chloro-2-formylbenzonitrile (A38)

[0426] To a solution of 4-chloro-2-(dibromomethyl)benzonitrile A37 (10.0 g, 32.3 mmol) in acetonitrile (75 mL) was added a solution of AgNO3 (16.5 g, 97.0 mmol) in water (17 mL), and the mixture was heated to reflux for 20 minutes and then allowed to cool to room temperature. The precipitate was removed by filtration and washed with DCM (3 x 200 mL). The combined filtrate was washed with water (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / Et0Ac = 100:1 to 20:1) to give the title compound (5.30 g, 99%) as a yellow solid. LCMS-B (ES-API): rt 3.35 min, m / z 166.0, 168.0 [M+H] + . (c) 4-chloro-2-(dimethoxymethyl)benzonitrile (A39)

[0427] To a solution of 4-chloro-2-formylbenzonitrile A38 (5.00 g, 30.2 mmol) in MeOH (150 mL) were added trimethoxymethane (6.41 g, 60.4 mmol) and TsOH (520 mg, 3.02 mmol), and the mixture was heated to reflux for 16 h. The mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1 to 70:1) to give the title compound (5.30 g, 83%) as a yellow oil. LCMS-B (ES-API): rt 3.83 min, m / z 212.1, 214.1 [M+H] + . (d) 5-(4-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A40)

[0428] A mixture of 4-chloro-2-(dimethoxymethyl)benzonitrile (3.00 g, 14.2 mmol), EtN HCl (2.73 g, 19.9 mmol), and NaN (2.76 g, 42.5 mmol) in DMF (40 mL) was heated at 110 °C under N for 16 h. The mixture was poured into water (200 mL) and washed with EtOAc (100 mL × 3). The aqueous layer was lyophilized to dryness, and the residue was purified by silica gel chromatography (DCM / MeOH = 100:1 to 20:1) to give the title compound (2.20 g, 61%) as a yellow oil. LCMS-B (ES-API): rt 3.27 min, m / z 253.0, 255.0 [MH] - . (e) 5-chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A41)

[0429] To a solution of 5-(4-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole A40 (900 mg, 3.53 mmol) in acetone (36 mL) was added 2M aqueous HSO (36 mL, 70.6 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc, and the combined organic layers were washed with water, brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (365 mg, 50%) as a white solid. LCMS-B (ES-API): rt 2.94 min, m / z 209.0, 211.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.97 - 7.96 (m, 2H). (f) 1,1'-(ethane-1,2-diyl)bis(2-(5-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (42)

[0430] A solution of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) I13 (200 mg, 0.51 mmol), 5-chloro-2-(2H-tetrazol-5-yl)benzaldehyde A41 (236 mg, 0.58 mmol), and Oxone® (380 mg, 0.61 mmol) in DMF (6 mL) was stirred at room temperature under N for 2 h. The mixture was poured into water (30 mL), and the resulting precipitate was collected by filtration and recrystallized from methanol to give the title compound (55 mg, 14%) as a gray solid. LCMS-B (ES-API): rt 2.76 min, m / z 765.0, 767.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.4 Hz, 2H), 7.67 - 7.65 (m, 4H), 7.61 (d, J = 8.1 Hz, 2H), 7.45 (br s, 2H), 6.93 - 6.91 (m, 4H), 4.29 (s, 6H), 4.17 (s, 4H). Example 20 1,1'-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (43) [ka] (a) 2-Bromo-3,5-difluorobenzonitrile (A42)

[0431] To a solution of 3,5-difluorobenzonitrile (5.00 g, 35.9 mmol), 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (10.3 g, 36.0 mmol), and ACN (5.90 g, 143.8 mmol) in DCM (75 mL) at 0 °C was added concentrated H2SO4 (14.1 g, 143.8 mmol) dropwise over 30 min. The mixture was warmed to room temperature and then heated at 50 °C for 4 h. The mixture was partitioned between 1 M aqueous sodium sulfite solution (120 mL) and DCM (70 mL), the layers were separated, and the organic phase was washed with 1 M aqueous sodium sulfite solution (120 mL), water (70 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / Et0Ac=200:1 to 100:1) to give the title compound (7.2 g, 92%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.98 - 7.94 (m, 1H), 7.92 (dd, J = 8.9, 2.8 Hz, 1H). (b) 3,5-Difluoro-2-vinylbenzonitrile (A43)

[0432] To a solution of 2-bromo-3,5-difluorobenzonitrile A42 (5.00 g, 22.9 mmol) and tributyl(vinyl)stannane (21.8 g, 68.8 mmol) in toluene (100 mL) was added Pd(PPh3)4 (2.65 g, 2.29 mmol), and the mixture was heated to reflux under N2 for 16 h. The mixture was poured into water (400 mL) and extracted with EtOAc (200 mL × 3). The combined organic extracts were washed with water (100 × 2 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 500:1 to 200:1) to give the title compound (2.00 g, 54%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.86 - 7.72 (m, 2H), 6.77 (dd, J = 17.8, 11.8 Hz, 1H), 6.05 (d, J = 17.8 Hz, 1H), 5.82 (d, J = 11.7 Hz, 1H). (c) 5-(3,5-difluoro-2-vinylphenyl)-1H-tetrazole (A44)

[0433] A solution of 3,5-difluoro-2-vinylbenzonitrile A43 (2.00 g, 12.1 mmol), EtN.HCl (2.34 g, 18.8 mmol), and NaN (2.36 g, 36.3 mmol) in DMF (40 mL) was heated at 110 °C under N for 16 h. The mixture was poured into water (400 mL) and washed with EtOAc (250 mL × 3). The aqueous phase was lyophilized to dryness, and the residue was purified by silica gel chromatography (DCM / MeOH = 100:1 to 20:1) to give the title compound (500 mg, 20%) as a brown solid. LCMS-B (ES-API): rt 3.23 min, m / z 209.0 [M+H] + . (d) 2,4-Difluoro-6-(1H-tetrazol-5-yl)benzaldehyde (A45)

[0434] A solution of 5-(3,5-difluoro-2-vinylphenyl)-1H-tetrazole A44 (500 mg, 2.40 mmol) in DCM / MeOH (6 mL / 6 mL) was cooled to -70 °C and O gas was bubbled through until the blue color persisted. Dimethyl sulfide (746 mg, 12.0 mmol) was then added, and the mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM / MeOH = 100:1 to 50:1) to afford the title compound (360 mg, 71%) as a yellow solid. LCMS-B (ES-API): rt 2.34 min, m / z 211.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 7.78 - 7.70 (m, 1H), 7.67 (d, J = 8.9 Hz, 1H). (e) 1,1'-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (43)

[0435] A solution of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) I13 (160 mg, 0.41 mmol), 2,4-difluoro-6-(1H-tetrazol-5-yl)benzaldehyde A45 (190 mg, 0.90 mmol), and Oxone® (304 mg, 0.49 mmol) in DMF (8 mL) was stirred at room temperature under N for 1 hour. The mixture was poured into water (50 mL), and the resulting precipitate was collected by filtration. Purification by preparative HPLC (Agilent, BOSTON 250 × 2.12 mm, 10 μm column, eluted with a gradient of ACN in water containing 0.1% HCOH at a flow rate of 20.0 mL / min) afforded the title compound (5 mg, 2%) as a gray solid. LCMS-B(ES-API): rt 2.57 min, m / z 769.4[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.66 (m, 4H), 7.59 (d, J = 8.4 Hz, 2H), 7.48 - 7.40 (m, 4H), 7.06 - 6.97 (m, 2H), 4.75 - 4.63 (m, 2H), 4.36 - 4.23 (m, 2H), 4.16 (s, 6H). Example 21 1,1'-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (44) [ka] (a) Di-tert-butyl 2,2'-(2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoyl))bis(hydrazine-1-carboxylate) (A46)

[0436] To a solution of 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) 16 (500 mg, 0.7 mmol) in THF (2.5 mL) was added T3P® (50% w / w in EtOAc, 2.23 g, 3.5 mmol), tert-butyl carbazate (370 mg, 2.8 mmol), and EtN (1.4 g, 14.0 mmol), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and LCMS analysis indicated an incomplete reaction. The residue was dissolved in THF (2.5 mL), T3P® (50% w / w in EtOAc, 2.23 g, 3.5 mmol), tert-butyl carbazate (370 mg, 2.8 mmol), and EtN (1.4 g, 14.0 mmol) were added, and the mixture was heated at 80° C. for 7 h. The solvent was removed under reduced pressure, and LCMS analysis indicated an incomplete reaction. The residue was dissolved in THF (2.5 mL), T3P® (50% w / w in EtOAc, 2.23 g, 3.5 mmol), tert-butyl carbazate (370 mg, 2.8 mmol), and EtN (1.4 g, 14.0 mmol) were added, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and LCMS analysis indicated an incomplete reaction. The residue was dissolved in THF (2.5 mL), T3P® (50% w / w in EtOAc, 2.23 g, 3.5 mmol), tert-butyl carbazate (370 mg, 2.8 mmol), and EtN (1.4 g, 14.0 mmol) were added, and the mixture was heated at 50° C. for 4 h. The solvent was removed under pressure, and the residue was washed with diethyl ether (×3) to give the title compound (290 mg, 44%) as a light brown solid. LCMS-C (ES-API): rt 3.61 min; m / z 949.4 [M+H] + . (b) 1,1'-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) hydrochloride (A47)

[0437] To a solution of di-tert-butyl 2,2'-(2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoyl))bis(hydrazine-1-carboxylate) A46 (290 mg, 0.3 mmol) in dioxane (1 mL) was added dropwise a 4 M solution of HCl in dioxane (20 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was washed with diethyl ether, petroleum ether and DCM to give the title compound (290 mg) as a yellow solid, which was used directly in the next step without further purification. LCMS-C (ES-API): rt 2.22 min; m / z 749.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.3 (s, 2H), 10.4 (s, 2H), 7.77 - 7.74 (m, 6H), 7.39 - 7.34 (m, 8H), 5.00 - 4.00 (m, 10H). (c) 1,1'-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (44)

[0438] To a solution of 1,1'-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) hydrochloride A47 (100 mg, assumed 0.10 mmol) in DMF (1 mL) was added CDI (64.9 mg, 0.40 mmol) and EtN (40.5 mg, 0.40 mmol), and the mixture was heated at 40 °C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Agilent YMC-C18, 5 μm, 250 × 20 mm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to give the title compound (2.5 mg, 3%) as a white solid. LCMS-B(ES-API): rt 4.08 min, m / z 801.0[M+H] + . 1 H NMR (400 MHz, room temperature, DMSO-d6) δ 12.7 (br s, 2H), 7.81 - 7.73 (m, 3H), 7.69 - 7.51 (m, 6H), 7.17 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 4.56 (d, J = 9.6 Hz, 2H), 4.39 (s, 6H), 4.18 (d, J = 9.6 Hz, 2H). 1 H NMR (400 MHz, 60 °C, DMSO-d6) δ 12.6 (s, 2H), 7.66 - 7.56 (m, 7H), 7.34 (s, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 4.50 (s, 2H), 4.35 (s, 6H), 4.18 (s, 2H). Example 22 1,1'-(ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (45) and 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (46) [ka] (a) 2-Bromo-4-chloro-6-fluorobenzaldehyde (A48)

[0439] To a solution of 1,2-dibromo-5-chloro-3-fluorobenzene (2.0 g, 6.94 mmol) in dry THF (10 mL) at −65° C. under N2, i-PrMgCl (2 M solution in THF, 3.81 mL, 7.63 mmol) was added dropwise at a rate such that the temperature of the mixture did not exceed −50° C. The mixture was then cooled to −72° C. and stirred for 1 h. DMF (2.54 g, 34.6 mmol) was then added dropwise at a rate such that the temperature of the mixture did not exceed −55° C., and stirring was continued at −70° C. for 15 min. The mixture was quenched by the dropwise addition of water (5 mL) and then extracted with EtOAc (50 mL×2). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether) to afford the title compound (800 mg, 50%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 10.20 (d, J = 1.2 Hz, 1H), 7.45 (t, J = 1.7 Hz, 1H), 7.13 (dd, J = 10.0, 2.0 Hz, 1H). (b) 1,1'-(ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (45)

[0440] A mixture of 2-bromo-4-chloro-6-fluorobenzaldehyde (A48) (1.34 g, 5.67 mmol), 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (1.0 g, 2.57 mmol), and NaHSO (670 mg, 6.44 mmol) in DMF (16.8 mL) was heated at 80 °C overnight. The mixture was allowed to cool to room temperature and poured into water, and the resulting precipitate was collected by filtration. The collected solid was recrystallized from formic acid to give the title compound (700 mg, 33%) as a brown solid. LCMS-B (ES-API): rt 3.28 min, m / z 820.9, 822.9 [M+H] + . (c) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-cyano-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (A49)

[0441] A mixture of 1,1'-(ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (45) (700 mg, 0.85 mmol) and CuCN (228 mg, 2.55 mmol) in NMP (3.5 mL) was heated at 170 °C for 4 h. The mixture was allowed to cool to room temperature and poured into water, and the resulting precipitate was collected by filtration. The collected solid was purified by silica gel chromatography (DCM / MeOH, 100:1 to 10:1) to afford the title compound (330 mg, 54%) as a brown solid. LCMS-C (ES-API): rt 3.49 min, m / z 715.06 [M+H] + . (d) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (46)

[0442] A mixture of 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-cyano-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (A49) (130 mg, 0.182 mmol), EtN.HCl (150 mg, 1.09 mmol), and NaN (141.7 mg, 2.18 mmol) in DMF (2.4 mL) was heated at 80 °C under N overnight. The mixture was allowed to cool to room temperature and poured into water. No precipitate formed, so the mixture was concentrated under reduced pressure at 55° C., and the residue was purified by silica gel chromatography (DCM / MeOH, 5:1, containing 2.5% v / v concentrated aqueous NH4OH) followed by preparative HPLC (Agilent, YMC-C18, 150×20 mm, 5.0 μm column, eluting with a gradient of MeOH in water containing 0.1% TFA at a flow rate of 15.0 mL / min) to give the title compound (14.7 mg, 11%) as a white solid. LCMS-B (ES-API): rt 2.68 min, m / z 801.2, 803.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.63 (m, 6H), 7.58 - 7.33 (m, 4H), 7.24 - 7.09 (m, 2H), 4.84 - 4.55 (m, 2H), 4.43 - 4.25 (m, 2H), 4.14 (s, 6H). Example 23 2-(5-carbamoyl-1-(2-(5-carbamoyl-2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)-4-methoxy-1H-benzo[d]imidazol-2-yl)-5-chloro-3-fluorobenzoic acid (47) [ka]

[0443] A mixture of 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (100 mg, 0.26 mmol), 4-chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A18) (54 mg, 0.26 mmol), 5-chloro-3-fluoro-2-formylbenzoic acid (A25) (52 mg, 0.26 mmol), and NaHSO (80 mg, 0.78 mmol) in DMF (8.0 mL) was heated at 120 °C under a N atmosphere for 16 h. The mixture was allowed to cool to room temperature and poured into water (40 mL), and the resulting precipitate was collected by filtration. Purification by preparative HPLC (Agilent 10 prep-C18, 10 μm, 250 × 21.3 mm column, eluting with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 20 mL / min) afforded the title compound (8.0 mg, 4%) as a white solid. LCMS-B (ES-API): rt 2.630 min, m / z 759.1, 761.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 1.6 Hz, 1H), 7.74 - 7.62 (m, 5H), 7.51 - 7.42 (m, 2H), 7.23 - 6.96 (m, 4H), 6.71 - 6.61 (m, 1H), 4.41 - 4.25 (m, 2H), 4.37 (s, 3H), 4.27 (s, 3H), 4.22 - 4.11 (m, 2H). Example 24 1,1'-(ethane-1,2-diyl)bis(2-(2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (48) [ka] (a) 2-(Bromomethyl)-3-fluorobenzonitrile (A50)

[0444] To a solution of 3-fluoro-2-methylbenzonitrile (4.4 g, 32.6 mmol) in CCl4 (45 mL) was added NBS (29.0 g, 163 mmol) and BPO (0.8 g, 3.3 mmol), and the mixture was heated to reflux overnight. The mixture was allowed to cool to room temperature, and the solid was removed by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Pet. ether / EtOAc = 200:1 to 50:1) to give the title compound (5.2 g, 74%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (dd, J = 7.6, 0.8 Hz, 1H), 7.70 - 7.60 (m, 2H), 4.74 (d, J = 0.8 Hz, 2H). (b) 3-Fluoro-2-formylbenzonitrile (A51)

[0445] To a solution of 2-(bromomethyl)-3-fluorobenzonitrile (A50) (1.0 g, 4.8 mmol) in acetonitrile (20 mL) was added NMO (2.3 g, 19.2 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc, and the organic extract was dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (540 mg, 75%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 7.94 - 7.85 (m, 2H), 7.85 - 7.77 (m, 1H). (c) 1,1'-(ethane-1,2-diyl)bis(2-(2-cyano-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (A52)

[0446] To a solution of 3-fluoro-2-formylbenzonitrile (A51) (500 mg, 3.35 mmol) in DMF (5.0 mL) was added 4,4'-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (592 mg, 1.52 mmol) and NaHSO3 (397 mg, 3.81 mmol), and the mixture was heated at 80 °C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM / MeOH = 150:1 to 30:1) to give the title compound (76 mg, 8%) as a brown solid. LCMS-A (ES-API): rt 2.8 min, m / z 647.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (br s, 2H), 7.66 - 7.64 (m, 4H), 7.55 (br s, 2H), 7.44 - 7.41 (m, 4H), 7.07 (d, J = 8.7 Hz, 2H), 4.65 (s, 4H), 4.42 (s, 6H). (d) 1,1'-(ethane-1,2-diyl)bis(2-(2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (48)

[0447] To a solution of 1,1'-(ethane-1,2-diyl)bis(2-(2-cyano-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (A52) (76 mg, 118 mmol) in DMF (0.5 mL) was added EtN.HCl (97 mg, 0.705 mmol) and NaN (92 mg, 1.42 mmol), and the mixture was heated at 80 °C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Agilent YMC-C18, 5 μm, 150 × 20 mm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to give the title compound (4.6 mg, 5%) as a brown solid. LCMS-B(ES-API):rt 2.445min;m / z 733.2[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.70 - 7.58 (m, 4H), 7.56 - 7.37 (m, 4H), 6.96 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 8.4 Hz, 1H), 4.40 - 4.25 (m, 2H), 4.19 (s, 6H), 4.09 - 3.99 (m, 2H). Example 25 1,1'-(ethane-1,2-diyl)bis(2-(2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (49) [ka] (a) Methyl 2-bromo-3-fluorobenzoate (A53)

[0448] To a solution of 2-bromo-3-fluorobenzoic acid (5.00 g, 22.9 mmol) in MeOH (40 mL) was added concentrated H2SO4 (3.0 mL), and the mixture was heated to reflux overnight. The mixture was diluted with water and extracted with DCM, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (4.8 g, 90%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.71 - 7.49 (m, 3H), 3.88 (s, 3H). (b) 2-Bromo-3-fluorobenzohydrazide (A54)

[0449] To a solution of methyl 2-bromo-3-fluorobenzoate (A53) (4.8 g, 20.6 mmol) in EtOH (30 mL) was added hydrazine hydrate (80% in water, 16.0 g, 329 mmol) and the mixture was heated at 55° C. for 3 h. The mixture was allowed to cool to room temperature and poured into ice water, and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (3.2 g, 67%) as a white solid. LCMS-B (ES-API): rt 1.54 min, m / z 233.0, 235.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (br s, 1H), 7.52 - 7.40 (m, 2H), 7.20 (ddd, J = 6.9, 2.0, 0.8 Hz, 1H), 4.53 (br s, 2H). (c) 5-(2-bromo-3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (A55)

[0450] To a solution of 2-bromo-3-fluorobenzohydrazide (A54) (3.2 g, 13.7 mmol) in DMF (26.0 mL) was added EtN (4.2 g, 41.2 mmol) and CDI (6.7 g, 41.2 mmol), and the mixture was heated at 40 °C for 3 h. The mixture was poured into water and extracted with DCM, and the organic extract was washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / Et0Ac=5:1) to give the title compound (1.5 g, 43%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.9 (br s, 1H), 7.67 - 7.59 (m, 3H). (d) 5-(3-fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A56)

[0451] To a solution of 5-(2-bromo-3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (A55) (600.0 mg, 2.33 mmol) and tributyl(vinyl)stannane (2.2 g, 6.98 mmol) in toluene (9 mL) was added Pd(PPh3)4 (265.8 mg, 0.23 mmol), and the mixture was heated to reflux under N2 for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (9 mL × 3). The combined organic extracts were washed with water (9 mL × 2), brine (9 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 50:1 to 10:1) to afford the title compound (420 mg, 87%) as a white solid. LCMS-B(ES-API): rt 3.307 min, m / z 207.0[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.7 (br s, 1H), 7.60 - 7.56 (m, 1H), 7.51 - 7.44 (m, 2H), 6.99 (dd, J = 17.9, 11.8 Hz, 1H), 5.78 (ddd, J = 17.9, 2.6, 1.6 Hz, 1H), 5.67 (dt, J = 11.8, 1.8 Hz, 1H). (e) 2-Fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A57)

[0452] A solution of 5-(3-fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A56) (200 mg, 0.97 mmol) in DCM / MeOH (6.0 mL / 6.0 mL) was cooled to -70 °C and O gas was bubbled through until the pale blue color persisted. Dimethyl sulfide (746 mg, 12.0 mmol) was added, and the mixture was allowed to warm to room temperature and then stirred for 1 h. The mixture was concentrated under reduced pressure to give the title compound (250 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS-B (ES-API): rt 2.69 min, m / z 207.0 [M−H]- (f) 1,1'-(ethane-1,2-diyl)bis(2-(2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (49)

[0453] A solution of 2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A57) (crude material from the previous step, 250 mg), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (120 mg, 0.41 mmol) and Oxone® (304 mg, 0.49 mmol) in DMF (3.0 mL) was stirred at room temperature for 1 h. The mixture was poured into water (10.0 mL), and the resulting precipitate was collected by filtration and purified by preparative HPLC (Agilent YMC-C18, 5 μm, 150 × 20 mm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to give the title compound (9.0 mg, 2.4% over two steps) as a white solid. NMR analysis indicated the presence of approximately 0.05 equivalents of formic acid. LCMS-B (ES-API): rt 2.63 min, m / z 765.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.62 (m, 6H), 7.62 - 7.46 (m, 5H), 7.28 - 7.15 (m, 2H), 7.00 - 6.92 (m, 1H), 4.67 - 4.54 (m, 2H), 4.29 (s, 6H), 4.18 - 4.05 (m, 2H). Example 26 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (50) [ka] (a) Methyl 2-bromo-5-chloro-3-fluorobenzoate (A58)

[0454] To a solution of 2-bromo-5-chloro-3-fluorobenzoic acid (A24) (4.0 g, 15.8 mmol) in DMF (52 mL) was added CHI (4.5 g, 31.6 mmol) and KCO (6.4 g, 47.4 mmol), and the mixture was stirred at room temperature for 30 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1:0 to 50:1) to give the title compound (3.97 g, 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d-6) δ 7.87 (dd, J = 8.6, 2.4 Hz, 1H), 7.70 (dd, J = 2.3, 1.5 Hz, 1H), 3.88 (s, 3H). (b) 2-Bromo-5-chloro-3-fluorobenzohydrazide (A59)

[0455] To a solution of methyl 2-bromo-5-chloro-3-fluorobenzoate (A58) (1.5 g, 5.6 mmol) in EtOH (10 mL) was added hydrazine hydrate (80% in water, 5.6 g, 89.5 mmol) and the mixture was heated at 55° C. for 2 h. The mixture was allowed to cool to room temperature and poured into ice water, and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (1.4 g, 93%) as a white solid. 1 H NMR (400 MHz, DMSO-d-6) δ 9.71 (br s, 1H), 7.74 (dd, J = 8.7, 2.4 Hz, 1H), 7.34 (dd, J = 2.4, 1.3 Hz, 1H), 4.55 (br s, 2H). (c) 5-(2-bromo-5-chloro-3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (A60)

[0456] To a solution of 2-bromo-5-chloro-3-fluorobenzohydrazide (A59) (1.4 g, 5.6 mmol) in DMF (15.0 mL) was added CDI (2.5 g, 15.7 mmol) and EtN (1.6 g, 15.7 mmol), and the mixture was heated at 40 °C overnight under N. The mixture was cooled to room temperature, poured into water, and extracted with DCM. The organic extract was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 50:1 to 10:1) to give the title compound (630 mg, 42%) as a white solid. LCMS-B (ES-API): rt 3.543 min; m / z 292.9, 294.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J = 8.6, 2.4 Hz, 1H), 7.70 (dd, J = 2.0, 1.2 Hz, 1H). (d) 5-(5-chloro-3-fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A61)

[0457] To a solution of 5-(2-bromo-5-chloro-3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (A60) (630 mg, 2.17 mmol) in toluene (7.0 mL) was added tributyl(vinyl)stannane (2.06 g, 6.5 mmol) and Pd(PPh3)4 (375.3 mg, 0.325 mmol), and the mixture was heated to reflux overnight under N2. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (pet. ether to pet. ether / EtOAc = 20:1) to give the title compound (380 mg, 73%) as a white solid. LCMS-B (ES-API): rt 3.656 min; m / z 241.0, 242.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 7.76 (dd, J = 10.9, 2.1 Hz, 1H), 7.76 (dd, J = 2.0, 0.8 Hz, 1H), 6.98 (dd, J = 18.0, 12.0 Hz, 1H), 5.82 - 5.68 (m, 2H). (e) 4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A62)

[0458] A solution of 5-(5-chloro-3-fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A61) (380 mg, 1.58 mmol) in DCM / MeOH (1:1, 5.0 mL) was cooled to -78 °C and O gas was bubbled through until the pale blue color persisted. Dimethyl sulfide (490 mg, 7.9 mmol) was then added, and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was concentrated at 25 °C to give the title compound (200 mg) as a brown oil, which was used directly in the next step without further purification. LCMS-B (ES-API): rt 3.144 min; m / z 241.0, 243.0 [M−H] - . (f) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (50)

[0459] A solution of 4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A62) (crude material from the previous step, 200 mg), 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-amino-2-methoxybenzamide) (I13) (87.5 mg, 0.23 mmol) and Oxone® (170 mg, 0.276 mmol) in DMF (1.0 mL) was stirred at room temperature for 1 h. The mixture was then diluted with water and freeze-dried, and the residue was purified by silica gel chromatography (DCM to DCM / MeOH=10:1) followed by preparative HPLC (Agilent YMC-C18, 5 μm, 150 × 20 mm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 15.0 mL / min) to give the title compound (7.2 mg, 1.1% over two steps) as a white solid. LCMS-B (ES-API): rt 2.799 min; m / z 833.1, 835.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (br s, 2H), 7.64 (s, 2H), 7.55 - 7.46 (m, 4H), 7.06 (d, J = 8.6 Hz, 2H), 6.89 (br s, 2H), 4.50 - 4.39 (m, 2H), 4.33 (s, 6H), 4.15 - 4.04 (m, 2H). Further examples

[0460] The following example compounds were prepared by analogous methods: [ka] [ka] [ka] [ka] [ka]

[0461] Assay The compounds disclosed herein are tested for the activity of STING modulators by the following assays.Each assay is designed to test different aspects of the potential interaction between compound and STING.Therefore, a compound is considered to be active if it shows binding or modulation in any one (or more) of these assays.

[0462] Protein production and purification Biophysical experiments were performed using three different recombinant human STING protein variants, designated according to the allelic nomenclature of Yi et al. (2013). Codon-optimized DNA sequences (for expression in Escherichia coli) encoding amino acid residues 149–345 (Swiss Prot Q86WV6) of human STING (WT), human STING (HAQ), and human STING (R232H) were synthesized by GenScript USA Inc. (Piscataway, New Jersey, USA). These were ligated into a modified pET43a E. coli expression vector designed to encode an N-terminal His tag followed by a tobacco etch virus protease (TEV) cleavage site and the STING gene sequence. The resulting protein sequences for the three allelic variants are listed below. [ka]

[0463] To produce recombinant human STING protein, expression plasmids encoding the aforementioned constructs were transformed into E. coli strain BL21 DE3 and grown to an OD of 0.8 in 2 x 1 L volumes of Terrific Broth (TB) supplemented with 100 μg / ml ampicillin. 600The cells were grown at 37°C with shaking until a .05% ...

[0464] Protein purification was initiated by thawing the cell pellet in lysis buffer (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 2 mM MgCl, 10 mM imidazole, 0.5 mg / ml lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, EDTA-free complete protease inhibitor tablets [Roche]) using a ratio of 7 ml of buffer per gram of cells. Cells were further lysed by passing three times through an ice-cold Avestin C5 cell crusher, followed by centrifugation at 48,000 × g at 4°C. The supernatant (cell lysate) was filtered through a 5 μm filter and loaded onto a 5 mL HiTrap IMAC Sepharose FF column (GE Healthcare) pre-equilibrated with IMAC Wash Buffer 1 (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 10 mM imidazole) using a Profinia affinity chromatography purification system (Bio-Rad). The IMAC column was then washed sequentially with IMAC Wash Buffer 1 and IMAC Wash Buffer 2 (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 20 mM imidazole), and the bound His-TEV-hSTING protein was eluted with IMAC elution buffer (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 250 mM imidazole). The IMAC-eluted protein was further purified by passage through a HiLoad 26 / 60 Superdex 75 column pre-equilibrated with storage buffer (25 mM Tris-HCl, pH 8.0, 150 mM NaCl, 5 mM DTT, 0.02% [w / v] sodium azide). Finally, the hSTING protein was concentrated to ≥2 mg / ml using an Amicon Ultra centrifugal filter unit (Utra-15 MWCO 10 kDa), flash-frozen in liquid nitrogen, and stored in a -70°C freezer.

[0465] Differential Scanning Fluorescence (DSF) Differential scanning fluorometry (DSF) is a rapid screening method for identifying low-molecular-weight ligands that bind to purified proteins and thereby stabilize (or sometimes destabilize) them (Niesen 2007). DSF monitors the thermal unfolding of proteins in the presence of a fluorescent dye and is typically performed using a real-time PCR instrument. The temperature at which the protein unfolds is measured by the increase in fluorescence of a dye that has affinity for the hydrophobic portion of the protein, which is gradually exposed during unfolding. The fluorescence of the dye is quenched in an aqueous environment, but its fluorescence increases when the dye associates with a hydrophobic site on the unfolded protein. The fluorescence intensity is plotted as a function of temperature, producing an S-shaped curve that can be described by a two-state transition. The inflection point (Tm) of the transition curve is calculated using a simple formula, e.g., Boltzmann's formula.

[0466] The thermal stability of STING protein (liganded and unliganded) was measured using a previously described methodology (Seabrook & Newman, 2013) with triplicate samples tested in a 96-well PCR microplate (AB Gene, ABGAB-0600 / W). In a final volume of 20 μL, 2 μM protein in 1× HBS buffer (50 mM HEPES, pH 7.4, 150 mM NaCl) was mixed with SYPRO Orange dye (Sigma-Aldrich S5692, final reaction mix dilution 1:1200) and compounds (final concentration 100 μM). The sealed plate was then run in a Bio-Rad CFX96 / C1000 thermocycler and in FRET scanning mode (λ ). excitation 490 nm, λ emission The melting curves were recorded by reading at each increment from 20°C to 100°C in 0.5°C increments every 30 seconds. The data were analyzed using the "Meltdown analysis" protocol described by Rosa (2015). The melting temperatures (T m) to the T obtained for the protein incubated with the ligand. m and subtract the ΔT listed in the table below m DSF data were generated for each compound for three different STING protein variants—human STING (WT), human STING (HAQ), and human STING (R232H). [Table 8-1] [Table 8-2]

[0467] Surface Plasmon Resonance (SPR) The binding interaction between the ligand and STING protein was quantified using surface plasmon resonance (SPR) by immobilizing minimally biotinylated STING protein on a streptavidin chip surface. This method yielded a highly active STING protein surface unimpaired by the low pH required for amine coupling methods. Minimal biotinylation of purified huSTING protein was performed using a previously described methodology (Chhabra 2012). Briefly, approximately 20 nmol of recombinant STING protein was mixed with EZ-Link™ sulfo-NHS-LC-LC-biotin (Thermofisher Scientific, catalog no. 21338) at a 1:0.6 molar ratio in 1x TBS buffer (25 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM DTT) and incubated on ice for 2 hours. To remove any unreacted biotin reagent, the protein / biotin mixture was passed through a Superdex 75 (10 / 300GL) column equilibrated with 10 mM HEPES, pH 7.4, 150 mM NaCl, 5 mM DTT, and 5% [v / v] glycerol. The protein peak containing the biotinylated huSTING protein was collected and stored in aliquots at −80°C.

[0468] Streptavidin was simultaneously immobilized on all four channels of a CM5 sensor chip docked to a Biacore instrument (either a Biacore S200 or Biacore T200, GE Healthcare) as previously described (Zender 2013). Minimally biotinylated STING protein was applied to the streptavidin-coated chip surface in SPR binding buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 2% [v / v] DMSO) at 8 °C until the desired capture level, typically 3000–7000 RU (1 RU = 1 pg / mm ). 2 The capture was performed by gradually injecting a single channel at a constant flow rate of 2 μL / min until a constant flow rate of 2 μL / min was achieved.

[0469] All binding experiments were performed in SPR binding buffer at 8°C. To determine binding affinity, compound interactions with immobilized STING protein were analyzed using dose-response experiments. Fresh 10 mM DMSO solutions of compounds were directly diluted in SPR binding buffer to a concentration of typically 50 μM, then further diluted 2- or 3-fold to target either a 5- or 7-point concentration series range. Concentration series of each ligand were injected at a constant flow rate of 60 μL / min with an association time of 90 seconds and a dissociation time of 180 seconds. These were modified for compounds with longer residence times to allow the curve to reach steady state or for the compound to fully dissociate before subsequent injections. Where appropriate, tighter-binding compounds (approximately K D <1 uM) were tested using a single cycle kinetic format (Karlsson 2006) with long association and dissociation times (typically 450 s and 1800 s, respectively).

[0470] Scrubber 2 (www.biologic.com.au) was used for data processing, and signals were referenced to a blank surface (streptavidin + D-biotin), further corrected for refractive index changes in DMSO, and then "double-referenced" using a buffer-blank injection (Papalia 2006). Responses were fit to either a 1:1 steady-state affinity model available within Scrubber or a 1:1 kinetic model (which included a mass transfer component). [Table 9-1] [Table 9-2] [Table 10-1] [Table 10-2]

[0471] THP-1 reporter cell line assay THP-1 STING Lucia ISG cells (InvivoGen number thpI-isg) were cultured in RPMI-1640 containing 2 mM L-glutamine, 25 mM HEPES, 100 μg / mL Normocin (InvivoGen), and 10% heat-inactivated FBS. Cells were cultured at 7 × 10 5 The cells were seeded at a density of 100 cells / mL, maintained at 37°C / 5% CO2, and passaged every 3-4 days. Selection pressure was maintained by adding 100 μg / mL Zeocin every two passages.

[0472] Assay conditions: Cells were harvested and plated in fresh growth medium at 5 x 10 5 From this cell preparation, 20 μL per well was dispensed into a 384-well cell culture plate (Greiner, no. 781098X) and incubated at 37° C. / 5% CO for 2 hours.

[0473] Concentration-response curves (typically 11 doses) were prepared by 2.5-fold serial dilutions starting from a 10 mM compound stock solution in DMSO. Compound dilutions were transferred to cell culture plates using a pintool (0.1 μL transfer), and control wells were matched for DMSO. Positive control wells received ML RR-S2 CDA (MedChemExpress HY12885B) in 5 μL of medium to a final concentration of 40 μM. All other wells received an additional 5 μL of medium simply to equalize the volume. Plates were incubated at 37°C / 5% CO2 for 24 hours.

[0474] For the detection step, QUANTI-Luc (InvivoGen product number rep-qlc1) was prepared according to the manufacturer's instructions and added at 10 μL per well to the culture plate. The plate was shaken for 10 seconds on an orbital shaker and allowed to stand at room temperature in the dark for 2 minutes before reading luminescence on a Perkin Elmer Envision plate reader.

[0475] Data analysis: The raw luminescence data was normalized to the % activity relative to the signal from the positive control wells and the negative control wells not treated with compound. The following formula was used to calculate the % normalized activity from the raw signal: Activity %=(Sample-Negative) / (Positive-Negative) ECs from THP-1 STING Lucia ISG cells 50 provides an assessment of the activity of the human HAQ isoform of STING. An equivalent method was performed to assess the activity of compounds against the WT human STING isoform; the cells used here were THP-1-Dual KI-hSTING-R232 (InvivoGen no. thpd-r232). [Table 11-1] [Table 11-2] [Table 11-3]

[0476] Description of the Invention 1. Formula I: [ka] Compounds of [In the formula, Y is (CH2) n (where n is 2 to 4), or -CH2-CH=CH-CH2-, R 1 and R 11 are independently -C(=O)OH, -C(=O)OR P1 , tetrazolyl, Br, F, oxo-oxadiazolyl and [ka] (2H-triazol-4-yl), wherein R P1 is selected from methyl and ethyl; A 1 is CR A or N, A 2 is CR B or N, A 3 is CR C or N, A 4 is CR D or N, where A 1 , A 2 , A 3 , and A 4 can be N, R A , R B , R C and R D wherein one, two or three (when present) of are selected from H, F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH; R A , R B, R C and R D the remainder (if any) of is H, A 11 is CR AA or N, A 12 is CR BB or N, A 13 is CR CC or N, A 14 is CR DD or N, where A 11 , A 12 , A 13 and A 14 can be N, R AA , R BB , R CC and R DD wherein one, two or three (when present) of are selected from H, F, Cl, Br, I, Me, Et, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH; R AA , R BB , R CC and R DD the remainder (if any) of is H, R C1 , R C3 and R C4 are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 selected from alkenyl and C5 heterocyclyl; R C11 , R C13 and R C14 are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl]. 2.A 11 =A 1 , A 12 =A 2 , A 13 =A3 , A 14 =A 4 , R C11 =R C1 , R C13 =R C3 , R C14 =R C4 , R 11 =R 1 The compound according to statement 1, 3.A 1 But, CR A 10. A compound according to statement 1 or 2, wherein 4.A 1 A compound according to statement 1 or 2, wherein is N. 5.A 2 But, CR B 5. The compound according to any one of statements 1 to 4, wherein 6.A 2 A compound according to any one of statements 1-4, wherein is N. 7.A 3 But, CR C 7. The compound according to any one of statements 1 to 6, 8.A 3 The compound according to any one of statements 1-6, wherein is N. 9.A 4 But, CR D 7. The compound according to any one of statements 1 to 6, 10.A 4 The compound according to any one of statements 1-6, wherein is N. 11.A 1 is CR A and A 2 is CR B and A 3 is CR C and A 4 is CR D 10. A compound according to statement 1 or 2, wherein 12.A 1 , A 2 , A 3 and A 4 A compound according to statement 1 or 2, wherein one of is N. 13.A 1 , A 2 , A 3 and A4 A compound according to statements 1 or 2, wherein two of are N. 14.A 11 But, CR AA 14. The compound according to any one of statements 1 to 13, 15.A 11 The compound according to any one of statements 1 to 13, wherein 16.A 12 But, CR BB 16. The compound according to any one of statements 1 to 15, 17.A 12 The compound according to any one of statements 1 to 15, wherein is N. 18.A 13 But, CR CC 18. The compound according to any one of statements 1 to 17, 19.A 13 The compound according to any one of statements 1 to 17, wherein 20.A 14 But, CR DD 20. The compound according to any one of statements 1 to 19, wherein 21.A 14 The compound according to any one of statements 1 to 19, wherein 22.A 11 is CR AA and A 12 is CR BB and A 13 is CR CC and A 14 is CR DD 14. The compound according to any one of statements 1 to 13, 23.A 11 , A 12 , A 13 and A 14 14. The compound according to any one of statements 1-13, wherein one of is N. 24.A 11 , A 12 , A 13 and A 14 14. The compound according to any one of statements 1-13, wherein two of are N. 25. The compound has the formula IIIb: [ka] 14. The compound according to any one of statements 1 to 13, 26. The compound has the formula IIIc: [ka] 14. The compound according to any one of statements 1 to 13, 27. The compound has the formula IIId: [ka] 14. The compound according to any one of statements 1 to 13, 28. The compound has the formula IIIe: [ka] 14. The compound according to any one of statements 1 to 13, 29.R A , R B , R C and R D and the remainder (if present) are H. 30.R A , R B , R C and R D and the remainder (if present) are H. 31.R A , R B , R C and R D 29. The compound according to any one of statements 1-28, wherein one, two, or three (if present) of are selected from H, F, Cl, Br, Me, CF3, and OMe, and the remainder (if present) are H. 32.R AA compound according to any one of statements 1-31 wherein (when present) is selected from H and F. 33.R B The compound according to any one of statements 1-32, wherein (when present) is selected from H, F and Cl. 34.R B A compound according to statement 33 wherein, when present, is selected from H and Cl. 35.R C The compound according to any one of statements 1-34, wherein (when present) is selected from H, F and Cl. 36.R D The compound according to any one of statements 1-35, wherein (when present) is selected from H, F and Cl. 37.R A , R B , R C and R D However, the following combination [ka] [ka] 12. The compound according to statement 11, selected from one of: 38.R A , R B , R C and R D The compound according to statement 37, wherein is selected from combinations 1, 3, 6 and 9. 39.R AA , R BB , R CC and R DD and the remainder (if present) is H. 40.R AA , R BB , R CC and R DDand the remainder (if present) are H. 41.R AA , R BB , R CC and R DD and the remainder (if present) are H. 42.R AA A compound according to any one of statements 1-41 wherein (when present) is selected from H and F. 43.R BB The compound according to any one of statements 1-42, wherein (when present) is selected from H, F and Cl. 44.R BB A compound according to statement 43 wherein, when present, is selected from H and Cl. 45.R CC The compound according to any one of statements 1-44, wherein (when present) is selected from H, F and Cl. 46.R DD The compound according to any one of statements 1-45, wherein (when present) is selected from H, F and Cl. 47.R AA , R BB , R CC and R DD However, the following combination [ka] [ka] 23. The compound according to statement 22, select...

Claims

1. Formula I: 【Chemistry 71】 Compound [In the formula, Y is (CH ２ ) ｎ [wherein n is 2 to 4], or -CH ２ -CH=CH-CH ２ - or R １ and R １１ are independently -C(=O)OH, -C(=O)OR Ｐ１ , Br, F, tetrazolyl, oxo-oxadiazolyl and 【Chemical 72】 (2H-triazol-4-yl), where R Ｐ１ is selected from methyl and ethyl; A １ is CR Ａ or N, A ２ is CR Ｂ or N, A ３ is CR Ｃ or N, A ４ is CR Ｄ or N, Here, A １ , A ２ , A ３ , and A ４ may be N, R Ａ , R Ｂ , R Ｃ and R Ｄ One, two or three (if present) of ３ , cyclopropyl, cyano, OMe, OEt, CH ２ O.H., C.H. ２ is selected from OMe and OH; R Ａ , R Ｂ , R Ｃ and R Ｄ the remainder (if any) are H; A １１ is CR ＡＡ or N, A １２ is CR ＢＢ or N, A １３ is CR ＣＣ or N, A １４ is CR ＤＤ or N, Here, A １１ , A １２ , A １３ and A １４ may be N, R ＡＡ , R ＢＢ , R ＣＣ and R ＤＤ One, two or three (if present) of ３ , cyclopropyl, cyano, OMe, OEt, CH ２ O.H., C.H. ２ is selected from OMe and OH; R ＡＡ , R ＢＢ , R ＣＣ and R ＤＤ the remainder (if any) are H; R Ｃ１ , R Ｃ３ and R Ｃ４ are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF ３ , C.H. ２ O.H., C.H. ２ OMe, C ２～４ Alkenyl and C ５ heterocyclyl; R Ｃ１１ , R Ｃ１３ and R Ｃ１４ are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF ３ , C.H. ２ O.H., C.H. ２ OMe, C ２～４ Alkenyl and C ５ heterocyclyl; or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof.

2. A １１ = A １ , A １２ = A ２ , A １３ = A ３ , A １４ = A ４ , R Ｃ１１ = R Ｃ１ , R Ｃ１３ = R Ｃ３ , R Ｃ１４ = R Ｃ４ , R １１ = R １ 2. The compound of claim 1, wherein:

3. A １ is CR Ａ And A ２ is CR Ｂ And A ３ is CR Ｃ And A ４ is CR Ｄ 3. The compound of claim 1 or claim 2, wherein:

4. A １１ is CR ＡＡ And A １２ is CR ＢＢ And A １３ is CR ＣＣ And A １４ is CR ＤＤ or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof.

5. The compound has the formula IIIb, IIIc, IIId and IIIe 【Chemical 73】 【Chemical 74】 3. The compound of claim 1 or claim 2, or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof, selected from:

6. R Ａ , R Ｂ , R Ｃ and R Ｄ One, two or three (if present) of the following are H, F, Cl, Br, Me, CF ３ 6. The compound of any one of claims 1 to 5, wherein R is selected from R, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R89, R91, R92, R93, R94, R95, R95, R96, R97, R98, R99, R100, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111,

7. A １ , A ２ , A ３ and A ４ However, combinations 1 to 30 【Chemistry 75】 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof, selected from:

8. R ＡＡ , R ＢＢ , R ＣＣ and R ＤＤ One, two or three (if present) of ３ 8. The compound of any one of claims 1 to 7, wherein R is selected from R, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62,

9. A １１ , A １２ , A １３ and A １４ However, combinations 1 to 30 【Chemical Formula 76】 【Chemical 77】 8. The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof, selected from:

10. R Ｃ１１ = R Ｃ１ , R Ｃ１３ = R Ｃ３ And R Ｃ１４ = R Ｃ４ 10. The compound of any one of claims 1 to 9, wherein:

11. R Ｃ１ , R Ｃ３ and R Ｃ４ However, combinations 1 to 4 【Chemical 78】 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof, selected from:

12. R Ｃ１１ , R Ｃ１３ and R Ｃ１４ However, combinations 1 to 4 【Chemical 79】 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof, selected from:

13. Y is (CH ２ ) ２ 13. The compound of any one of claims 1 to 12, wherein:

14. R １ and R １１ is selected from C(═O)OH, tetrazolyl and oxo-oxadiazolyl, or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof.

15. 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (1) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (2) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoic acid) (3) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (4) 2-(2-(1H-tetrazol-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazol-5-yl)phenyl)-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (5) 1,1'-(ethane-1,2-diyl)bis(2-(2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (6) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoic acid) (7) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-dichlorobenzoic acid) (8) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (9) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (10) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chloro-3-fluorobenzoic acid) (11) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chloro-3-fluorobenzoic acid) (12) Dimethyl 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoate) (13) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid) (14) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-difluorobenzoic acid) (15) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (16) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (17) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-7-fluoro-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (18) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-iodobenzoic acid) (19.1 and 19.2) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-7-fluoro-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (20) Dimethyl 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(2-bromobenzoate) (21) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (22) 1,1'-(ethane-1,2-diyl)bis(2-(2-chloro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (23) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-1,2,3-triazol-4-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (24) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-methylbenzoic acid) (25) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-methylbenzoic acid) (26) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (27) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-fluorobenzoic acid) (28) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid) (29.1 and 29.2) 3,3'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))diisonicotinic acid (30) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chloronicotinic acid) (31) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (32) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-ethylbenzoic acid) (33) (E)-6,6'-(but-2-ene-1,4-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid (34) 6,6'-(propane-1,3-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (35) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(2-bromobenzoic acid) (36) 1,1'-(ethane-1,2-diyl)bis(2-(3,4-dichloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (37) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-(trifluoromethyl)benzoic acid) (38). 6,6'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid) (39) 1,1'-(ethane-1,2-diyl)bis(2-(3-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (40) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-methoxybenzoic acid) (41) 1,1'-(ethane-1,2-diyl)bis(2-(5-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (42) 1,1'-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (43) 1,1'-(ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (44) 1,1'-(ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (45) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (46) 2-(5-carbamoyl-1-(2-(5-carbamoyl-2-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)-4-methoxy-1H-benzo[d]imidazol-2-yl)-5-chloro-3-fluorobenzoic acid (47). 1,1'-(ethane-1,2-diyl)bis(2-(2-fluoro-6-(2H-tetrazol-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (48) 1,1'-(ethane-1,2-diyl)bis(2-(2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (49) 1,1'-(ethane-1,2-diyl)bis(2-(4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (50). 2-(5-carbamoyl-1-(2-(5-carbamoyl-2-(2-carboxy-4-cyanophenyl)-4-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)-4-methoxy-1H-benzo[d]imidazol-2-yl)-5-cyanobenzoic acid (51). Methyl 2-(5-carbamoyl-1-(2-(5-carbamoyl-2-(4-cyano-2-(methoxycarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)-4-methoxy-1H-benzo[d]imidazol-2-yl)-5-cyanobenzoate (52).

15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof, selected from:

16. 16. A composition for use in a method of therapy comprising a compound according to any one of claims 1 to 15, or a pharma-ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof.

17. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt, solvate, stereoisomer, atropisomer, tautomer and / or N-oxide thereof, and a pharma- ceutically acceptable excipient.

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