Compound

Abstract

The present disclosure relates to compounds of formula (I), which are modulators of STING. Also disclosed are pharmaceutical compositions comprising compounds of formula (I) and methods of using compounds of formula (I) to treat or prevent diseases that are ameliorated by modulating STING.

Description

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

[0002] The present invention relates to substituted benzimidazole dimers and their use as medicaments, and in particular for treating diseases ameliorated by modulation of STING. Background Art

[0003] Vertebrates are constantly threatened by invading microorganisms and have evolved immune defense mechanisms to eliminate infectious pathogens. In mammals, this immune system consists of two branches; innate immunity and adaptive immunity. The innate immune system is the first line of defense and is initiated by pattern recognition receptors (PRRs) that detect ligands from pathogens as well as 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), as well as double-stranded DNA sensors. Activation of PRRs leads to upregulation of genes involved in inflammatory responses, including type 1 interferons, proinflammatory cytokines, and chemokines that inhibit pathogen replication and promote 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 cytosolic nucleic acids (Ishikawa 2008; WO2013 / 166000). Activation of STING leads to upregulation of the IRF3 and NF-κB pathways, resulting in the induction of type 1 interferons, including interferon-β and other cytokines. STING is essential for responses to cytosolic DNA of pathogen or host origin, as well as to unusual nucleic acids called cyclic dinucleotides (CDNs).

[0005] CDNs were originally identified as bacterial second messengers responsible for controlling a variety of reactions in prokaryotic cells. Bacterial CDNs (eg, c-di-GMP) are symmetrical molecules characterized by having two 3',5' phosphodiester bonds.

[0006]

[0007] Bacterial CDNs have recently been shown by X-ray crystallography to directly activate STING (Burdette 2013). Therefore, bacterial CDNs and their analogs have attracted interest as potential vaccine adjuvants (Libanova 2012; WO2007 / 054279; WO2005 / 087238).

[0008] Recently, the response to cytosolic 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 then activates STING. Unlike bacterial CDNs, cGAMP is an asymmetric molecule characterized by its mixed 2',5' and 3',5' phosphodiester bonds (Gao 2013A). X-ray crystallography has also demonstrated the interaction of cGAMP(II) with STING (Cai 2014).

[0009] Interferons were originally described as substances that can protect cells from viral infection (Isaacs 1957). In humans, type I interferons are a family of related proteins encoded by genes on chromosome 9 and encode at least 13 subtypes of interferon alpha (IFNα) and one subtype of interferon beta (IFNβ). Recombinant IFNα was the first approved biological therapy and has become an important treatment for viral infections and cancer. In addition to their direct antiviral activity on cells, interferons are known to be potent modulators of immune responses, acting on cells of the immune system.

[0010] Administration of small molecule compounds and other cytokines that can modulate innate immune responses, including activation or inhibition of type I interferon production, may become an important strategy for treating or preventing human diseases, including viral infections and autoimmune diseases. This type of immunomodulatory strategy has the potential to identify compounds that are useful not only for infectious diseases, but also for 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).

[0011] STING is essential for antimicrobial host defense, including protection against a range of DNA and RNA viruses and bacteria (reviewed in McNab 2015; Ma 2016). Herpesviridae, Flaviviridae, Coronaviridae, Papillomaviridae, Adenoviridae, Hepadnaviridae, Orthomyxoviridae and Paramyxoviridae, and Rhabdoviridae have evolved mechanisms to inhibit STING-mediated type I interferon production and escape 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.

[0012] Conversely, 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, excess type I IFN production has been found in patients with complex forms of autoimmune disease. Human genetic evidence and support from studies in animal models support the hypothesis that inhibition of STING leads to a reduction in type I IFN that drives autoimmune disease (Crow 2006; Stetson 2008). Therefore, STING inhibitors offer a treatment for patients with chronic type I IFN and proinflammatory cytokine production associated with infection or complex autoimmune disease. Allergic diseases are associated with a Th2-biased immune response to allergens. Th2 responses are associated with elevated levels of IgE, which, through its effects on mast cells, promote hypersensitivity reactions to allergens, leading to symptoms such as those seen in allergic rhinitis and asthma. In healthy individuals, the immune response to allergens is more balanced with a mixed Th2 / Th1 and regulatory T cell response. Induction of type 1 interferons has been shown to result in a reduction of Th2 type cytokines in the local environment and promote Th1 / Treg responses. In this context, induction of type 1 interferons, for example by activating STING, may be beneficial in the treatment of allergic diseases such as asthma and allergic rhinitis (Huber 2010).

[0013] 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 used to treat various conditions, such as allergic diseases and other inflammatory conditions (such as allergic rhinitis and asthma), infectious diseases, neurodegenerative diseases, precancerous syndromes and cancers, and can also be used as immunogenic compositions or vaccine adjuvants. Compounds that bind to STING can act as antagonists and can be used to treat, for example, autoimmune diseases. It is envisioned that targeting STING with activators or inhibitors may be a promising method for preventing and treating diseases and conditions that are beneficial for regulating the type 1 IFN pathway (including inflammation, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes) and as immunogenic compositions or vaccine adjuvants.

[0014] Skin cancer and various viral infections of the skin involve an immune privileged environment, and activation of local immune responses to lesions may be a topical treatment approach. STING agonists can be used to treat viral warts, superficial skin cancers, and precancerous actinic keratoses. Through a dual mechanism of action, STING activation (e.g., delivered by microneedle patches or topical formulations) can be used to directly control HPV by producing antiviral type I interferons, and indirectly control HPV by enhancing the adaptive immune response downstream of innate immune activation. STING agonists can activate innate immune responses in lesions and drive anti-HPV T cell responses.

[0015] Recent evidence suggests that spontaneous activation of the STING pathway within 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 can drive 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 by activating STING.

[0016] Furthermore, non-CDN compounds have been described as active agonists of STING.

[0017] Applications WO2019 / 069269, WO2019 / 069270, WO2017 / 175156 and WO2017 / 175147 and Ramanjulu 2018 describe certain aminobenzimidazole- and diaminobenzimidazole-based compounds and their use in STING modulation.

[0018] Applications WO2019 / 027858 and US2018 / 0093964 describe certain benzo[b]thiophene compounds and their use as STING agonists. WO2019 / 195063 describes azabenzothiophene compounds, and WO2019 / 195124 describes benzothiophenes and related compounds and their use as STING agonists. WO2019 / 219820 describes benzothiophenes, thienopyridines and thienopyrimidines as modulators of STING.

[0019] Applications WO2018 / 234808, WO2018 / 234807, GB2563642A, WO2018 / 234805 describe certain arylamino compounds and their use as STING modulators.

[0020] Application WO2019 / 165032 describes certain imidazole-pyridazine compounds and their use as STING agonists.

[0021] STING is known to have polymorphisms, including an allele encoding a histidine at position 232 that is insensitive to dual-3',5' (canonical) CDNs but sensitive to 2',5'-3',5' (non-canonical, mixed-junction) CDNs (Diner 2013; Jin 2011B). Single nucleotide polymorphisms in the STING gene have been reported to affect responses to canonical CDNs of bacterial origin (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).

[0022] The compounds of the present invention modulate the activity of STING and, therefore, may provide beneficial therapeutic effects in the prevention and treatment of diseases, disorders and / or conditions in which modulation of STING (stimulator of interferon genes) is beneficial, such as for inflammation, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes and as a vaccine adjuvant.

[0023] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0024] Any discussion of documents, acts, materials, devices, articles or the like included in this specification should not be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.

[0025] Unless expressly stated otherwise, any embodiment herein should be considered to be applicable mutatis mutandis to any other embodiment.

[0026] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods, as described herein, are clearly within the scope of the present invention. Summary of the invention

[0027] The first aspect of the present invention provides a compound of formula I:

[0028]

[0029] in:

[0030] Y is (CH 2 ) n , wherein n is 2 to 4, or -CH 2 -CH=CH-CH 2 -;

[0031] R 1 and R 11 independently selected from -C(=O)OH, -C(=O)OR P1 , Br, F, tetrazolyl, oxo-oxadiazolyl and (2H-triazol-4-yl), wherein R P1 is selected from methyl and ethyl;

[0032] A 1 CR A or N;

[0033] A 2 CR B or N;

[0034] A 3 CR C or N;

[0035] A 4 CR D or N;

[0036] Among them A 1 , A 2 , A 3 and A 4 No more than two of them can be N;

[0037] R A , R B , R C and R D One, two or three (if present) are selected from H, F, Cl, Br, I, Me, Et, CF 3, cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH;

[0038] The rest of R A , R B , R C and R D (if present) H;

[0039] A 11 CR AA or N;

[0040] A 12 CR BB or N;

[0041] A 13 CR CC or N;

[0042] A 14 CR DD or N;

[0043] Among them A 11 , A 12 , A 13 and A 14 No more than two of them can be N;

[0044] R AA , R BB , R CC and R DD One, two or three (if present) are selected from H, F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH;

[0045] The rest of R AA , R BB , R CC and R DD (if present) H;

[0046] R C1 , R C3 and R C4 independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 Alkenyl and C 5 Heterocyclic group;

[0047] RC11 , R C13 and R C14 independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 Alkenyl and C 5 Heterocyclic group.

[0048] The second aspect of the present invention provides the compound of the first aspect for use in a method of treatment. The second aspect also provides a pharmaceutical composition comprising the compound of the first aspect and a pharmaceutically acceptable excipient.

[0049] The third aspect of the present invention provides a method for treating or preventing a disease improved by regulating STING, the method comprising administering the compound of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention to a patient in need of treatment. The third aspect of the present invention also provides the use of the compound of the first aspect of the present invention in the preparation of a medicament for treating or preventing a disease improved by regulating STING, and the compound of the first aspect of the present invention or its pharmaceutical composition for treating or preventing a disease improved by regulating STING. DETAILED DESCRIPTION

[0050] definition

[0051] C 3-6 Cycloalkyl: As used herein, the term "C 3-6 The term "cycloalkyl" 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 (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ) and cyclohexyl (C 6 ).

[0052] C 3-7 Heterocyclyl: As used herein, the term "C 3-7 "Heterocyclyl" refers to a monovalent moiety obtained by removing hydrogen atoms from the ring atoms of a monocyclic heterocyclic compound (the moiety having 3 to 7 ring atoms); wherein 1-2 atoms are heteroatoms selected from oxygen, sulfur or nitrogen. 3-7 The heterocyclyl group can be a non-aromatic or aromatic ring system. 3-7 The heterocyclic group may be referred to as C 3-7 Heteroaryl groups.

[0053] In this context, a prefix (such as C 3-7) represents the number of ring atoms or a range of ring atoms, whether carbon atoms or heteroatoms. Thus, in some instances, the prefix "C" can be used interchangeably with an optional prefix defining the number of ring atoms, for example, the prefix "C" 3-7 " can be interchanged with the prefix "3-membered to 7-membered". In some embodiments, C 3-7 The heterocyclyl moiety may be C 3 , C 4 , C 5 , C 6 or C 7 Heterocyclyl or any combination of these rings / ring systems of varying sizes, such as C 3-6 , C 4-7 or C 5-6 Heterocyclyl group.

[0054] C 3-7 Examples of heterocyclic groups include, but are not limited to, those derived from:

[0055] N 1 :Aziridine (C 3 ), azetidine (C 4 ), pyrrolidine (tetrahydropyrrole) (C 5 ), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C 5 ), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoxazole) (C 5 ), pyrrole (C 5 ), piperidine (C 6 ), dihydropyridine (C 6 ), tetrahydropyridine (C 6 ), pyridine (C 6 ), aza (C 7 ), azepane (C 7 );

[0056] N 2 :Diaziridine (C 3 )Diazetidine (C 4 ), imidazolidine (C 5 ), pyrazolidine (oxadiazolidine) (C 5 ), imidazoline (C 5 ), pyrazoline (dihydropyrazole) (C 5 ), imidazole (C 5 ), pyrazole (C 5 ), piperazine (C 6 ), pyrazine (C 6 ), pyrimidine (C 6 ), pyridazine (C 6 ), diazepine (C 7 ), diazepane (C 7 );

[0057] O 1 :Oxetane (C 4 ), tetrahydrofuran (C 5 ); Oxane (C 6 );

[0058] O 2 :Dioxetane (C 4 ), dioxolane (C 5 ); dioxane (C 6 ), dioxolane (C 5 );

[0059] N 1 O 1 :Tetrahydrooxazole (C 5 ), dihydrooxazole (C 5 ), tetrahydroisoxazole (C 5 ), dihydroisoxazole (C 5 ), isoxazole (C 5 ), oxazole (C 5 ), morpholine (C 6 ), tetrahydrooxazole (C 6 ), dihydrooxazole (C 6 ), oxazine (C 6 );

[0060] S 1 :Thiacyclopropane (C 3 ), thietane (C 4 ), thiolane (tetrahydrothiophene) (C 5 ), thiophene (C 5 ), thiohexane (tetrahydrothiopyran) (C 6 ), thiophene alkane (C 7 );

[0061] N 1 S 1 :Thiazoline (C 5 ), thiazolidine (C 5 ), thiazole (C 5 ), isothiazole (C 5 ), thiomorpholine (C 6 ), Thiazide (C 6 );

[0062] O 1 S 1 :Thiomethylene (C 5 ), isothioethane (C 5 ), oxathiols (C 5 ), isothiocyanate (C 5 ) and oxathietane (thiane) (C6 ).

[0063] C 1-4 Alkyl: As used herein, the term "C 1-4 The "alkyl group" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having 1 to 4 carbon atoms.

[0064] Examples of saturated alkyl groups include, but are not limited to, Me: methyl (C 1 ), Et: Ethyl (C 2 ), Pr: Propyl (C 3 ) and Bu: butyl (C 4 ).

[0065] Examples of saturated straight chain alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), nPr: n-propyl (C 3 ) and nBu: n-butyl (C 4 ).

[0066] Examples of saturated branched alkyl groups include, but are not limited to, iPr: isopropyl (C 3 , -C(CH 3 ) 2 ), iBu: isobutyl (C 4 ), sBu: sec-butyl (C 4 ) and tBu: tert-butyl (C 4 ).

[0067] C 2-4 Alkenyl: As used herein, the term "C 2-4 "Alkenyl" refers to an alkyl group having 2 to 4 carbon atoms and having one or more carbon-carbon double bonds.

[0068] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH 2 ), 1-propenyl (-CH=CH-CH 3 ), 2-propenyl (allyl, -CH-CH=CH 2 ), isopropenyl (1-methylvinyl, -C(CH 3 )=CH 2 ) and butenyl (C 4 ).

[0069] C 1-4 Fluoroalkyl: As used herein, the term "C1-4 fluoroalkyl" refers to a C1-4 fluoroalkyl group substituted with one or more fluorine atoms. 1-4 alkyl.

[0070] Alkoxy: -OR, wherein R is C as defined above 1-4 Alkyl group. It can be represented as -OC 1-4 Examples of alkoxy groups include, but are not limited to, methoxy (OMe, C 1 ), ethoxy (OEt, C 2 ), propoxy (C 3 ) and butoxy (C 4 ).

[0071] Alkylcarbamoyl: -NHC(=O)OR, wherein R is C as defined above. 1-4 Examples of alkylcarbamoyl groups include, but are not limited to, -N(H)C(=O)OCH 3 、-N(H)C(=O)OCH 2 CH 3 and -N(H)C(=O)OC(CH 3 ) 3 .

[0072] Alkyl carbamate: -OC(=O)NRR', wherein R and R' are independently selected from H and C as defined above. 1-4 Examples of alkyl carbamate groups include, but are not limited to, -OC(=O)N(CH 3 ) 2 and -OC(=O)N(H)CH 3 .

[0073] Alkyl carboxyl ester: -OC(=O)OR, wherein R is C as defined above. 1-4 Alkyl groups. Examples of alkyl carboxylate groups include, but are not limited to, -OC(=O)OCH 3 、-OC(=O)OCH 2 CH 3 、-OC(=O)OC(CH 3 ) 3 and -OC(=O)OCH(CH 3 ) 2 .

[0074] Amino: -N(R)R', wherein R and R' are independently selected from H and C as defined above 1-4 Examples of amino groups include, but are not limited to, -NH 2 、N(H)CH 3 、-N(H)C(CH 3 ) 2 、-N(CH 3 ) 2 、-N(CH 2 CH3) 2 .

[0075] Amino (carbamoyl, carbamyl, aminocarbonyl, carboxamide, aminoacyl): -C(=O)N(R)R', wherein R and R' are independently selected from H and C as defined above 1-4 Examples of amino groups include, but are not limited to, C(=O)NH 2 、-C(=O)N(H)CH 3 、-C(=O)N(CH 3 ) 2 、-C(=O)N(H)CH 2 CH 3 and -C(=O)N(CH 2 CH 3 ) 2 .

[0076] Acylamino: -N(R)C(=O)R', wherein R and R' are independently selected from H and C as defined above. 1-4 Examples of acylamino groups include, but are not limited to, -N(H)C(=O)CH 2 CH 3 、-N(H)C(=O)CH 3 and -N(CH 3 )C(=O)CH 3 .

[0077] Phenyl: -C 6 H 5 , wherein the phenyl group itself may optionally be replaced by one or more C 1-4 An alkyl group, one or more C 1-4 A fluoroalkyl group, one or more C 1-4 The alkoxy group, one or more halogen substituents and one or more cyano substituents are substituted.

[0078] Benzyl: -CH 2 -phenyl, wherein phenyl is as defined above.

[0079] Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, wherein R is an ester substituent, for example, C as defined above 1-4 Alkyl group, C 3-7 A heterocyclic group or a phenyl group, preferably C 1-4 Examples of ester groups include, but are not limited to, -C(=O)OCH 3 、-C(=O)OCH 2 CH 3 、-C(=O)OC(CH 3 )3 and -C(=O)OPh.

[0080] Acyloxy (reverse ester): -OC(=O)R, wherein R is an acyloxy substituent, for example, C 1-4 Alkyl group, C 3-7 A heterocyclic group or a phenyl group, preferably C 1-4 Examples of acyloxy groups include, but are not limited to, -OC(=O)CH 3 (acetoxy), -OC(=O)CH 2 CH 3 、-OC(=O)C(CH 3 ) 3 and -OC(=O)Ph. Other examples of acyloxy groups include, but are not limited to, methyl ester (C 1 ), ethyl ester (C 2 ), propyl ester (C 3 ) and butyl ester (C 4 ).

[0081] Naturally occurring amino acids: As used herein, the term "naturally occurring amino acids" refers to a monovalent moiety obtained by removing a hydrogen atom from a carboxyl group or an amino group on one of the common amino acid compounds 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, most particularly valine.

[0082] In each of these groups, the carbon atom to which the carboxyl and amino groups are bonded is referred to as the alpha carbon, and the carboxyl and amino groups attached thereto are referred to as alpha-carboxyl and alpha-amino groups. The naturally occurring amino acids are optionally substituted with protecting groups on the alpha-amino group or any other amino group on the moiety, including but not limited to acetyl, methyl, fluorenylmethoxycarbonyl (Fmoc), carboxybenzyl (Cbz; benzyloxycarbonyl), phthalimide, and tert-butylcarbamate (boc) groups.

[0083] Phosphonate: -P(O)(OR)OR', wherein R and R' are independently selected from C 1-4 Examples of phosphonates include, but are not limited to -P(O)(OEt) 2 .

[0084] Cyano: -C≡N.

[0085] Pivaloyloxymethyl:

[0086] The group.

[0087] Tetrazolyl:

[0088] The group.

[0089] Oxo-oxadiazolyl: A 5-membered heterocyclic compound having two nitrogen ring atoms, an oxygen ring atom, and an oxo substituent. Examples of oxo-oxadiazolyl include:

[0090]

[0091] 2H-triazol-4-yl: a group of the formula:

[0092]

[0093] As used herein, the term "comprise" and variations of the term, such as "comprising," "comprises," and "comprised," are not intended to exclude further additives, components, integers or steps, unless the context requires otherwise.

[0094] It must be noted that, as used herein and in 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" may include a plurality of salts and reference to "at least one heteroatom" may include one or more heteroatoms, and so forth.

[0095] The term "and / or" can mean "and" or "or".

[0096] The term "(s)" following a noun contemplates the singular or plural, or both.

[0097] Various features of the present invention are described with reference to a certain value or range of values. These values ​​are intended to be related to the results of various appropriate measurement techniques and should therefore be interpreted as including the error range inherent to any particular measurement technique. Some values ​​mentioned herein are represented by the term "about" to at least partially account for this variability. When used to describe a value, the term "about" can represent an amount within ±10%, ±5%, ±1%, or ±0.1% of the value.

[0098] Including other forms

[0099] Unless otherwise indicated, the above includes the well-known ionic, salt, solvate and protected forms of these substituents. For example, a reference to a carboxylic acid (-COOH) also includes its anionic (carboxylate) form (-CO - ), salts or solvates, as well as conventional protected forms. Similarly, reference to an amino group includes the protonated form of the amino group (—N+ HR 1 R 2 ), salts or solvates, such as hydrochloride, and conventional protected forms of amino groups. Similarly, reference to a hydroxyl group also includes its anionic form (—O - ), salts or solvates, and conventional protected forms.

[0100] Salts

[0101] It may be convenient or desirable to prepare, purify, and / or handle the active compound as a corresponding salt, e.g., a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0102] For example, if the compound is anionic, or has a functional group that can be anionic (e.g., -COOH can be -COO - ), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions (e.g., Na + and K + ), alkaline earth metal cations (such as Ca 2+ and Mg 2+ ) and other cations (such as Al +3 Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH 4 + ) and substituted ammonium ions (e.g. NH 3 R + NH 2 R 2 + 、NHR 3 + NR 4 + Some examples of suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .

[0103] If the compound is cationic, or has a functional group that can be cationic (e.g., -NH 2 It can be -NH 3 +), then a salt may be formed with a suitable 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.

[0104] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucuronic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, palmitic acid, pantothenic acid, phenylacetic acid, benzenesulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, trifluoroacetic acid, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethylcellulose.

[0105] Solvate

[0106] It may be convenient or desirable to prepare, purify and / or handle the corresponding solvate of the active compound. The term "solvate" is used in the conventional sense herein to refer to a complex of a solute (e.g., an active compound, a salt of an active compound) and a solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, such as a monohydrate, a dihydrate, a trihydrate, etc.

[0107] Prodrug

[0108] The active compound may be prepared as a prodrug. In particular, the carboxyl group R 1 and R 11 It can be in the form of ester, acylamino (-C(=O)NH 2 ) and substituted acylamino groups. In some embodiments, R 1 and R 11 may be independently selected from -C(=O)OR P 、-C(=O)NH 2 and -C(=O)NHR P , where R P Selected from:

[0109] (i)C 3-6 Cycloalkyl;

[0110] (ii) C optionally substituted by a group selected from 3-7 Heterocyclic group:

[0111] Methyl; and

[0112] Esters; and

[0113] (iii) a linear or branched C optionally substituted by a group selected from 1-4 alkyl:

[0114] Alkoxy;

[0115] Amino;

[0116] Amide;

[0117] Acylamino;

[0118] acyloxy;

[0119] Alkyl carboxyl esters;

[0120] Alkylcarbamoyl;

[0121] Alkyl carbamates;

[0122] Phenyl;

[0123] Phosphonates;

[0124] C optionally substituted by a group selected from methyl and oxo 3-7 Heterocyclic group;

[0125] Naturally occurring amino acids, optionally N-substituted with a group selected from methyl, acetyl and boc;

[0126] In some embodiments, R 1 and R 11 -C(=O)NH 2 In these embodiments, the compound is a compound of Formula Ic:

[0127]

[0128] Among them A 1 -A 4 , A 11 -A 14 , R C1 , R C3 , R C4 , R C11 , R C13 , R C14 and Y are as defined above.

[0129] In some embodiments, R P is an optionally substituted straight or branched chain C 1-4 In some embodiments, R P For unsubstituted C 1-4 In some embodiments, R P To replace C 1-4 alkyl.

[0130] When R P C 1-4 When alkyl, in some of these embodiments, R P In other of these embodiments, R P In other of these embodiments, R P is propyl (e.g., isopropyl, n-propyl). In other of these embodiments, R P is butyl (e.g., isobutyl, sec-butyl, tert-butyl).

[0131] In some embodiments, R P C 3-6 In some of these embodiments, R P In other of these embodiments, R P In other of these embodiments, R P In other of these embodiments, R P It is cyclohexyl.

[0132] In some embodiments, R P C 3-7 In some of these embodiments, C 3-7 The heterocyclyl group 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 In some of these embodiments, R P It is piperidinyl.

[0133] R P Substituents on

[0134] In some embodiments, when R P C 3-7 When R is a heterocyclic group, it is substituted by a group selected from methyl and ester. P C 3-7 In some embodiments, when R P C 3-7 When it is a heterocyclic group, it is substituted by an ester.

[0135] In some embodiments, when R P Straight or branched chain C 1-4 When alkyl is selected from alkoxy, amino, acylamino, acylamino, acyloxy, alkylcarboxyl ester, alkylcarbamoyl, alkylcarbamate, phenyl, phosphonate C 3-7The heterocyclyl radical is optionally substituted with a radical selected from methyl and oxo and a naturally occurring amino acid, optionally N-substituted with a radical selected from methyl, acetyl and boc.

[0136] In some embodiments, when R P Straight or branched chain C 1-4 In some embodiments, when RP is a straight or branched C alkyl group substituted with an acyloxy group, it is substituted with a group selected from acyloxy and phenyl. 1-4 When alkyl is pivaloyloxymethyl, the group is:

[0137]

[0138] In some embodiments, when R P is a straight or branched chain C substituted with an acyloxy group 1-4 When alkyl is present, it is propionyloxyisobutyl; a group of the formula:

[0139]

[0140] In some embodiments, when R P is a straight or branched chain C substituted by a phenyl group 1-4 When it is alkyl, it is benzyl.

[0141] In some embodiments, when R P Straight or branched chain C 1-4 alkyl, it is substituted by a naturally occurring amino acid, optionally N-substituted by a group selected from methyl, acetyl and boc. P A linear or branched C 1-4 When R is alkyl, the naturally occurring amino acid is valine. P A linear or branched C 1-4 When R is alkyl, the naturally occurring amino acid is N-methyl valine. P A linear or branched C 1-4 When R is alkyl, the naturally occurring amino acid is N-acetyl valine. P A linear or branched C 1-4 When the alkyl group is present, the naturally occurring amino acid is N-boc valine.

[0142] In some embodiments, when R P Straight or branched chain C 1-4 In some embodiments, when R PStraight or branched chain C 1-4 In some embodiments, when R P Straight or branched chain C 1-4 In some embodiments, when R P Straight or branched chain C 1-4 In some embodiments, when R P Straight or branched chain C 1-4 In some embodiments, when R P Straight or branched chain C 1-4 In some embodiments, when R P Straight or branched chain C 1-4 In some embodiments, when R P Straight or branched chain C 1-4 In some embodiments, when R P Straight or branched chain C 1-4 When the alkyl group is alkyl, it is substituted with a phosphonate.

[0143] In some embodiments, when R P Straight or branched chain C 1-4 When alkyl is 3-7 In some embodiments, when R P For C 3-7 Heterocyclic substituted straight or branched chain C 1-4 When alkyl, C 3-7 The heterocyclyl group is dioxolane, optionally substituted by a group selected from methyl and oxo.

[0144] Isomers

[0145] Certain compounds of the present invention may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, diastereomeric, 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; cis and trans forms; syncline and anticline forms; α and β forms; axial and planar forms; boat, chair, twist, envelope and half-chair forms; M and P forms; Δ and Δ forms; R a- and S a- forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomer forms").

[0146] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image partner, whereas the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0147] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ in the way the atoms or groups are arranged in space.

[0148] "Diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography.

[0149] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0150] "Atropisomers" refers to two stereoisomers of a compound that arise due to restricted rotation about a single bond, wherein rotation about the bond is sufficiently hindered so that the individual conformers can be separated and the conformers are either non-superimposable mirror images of one another (enantiomers) or stereoisomers that are not mirror images of one another (diastereomers).

[0151] The stereochemical definitions and conventions used herein generally follow those in 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 exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and 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. When describing an optically active compound, the prefixes D and L, or R and S, M and P, Δ and Λ, R and a and S aUsed to indicate the absolute configuration of a molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of the compound with respect to plane polarized light, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. 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 may be referred to as an enantiomer, and a mixture of these isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric substances that is optically inactive.

[0152] Of particular relevance to the compounds of the present invention is atropisomerism, whereby single bond rotation between the two aromatic ring systems in each half of the dimer may be restricted - this may occur when A1 and / or A11 are of certain sizes.

[0153] Note that, in addition to tautomeric forms as discussed below, the term "isomer" as used herein specifically excludes structural (or constitutional) isomers (i.e., isomers that differ in the connectivity between their atoms rather than merely the positions of the atoms in space). For example, referring to the methoxy group -OCH 3 It should not be construed as a reference to its structural isomer, the hydroxymethyl group -CH 2 OH. Similarly, reference to o-chlorophenyl should not be construed as reference to its structural isomer m-chlorophenyl. However, reference to a class of structures may include structural isomeric forms belonging to that class (e.g., C 1-7 Alkyl includes n-propyl and isopropyl; butyl includes n-, iso-, sec- and tert-butyl; methoxyphenyl includes o-, m- and p-methoxyphenyl).

[0154] The above exclusion does not relate to tautomeric forms, e.g., keto, enol and enolate forms, such as in the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thione / enethiol, N-nitroso / hydroxyazo and nitro / acid nitro.

[0155]

[0156] 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 proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonded electrons.

[0157] Note that specifically included in the term "isomer" are compounds having one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O etc.

[0158] Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 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 isotope-labeled compounds of the present invention, for example, compounds incorporating radioactive isotopes (e.g. 3 H. 13 C and 14 C). Such isotope-labeled compounds can be used for metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determinations, or for patients treated with radiotherapy. Deuterium-labeled or substituted therapeutic compounds of the present invention can have improved DMPK (drug metabolism and pharmacokinetics) properties, involving distribution, metabolism and excretion (ADME). Substitution with heavier isotopes (e.g., deuterium) may bring certain therapeutic advantages, which are derived from higher metabolic stability, such as increased half-life in vivo or reduced dosage requirements. 18F-labeled compounds can be used for PET or SPECT studies. Isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by the procedures disclosed in the schemes or in the examples and the preparation methods described below by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents. In addition, the use of heavier isotopes, particularly deuterium (i.e. 2 H or D) substitution can provide certain therapeutic advantages, these advantages are derived from higher metabolic stability, such as increased half-life in vivo or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium is considered as a substituent herein. 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 specific isotope refers to any stable isotope representing the atom.

[0159] Unless otherwise indicated, reference to a particular compound includes all such isomeric forms, including (whole or partial) racemates and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic methods) of such isomeric forms are either known in the art or readily obtained by adopting the methods taught herein or known methods in a known manner.

[0160] Polymorph

[0161] The compounds disclosed herein (in any of the various forms described herein) that form crystalline solids may exhibit polymorphism. All polymorphic forms of the compounds are within the scope of the present disclosure.

[0162] N-oxides

[0163] Nitrogen-containing groups can also be oxidized to form N-oxides.

[0164] Treatment Indications

[0165] The compounds disclosed herein may provide therapeutic benefit in a number of conditions, particularly in the treatment or prevention of diseases ameliorated by modulation of STING.

[0166] One aspect of the invention provides methods for treating or preventing STING-mediated diseases and conditions, in which agonizing STING is beneficial. Exemplary diseases / conditions include, but are not limited to, cancer and infectious diseases (e.g., diseases caused by viruses (e.g., HIV, HBV, HCV, HPV, influenza, and coronaviruses (including rhinoviruses, SARS, MERS, and SARS-CoV-2)) and bacteria). Another aspect of the invention provides the use of STING agonists as vaccine adjuvants.

[0167] 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. The present invention particularly provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a STING-mediated disease or condition.

[0168] The present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use as a vaccine adjuvant. Therefore, an immune composition or vaccine adjuvant comprising a compound of formula I or a pharmaceutically acceptable salt thereof is also provided. In another 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.

[0169] In another embodiment, the present invention provides a compound of the present invention for use in treating a STING-mediated disease or condition and / or as an immune 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 improving organ damage or impairment caused by a STING-mediated disease or condition.

[0170] The present invention further provides the use of the compounds of the present invention in the manufacture of a medicament for treating a STING-mediated disease or condition. 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 treating a STING-mediated disease or condition (e.g., the diseases and conditions described herein).

[0171] 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 production of a vaccine. Further provided is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the production of an immunogenic composition comprising an antigen or an 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 in the production of a vaccine composition comprising an antigen or an antigenic composition for the treatment or prevention of a disease.

[0172] In another embodiment, the present invention relates to a method for treating a STING-mediated disease or condition, comprising administering to a human in need thereof a therapeutically effective amount of a compound of the present invention. In another embodiment, the present invention relates to a method for treating a STING-mediated disease or condition, comprising administering to a human in need thereof a therapeutically effective amount of a compound of formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof.

[0173] Infectious Diseases

[0174] The compounds of the present invention can be used to treat infectious diseases, which are any diseases caused by pathogen infection or occurring simultaneously. Pathogens are broadly defined as any biological species foreign to the human tissue environment. Common pathogens that cause diseases include bacteria (many such as TB), viruses (many such as HBV, HIV, influenza, coronaviruses) and parasitic protozoa (such as Plasmodium falciparum that causes malaria). The compounds of the present invention can be used to treat infectious diseases derived from bacteria, such as TB infection (Mycobacterium tuberculosis), Chlamydia, Tularemia infection (Francisella tularensis), Plasmodium infection or DNA or RNA virus infection. The compounds of the present invention can be used to treat infectious diseases derived from the DNA virus family: Herpesviridae (Herpes simplex virus-1, Kaposi sarcoma-associated virus and Epstein-Barr virus), Papillomaviridae (Human papillomavirus), Adenovirus and Hepatoviridae (Hepatitis B virus). Examples of RNA virus families include Retroviridae (human immunodeficiency virus), Flaviviridae (dengue virus, hepatitis C virus), Orthomyxoviridae (influenza), and Coronaviridae (human coronavirus and SARS coronavirus, including SARS-CoV-2).

[0175] cancer

[0176] As used herein, the terms "cancer", "neoplasm" and "tumor" are used interchangeably and, in the singular or plural, refer to cells that have undergone malignant transformation, which makes them pathological to the host organism. Primary cancer cells can be easily distinguished from non-cancerous cells by established techniques, particularly histological examination. As used herein, the definition of cancer cells includes not only primary cancer cells, but also any cells derived from cancer cell ancestors. This includes metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to a cancer that usually manifests as a solid tumor, a "clinically detectable" tumor refers to a tumor that can be detected based on a tumor mass; for example, a physical examination is performed by a procedure (such as a computed tomography (CT) scan, magnetic resonance imaging (MRI), X-ray, ultrasound, or palpation), and / or a sample that can be obtained from a patient due to the expression of one or more cancer-specific antigens. The tumor can be a hematopoietic (or blood or hematological or blood-related) cancer, such as a cancer derived from blood cells or immune cells, which can be referred to as a "liquid tumor". Specific examples of hematological neoplasm-based clinical conditions 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; and the like.

[0177] Cancer can be any cancer in which there is an abnormal number of mother cells or undesired cell proliferation or is diagnosed as a blood cancer (including lymph and bone marrow malignancies). Myeloid malignancies include but are not limited to acute myeloid (or myeloid or myeloid or myeloblastic) leukemia (undifferentiated or differentiated), acute early myeloid (or promyeloblastic or early myeloid or primitive granulocyte (promyeloblastic)) leukemia, acute myelomonocytic (or myeloblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocyte (or megakaryoblastic) leukemia. These leukemias can be collectively referred to as acute myeloid (or myeloid or myeloid) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPD), which include but are not limited to chronic myeloid (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocythemia) and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be termed refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in metastatic settings (RAEBT); and myelofibrosis (MFS) with or without idiopathic myeloid metaplasia.

[0178] Hematopoietic cancers also include lymphoid malignancies, which may affect lymph nodes, spleen, bone marrow, peripheral blood and / or extranodal sites. Lymphoid cancers include B-cell malignancies, including but not limited to B-cell non-Hodgkin lymphoma (B-NHL). B-NHL can be indolent (or low-grade), intermediate (or aggressive) or high-grade (very aggressive). Indolent B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL), including lymph node 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 leukemia, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHL includes Burkitt lymphoma (BL), Burkitt-like lymphoma, small non-cleaved 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 macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL may 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 disease (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sezary syndrome.

[0179] Hematopoietic cancer also includes Hodgkin lymphoma (or disease), including classical Hodgkin lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cell type Hodgkin lymphoma, lymphocyte-based (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma and lymphocyte depletion type Hodgkin lymphoma. Hematopoietic cancer also includes plasma cell disease or cancer, such as multiple myeloma (MM), including smoldering MM, undetermined (or unknown or unclear) monoclonal gammopathy (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom macroglobulinemia, plasma cell leukemia and primary amyloidosis (AL). Hematopoietic cancer can also include cancers of other hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer cells. Tissues comprising hematopoietic cells, referred to herein as "hematopoietic cell tissue," include bone marrow; peripheral blood; thymus; peripheral lymphoid tissues, such as the spleen, lymph nodes, mucosa-associated lymphoid tissue (e.g., gut-associated lymphoid tissue), tonsils, Peyer's patches, and appendix, as well as lymphoid tissues associated with other mucosa, such as the bronchial lining.

[0180] Examples of cancer diseases and conditions for 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, intestinal cancer, endocrine system, thyroid, parathyroid, adrenal glands, urethra, prostate, penis, testis, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, renal pelvis cancer, carcinoma, renal cell carcinoma; soft tissue sarcoma; myxoma; rhabdoid tumor; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatocarcinoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphoma; primary CNS lymphoma; CNS neoplasm; spinal tumor; squamous cell carcinoma; synovial sarcoma; malignant pleural mesothelioma; brain stem glioma; pituitary adenoma; bronchial adenoma; enchondroma hamartoma; mesothelioma; Hodgkin's disease, or a combination of one or more of the foregoing cancers.

[0181] Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from the group consisting of: brain (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphocytic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia disease, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphocytic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryocytic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphocytic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, oral cancer, mouth cancer, GIST (gastrointestinal stromal tumor) and testicular cancer.

[0182] 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 sarcomas, breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (RCC), lymphoma, head and neck squamous cell carcinoma (SCCHN), hepatocellular carcinoma (HCC) and / or non-Hodgkin's lymphoma (NHL). Suitably, the present invention relates to a method for treating a precancerous syndrome of a mammal (including humans) or reducing its severity, wherein the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammopathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevus (melanoma precursor), prostatic intraepithelial (intraductal) neoplasia (PIN), ductal carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

[0183] On the one hand, people suffer from solid tumors.On the one hand, tumors are 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.On the one hand, people suffer from one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung cancer, mesothelioma and prostate cancer.On the other hand, people suffer from liquid tumors, such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lymphocytic leukemia (CLL), follicular lymphoma, acute myeloid leukemia and chronic myeloid leukemia.In one embodiment, the compounds of the present invention can be used to treat skin cancer (e.g., non-melanoma skin cancer, squamous cell carcinoma, basal cell carcinoma) or actinic keratosis. In addition to the field effect of clearing superficial skin cancers, the compounds of the present invention may also prevent the development of subsequent skin cancers and precancerous actinic keratoses in treated patients.

[0184] Autoimmune diseases

[0185] Related autoimmune diseases include, but are not limited to, STING-associated vasculitis of infancy (SAVI), Aicardi Goutieres syndrome (AGS), lupus pernio, ataxia telangiectasia (also known as Louis-Bar syndrome), retinal vasculopathy with leukodystrophy (RCVL), systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, psoriasis, diabetes including insulin-dependent diabetes mellitus (IDDM), dermatomyositis, human immunodeficiency virus (HIV), AIDS, polymyositis, systemic sclerosis (scleroderma) and Sjögren'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, Behçet's disease, spondylitis, giant cell arteritis, polymyalgia rheumatica, Raynaud's phenomenon, primary biliary cirrhosis, primary angiitis of the central nervous system with microscopic polyangiitis, neuromyelitis optica, and mixed connective tissue disease.

[0186] Inflammation

[0187] Inflammation represents a group of vascular, cellular, and neural responses to trauma. Inflammation can be characterized by the movement of inflammatory cells (e.g., monocytes, neutrophils, and granulocytes) into tissues. This is often associated with decreased endothelial barrier function and edema within the tissue. Inflammation can be classified as acute or chronic. Acute inflammation is the body's initial response to noxious stimuli and is achieved by increased movement of plasma and leukocytes from the blood into injured tissues. A cascade of biochemical events allows the inflammatory response to propagate and mature, involving the local vasculature, the immune system, and various cells within the injured tissue. Long-term inflammation, known as chronic inflammation, results in a progressive shift in the cell types present at the site of inflammation and is characterized by simultaneous tissue destruction and healing during the inflammatory process.

[0188] Inflammation can be beneficial and is usually self-limiting when it occurs as part of an immune response to infection or as an acute response to trauma. However, inflammation can be harmful in a variety of situations. This includes excessive inflammation in response to infectious agents, which can lead to severe organ damage and death (e.g., in the case of sepsis). In addition, chronic inflammation is often harmful and is the root cause of many chronic diseases, causing severe and irreversible damage to tissues. In this case, the immune response is usually directed against one's own tissues (autoimmunity), although chronic responses to foreign entities can also lead to bystander damage to one's own tissues.

[0189] Therefore, the goal of anti-inflammatory therapy is to reduce this inflammation to suppress autoimmunity when present and allow the physiological processes or healing and tissue repair to progress.

[0190] The compounds of the present invention can be used to treat inflammation of any tissue and organ of the body, including musculoskeletal inflammation, vascular inflammation, neurological inflammation, digestive system inflammation, ocular inflammation, reproductive system inflammation and other inflammations, as exemplified below

[0191] Musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, particularly those affecting skeletal joints (including joints of the hands, wrists, elbows, shoulders, jaws, spine, neck, hips, knees, ankles, and feet), and conditions affecting tissues connecting muscle to bone (e.g., tendons). Examples of musculoskeletal inflammation treatable with the compounds of the invention include arthritis (including, e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendinitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, e.g., Paget's disease, osteitis pubis, and osteitis fibrosa cystica).

[0192] Ocular inflammation refers to inflammation of any structure of the eye, including the eyelids. Examples of ocular inflammation that can be treated with the compounds of the invention include blepharitis, blepharchalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eyes), scleritis, trichiasis, and uveitis.

[0193] Examples of inflammatory diseases 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.

[0194] Examples of inflammatory diseases of the vasculature or lymphatic system that may be treated with the compounds of the invention include arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

[0195] Examples of inflammatory disorders of the digestive system that may be treated with the compounds of the invention include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), ileitis, and proctitis.

[0196] Examples of inflammatory disorders 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.

[0197] The compounds of the invention are useful for treating autoimmune conditions with an inflammatory component. Such conditions include universal acute disseminated alopecia, Behcet's disease, Chagas disease, STING-associated vasculitis of infancy (SAVI), Aicardi Goutieres syndrome (AGS), lupus pernio, ataxia telangiectasia (also known as Louis-Bar syndrome), retinal vasculopathy with leukodystrophy (RCVL), ANCA-associated vasculitis, chronic fatigue syndrome, autonomic dysfunction, encephalomyelitis, ankylosing spondylitis, aplastic anemia, suppurative hidradenitis, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes, giant cell arteritis, goodp Asture syndrome, Graves disease, Guillain-Barre syndrome, Hashimoto disease, Henoch-Schonlein purpura, Kawasaki disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter 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.

[0198] The compounds of the invention are useful for treating T cell-mediated hypersensitivity diseases with an inflammatory component. These conditions include contact hypersensitivity, contact dermatitis (including dermatitis caused by poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0199] Other inflammatory conditions that may be treated with the compounds of the invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, pneumonia, prostatitis, pyelonephritis, stomatitis, transplant rejection (affecting organs such as the kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small intestine, skin allografts, skin allografts, and heart valve xenografts, serum sickness, and graft-versus-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sezary syndrome, congenital adrenal hyperplasia, non-suppurative Thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug allergic reaction, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, chemotherapy for fulminant or disseminated pulmonary tuberculosis, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphoma in adults, acute leukemia in children, local enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis. Preferred treatments include 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 diseases (eg, sepsis). In one embodiment, the compounds of the invention are useful for treating asthma.

[0200] Cell proliferation

[0201] The compounds of the invention may also be used to treat one or more diseases affecting mammals characterized by cell proliferation in the field of disorders associated with neovascularization and / or vascular permeability, including vascular proliferative diseases, including arthritis (rheumatoid arthritis) and restenosis; fibrotic diseases, including cirrhosis and atherosclerosis; mesangial cell proliferative diseases, including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, proliferative retinopathy, organ transplant rejection and glomerulopathy; and metabolic disorders, including psoriasis, diabetes, chronic wound healing, inflammation and neurodegenerative diseases.

[0202] Neurodegenerative diseases

[0203] 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).

[0204] combination

[0205] The compounds of the present invention can be used alone or in combination with other therapeutic agents. As modulators of immune responses, the compounds of the present invention can also be used in monotherapy or in combination with another therapeutic agent for the treatment of diseases and conditions in which regulation of STING is beneficial. Therefore, the combination therapy according to the present invention comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent. In one embodiment, the combination therapy according to the present invention comprises administering at least one compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent. The compound of Formula I and its pharmaceutically acceptable salt and the other therapeutic agent can be administered together or separately in a single pharmaceutical composition, and when administered separately, this can be performed simultaneously or sequentially in any order. The amount of the compound of Formula I and its pharmaceutically acceptable salt and the other therapeutic agent and the relative time of administration will be selected to achieve the desired combined therapeutic effect. Therefore, in another aspect, a combination is provided, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents.

[0206] The compounds of Formula I and pharmaceutically acceptable salts thereof can be used in combination with one or more other therapeutic agents that can be used to prevent or treat allergic diseases, inflammatory diseases or autoimmune diseases, for example; antigen immunotherapy, antihistamines, steroids, nonsteroidal anti-inflammatory drugs, bronchodilators (e.g., β2 agonists, adrenergic agonists, anticholinergics, theophylline), methotrexate, leukotriene modifiers and similar drugs; monoclonal antibody therapy, such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar drugs; receptor therapy, such as etanercept and similar drugs; antigen nonspecific immunotherapy (e.g., interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists and similar agents).

[0207] The compounds of formula I and their pharmaceutically acceptable salts can be used in combination with radiotherapy and / or surgery and / or at least one other therapeutic agent that can be used to treat cancer and precancerous syndromes. Any anti-tumor agent that is active against the susceptible tumor being treated can be used in combination. Typical anti-tumor agents that can be used 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), oxazolidinones, alkyl sulfonates (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 podophyllotoxins (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 camptothecins (e.g., irinotecan, topotecan and the various optical forms of 7-(4-methylpiperazinyl-methylene)-10,11-ethylenedioxy-20-camptothecin); (h) hormones and hormone analogs (e.g., adrenocortical hormones used to treat childhood malignant lymphomas and acute leukemias, such as Prednisone and prednisolone; aminoglutamine and other aromatase inhibitors, such as anastrozole, letrozole, vorozole, and exemestane, can be used to treat adrenocortical carcinoma and hormone-dependent breast cancer that contain estrogen receptors; progestins, such as megestrol acetate, can be used to treat hormone-dependent breast cancer and endometrial cancer; estrogens and anti-estrogens, such as fulvestrant, flutamide, nilutamide, bicalutamide, cyproterone acetate, and 5-reductase inhibitors, such as finasteride and dutasteride, can be used to treat prostate cancer and benign prostatic hypertrophy; anti-estrogens, such as tamoxifen, toremifene, raloxifene, droloxifene, edoxifene, 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, which are useful for treating hormone-dependent breast cancer and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and its analogs, which stimulate the release of luteinizing hormone (LH) and / or follicle-stimulating hormone (FSH) to treat prostate cancer, e.g., LHRH agonists and antagonists, such as goserelin acetate and leuprolide); (i) signal transduction pathway inhibitors; (j) non-receptor tyrosine angiogenesis inhibitors;(k) immunotherapeutic agents (e.g., ex vivo and in vivo methods of increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, methods of reducing T cell energy, methods using transfected immune cells (e.g., dendritic cells transfected with cytokines), methods using tumor cell lines transfected with cytokines, and methods using anti-idiotypic antibodies); (l) pro-apoptotic agents (e.g., bcl-2 antisense oligonucleotides); (m) cell cycle signaling inhibitors; (n) immuno-oncology agents and (o) immunostimulatory agents. ;

[0208] Signal transduction pathway inhibitors

[0209] Signal transduction pathway inhibitors are those that block or inhibit the chemical processes that cause changes in cells. As used herein, such changes are cell proliferation or differentiation. Signal transduction inhibitors that can be used in the present invention include receptor tyrosine kinase inhibitors, non-receptor tyrosine kinase inhibitors, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidylinositol 3-kinases, inositol signaling and Ras oncogenes.

[0210] Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in regulating cell growth. Such protein tyrosine kinases can be broadly classified as either receptor or non-receptor kinases.

[0211] Receptor tyrosine kinases are transmembrane proteins with 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 commonly referred to as growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e., aberrant kinase growth factor receptor activity, e.g., by overexpression or mutation, has been shown to lead to uncontrolled cell growth. Therefore, aberrant activity of such kinases is associated with malignant tissue growth. Therefore, inhibitors of such kinases may provide a cancer therapy approach. 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 receptor (TrkA, TrkB and TrkC), ephrin (eph) receptor and RET proto-oncogene. Several growth receptor inhibitors 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.

[0212] Tyrosine kinases that are not growth factor receptor kinases are called non-receptor tyrosine kinases. Non-receptor tyrosine kinases that can be used in the present invention are targets or potential targets of anticancer drugs, including cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons tyrosine kinase and Bcr-Abl. Such non-receptor kinases and agents that inhibit the function of non-receptor tyrosine kinases are described in Sinh 1999; and Bolen 1997.

[0213] SH2 / SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins, including PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2), and Ras-GAP. SH2 / SH3 domains as targets for anticancer drugs were discussed in Smithgall 1995.

[0214] Serine / threonine kinase inhibitors, including 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 member blockers, including PKC blockers (α, β, γ, ε, μ, λ, η, ζ). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members and TGFβ receptor kinase. Such serine / threonine kinases and their inhibitors are described in Yamamoto 1999; Brodt 2000; Massagué 1996; Philip 1995; Lackey 2000; U.S. Patent No. 6268391; and Martínez-Lacaci 2000.

[0215] Inhibitors of members of the phosphatidylinositol-3 kinase family, including blockers of Pekinese, ATM, DNA-PK and Ku, may also be used in the present invention. Such kinases are discussed in Abraham 1996; Canman 1998; Jackson 1997; and Zhong 2000.

[0216] Also useful in the present invention are inositol signaling inhibitors, such as phospholipase C blockers and inositol analogs. Such signaling inhibitors are described in Powis 1994.

[0217] Another group of signal transduction pathway inhibitors are Ras oncogene inhibitors. This class of inhibitors includes inhibitors of farnesyltransferase, geranyl-geranyltransferase, and CAAX proteases as well as antisense oligonucleotides, ribozymes, and immunotherapies. This class of inhibitors has 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.

[0218] As mentioned above, antibody antagonists of receptor kinase ligand binding can also be used as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies directed against the extracellular ligand binding domain of receptor tyrosine kinases. For example, Imclone C225 EGFR-specific antibody (see Green 2000); erbB2 antibody (see Stern 2000); and 2CB VEGFR2-specific antibody (see Brekken 2000).

[0219] Non-receptor tyrosine angiogenesis inhibitors

[0220] Anti-angiogenic therapeutics, including non-receptor MEK angiogenesis inhibitors, may also be useful. Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, (e.g., the anti-vascular endothelial growth factor antibody bevacizumab [Avastin TM ]), as well as compounds that act through other mechanisms (e.g., linomide, inhibitors of integrin αvβ3 function, endostatin, and angiostatin).

[0221] Cell cycle signaling inhibitors

[0222] 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 of the eukaryotic cell cycle. Cooperative activation and inactivation of different cyclin / CDK complexes are necessary for the normal progression of the cell cycle. Several cell cycle signaling inhibitors 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.

[0223] Immunomodulators

[0224]

[00136] Additional examples of other therapeutic agents (eg, anti-neoplastic agents) for combined or co-administration with a compound of Formula I are immunomodulators.

[0225] As used herein, "immunomodulator" refers to any substance including monoclonal antibodies that affect the immune system. Immunomodulators can be used as anti-tumor 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 (Odivo / 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.

[0226] Anti-PD-L1 agents

[0227] Another example of other therapeutic agents (anti-tumor agents) administered in combination or co-administered with the compounds of the present invention is an anti-PD-L1 agent. Anti-PD-L1 antibodies and methods for preparing them are known in the art. Such antibodies against PD-L1 can be polyclonal or monoclonal, and / or recombinant, and / or humanized. Exemplary PD-L1 antibodies are disclosed in U.S. Patent Nos. 8217149, 8383796, 8552154, 9212224, and 8779108 and U.S. Patent Application Publication Nos. 2011 / 0280877, 2014 / 0341902, and 2013 / 0045201. Other exemplary antibodies and methods of use for PD-L1 (also known as CD274 or B7-H1) are disclosed in U.S. Patent Nos. 7943743, 8168179, and 7595048; WO2014 / 055897, WO2016 / 007235; and U.S. Patent Application Publication Nos. 2013 / 0034559 and 2015 / 0274835. PD-L1 antibodies are being developed as immunomodulators for the treatment of cancer.

[0228] In one embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. Patent No. 8217149. In another embodiment, the anti-PD-L1 antibody comprises the CDR of the antibody disclosed in U.S. Patent No. 8217149. In another embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. Patent No. 8779108. In another embodiment, the anti-PD-L1 antibody comprises the CDR of the antibody disclosed in U.S. Application No. 8779108. In another embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. Patent Application Publication No. 2013 / 0045201. In another embodiment, the anti-PD-L1 antibody comprises the CDR of the antibody disclosed in U.S. Patent Application Publication No. 2013 / 0045201. In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105), which is described in WO2007 / 005874. In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446). In another embodiment, the anti-PD-L1 antibody is MEDI4736, which is an anti-PD-L1 monoclonal antibody described in WO2011 / 066389 and US 2013 / 034559. In another embodiment, the anti-PD-L1 antibody is TECENTRIQ TM(atezolizumab), which is an anti-PD-L1 cancer immunotherapy, was approved in the United States in May 2016 for a specific type of bladder cancer. In another embodiment, the anti-PD-L1 antibody is YW243.55.S70, which is an anti-PD-L1 described in WO2010 / 077634 and U.S. Patent No. 8217149. Examples of anti-PD-L1 antibodies that can be used in the methods of the present invention and methods for making them are described in PCT patent applications WO 2010 / 077634, WO 2007 / 005874, WO2011 / 066389, U.S. Patent No. 8217149 and US 2013 / 034559.

[0229] PD-1 antagonists

[0230] Another example of other therapeutic agents (anti-tumor agents) administered in combination or co-administered with the compounds of the present invention is a PD-1 antagonist. "PD-1 antagonist" means blocking 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 blocking the binding of PD-L2 expressed on cancer cells to PD-1 expressed by immune cells. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCDDILI, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any embodiment of the aspects of the invention or embodiments of the invention, wherein a human subject is to be treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, preferably blocks the binding of human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be found in NCBI locus number: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found in NCBI locus numbers: NP_054862 and NP_079515, respectively.

[0231] PD-1 antagonists that can be used in any aspect of the present invention include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, preferably to human PD-1 or human PD-L1. mAbs can be human antibodies, humanized antibodies, or chimeric antibodies, and can include human constant regions. 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.

[0232] Examples of mAbs that bind to human PD-1 and are useful in various aspects and embodiments of the invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004 / 004771, WO2004 / 072286, WO2004 / 056875 and US2011 / 0271358. Specific anti-human PD-1 mAbs used as PD-1 antagonists in any aspects and embodiments of the invention include: MK-3475, a humanized IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013), and comprising the heavy chain and light chain amino acid sequences shown in Figure 6; nivolumab, a human IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 1, pp. 68-69 (2013), and comprising the heavy chain and light chain amino acid sequences shown in Figure 7; humanized antibodies h409All, h409A16 and h409A17 described in WO2008 / 156712, and AMP-514 developed by Medimmune.

[0233] Other PD-1 antagonists useful in any aspect and embodiment of the invention include immunoadhesins that specifically bind to PD-1, preferably to human PD-1, for example, fusion proteins containing an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., 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. Specific fusion proteins used as PD-1 antagonists in the methods of treatment, medicaments, and uses of the invention include AMP-224 (also referred to as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.

[0234] Other examples of mAbs that bind to human PD-L1 and can be used in the methods of treatment, medicines and uses of the present invention are described in WO2013 / 019906, WO2010 / 077634 and US8383796. Specific anti-human PD-L1 mAbs used as PD-1 antagonists in the methods of treatment, medicines and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C.

[0235] 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.

[0236] Opdivo / Nivolumab is a full-length human monoclonal antibody marketed by Bristol Myers Squibb that targets 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 and blocks the activation of the Ig superfamily transmembrane protein PD-1 through its ligands PD-L1 and PD-L2, thereby activating T cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T cell activation and effector function by inhibiting PI3K / Akt pathway activation. Other names for Nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence for Nivolumab and methods of use and preparation are disclosed in U.S. Patent No. US 8008449.

[0237] Antibodies against ICOS

[0238] Another example of other therapeutic agents (anti-tumor agents) for co-administration or co-administration with a compound of Formula I is an antibody against ICOS. ICOS is a co-stimulatory T cell receptor with a structural and functional relationship with the CD28 / CTLA-4-Ig superfamily (Hutloff 1999). Activation of ICOS occurs through binding of ICOS-L (B7RP-1 / B7-H2). Neither B7-1 nor B7-2 (ligands for CD28 and CTLA4) binds to or activates ICOS. However, ICOS-L has been shown to bind weakly to CD28 and CTLA-4 (Yao 2011). The expression of ICOS appears to be limited to T cells. ICOS expression levels vary between different T cell subsets and T cell activation states. ICOS expression has been shown on resting TH17, T follicular helper cells (TFH), and regulatory T (Treg) cells; however, unlike CD28; it is not highly expressed in naive TH1 and TH2 effector T cell populations (Paulos 2010). ICOS expression is highly induced on both CD4+ and CD8+ effector T cells following activation via TCR engagement (Wakamatsu 2013).

[0239] The CDRs of mouse antibodies against human ICOS with agonist activity are shown in PCT / EP2012 / 055735 (WO2012 / 131004). Antibodies to ICOS are also disclosed in WO 2008 / 137915, WO 2010 / 056804, EP1374902, EP1374901 and EP1125585. Agonist antibodies to ICOS or ICOS binding proteins are disclosed in WO2012 / 131004, WO2014 / 033327, WO2016 / 120789, US20160215059 and US20160304610. In one embodiment, an agonist antibody to ICOS comprises an ICOS binding protein, or an antigen binding portion thereof, comprising one or more of: CDRH1 as shown in SEQ ID NO: 1; CDRH2 as shown in SEQ ID NO: 2; CDRH3 as shown in SEQ ID NO: 3; CDRL1 as shown in SEQ ID NO: 4; CDRL2 as shown in SEQ ID NO: 5 and / or CDRL3 as shown in SEQ ID NO: 6, or a direct equivalent of each CDR, wherein the direct equivalent has no more than two amino acid substitutions in the CDRs disclosed in WO2016 / 120789 (which is incorporated herein by reference in its entirety). In one embodiment, the ICOS binding protein or its antigen binding portion is an agonist antibody to ICOS, comprising a VH domain and / or a VL domain, the VH domain comprising an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO:7, the VL domain comprising an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO:8, as shown in WO2016 / 120789, wherein the ICOS binding protein specifically binds to human ICOS. In one embodiment, the ICOS binding protein is an agonist antibody to ICOS, comprising a VH domain and a VL domain, the VH domain comprising the amino acid sequence shown in SEQ ID NO:7, the VL domain comprising the amino acid sequence shown in SEQ ID NO:8, as shown in WO2016 / 120789. Yiwo (ipilimumab) is a full-length human CTLA-4 antibody marketed 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.

[0240] CD134, also known as OX40, is a member of the TNFR receptor superfamily and, unlike CD28, is not constitutively expressed on resting naive T cells. OX40 is a secondary co-stimulatory molecule expressed 24 to 72 hours after activation; its ligand OX40L is also not expressed on resting antigen-presenting cells, but is expressed after their activation. The expression of OX40 depends on the full activation of T cells; in the absence of CD28, the expression of OX40 is delayed and the level is reduced fourfold. OX-40 antibodies, OX-40 fusion proteins and methods of use thereof are disclosed in U.S. Patent Nos.: US 7504101; US ​​7758852; US 7858765; US 7550140; US7960515; WO2012 / 027328; WO2013 / 028231. In one embodiment, the OX40 antigen binding protein is one disclosed in WO2012 / 027328 (PCT / US2011 / 048752), filed on August 23, 2011. In another embodiment, the antigen binding protein comprises a CDR of an antibody disclosed in WO2012 / 027328 (PCT / US2011 / 048752), filed on August 23, 2011, or a CDR with 90% identity to the disclosed CDR sequence. In another embodiment, the antigen binding protein comprises a VH, VL, or both of an antibody disclosed in WO2012 / 027328 (PCT / US2011 / 048752), filed on August 23, 2011, or a VH or VL with 90% identity to the disclosed VH or VL sequence.

[0241] In another embodiment, the OX40 antigen binding protein is disclosed in WO2013 / 028231 (PCT / US2012 / 024570), which has an international filing date of 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), which has an international filing date of February 9, 2012, or a CDR having 90% identity with the disclosed CDR sequence. In a further embodiment, the antigen binding protein comprises a VH, a VL, or both of an antibody disclosed in WO2013 / 028231 (PCT / US2012 / 024570), which has an international filing date of February 9, 2012, or a VH or a VL having 90% identity with the disclosed VH or VL sequence. In one embodiment, the OX40 antigen binding protein is an isolated OX40 agonist antibody comprising a light chain variable region having a sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 10 as shown 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 shown in WO2013 / 028231. In one embodiment, the OX40 antigen binding protein is an isolated antibody comprising a light chain variable region having an amino acid sequence of SEQ ID NO: 10 as shown in WO2013 / 028231 and a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 4 as shown in WO2013 / 028231.

[0242] Immunostimulants

[0243] Another example of other therapeutic agents for co-administration or co-administration with a compound of Formula I or its salt is an immunostimulant. As used herein, an "immunostimulant" refers to any agent that can stimulate the immune system. As used herein, immunostimulants include but are not limited to vaccine adjuvants, such as Toll-like receptor agonists, T cell checkpoint blockers, such as mAbs and T cell checkpoint agonists for PD-1 and CTL4, such as agonist mAbs for OX-40 and ICOS. As used herein, an "immunostimulant" refers to any agent that can stimulate the immune system. As used herein, immunostimulants include but are not limited to vaccine adjuvants.

[0244] As used herein, the term "Toll-like receptor" (or "TLR") refers to a member of the Toll-like receptor protein family or a fragment thereof, which senses microbial products and / or triggers an adaptive immune response. In one embodiment, TLR activates dendritic cells (DC). Toll-like receptors (TLRs) are a family of pattern recognition receptors, originally identified as sensors of the innate immune system that recognize microbial pathogens. TLRs recognize different structures in microorganisms, commonly referred to as "PAMPs" (pathogen-associated molecular patterns). Ligands bound to TLRs trigger intracellular cascade signal transduction pathways that induce the production of factors involved in inflammation and immunity. In humans, ten TLRs have been identified. TLRs expressed on the cell surface include TLR-1, TLR-2, TLR-4, TLR-5, and TLR-6, ​​while TLR-3, TLR-7 / 8, and TLR-9 are expressed in the ER compartment. Human DC subsets can be identified based on different TLR expression patterns. For example, myeloid or "conventional" DC subsets (mDC) express TLR 1-8 when stimulated and produce a range of activation markers (e.g., CD80, CD86, MHC class I and class II, CCR7), proinflammatory cytokines, and chemokines. The result of this stimulation and the resulting expression is the initiation of antigen-specific CD4+ and CD8+ T cells. These DCs acquire an enhanced ability to absorb antigens and present them to T cells in an appropriate form. In contrast, the plasmacytoid subset of DC (pDC) only expresses TLR7 and TLR9 when activated, thereby activating NK cells as well as T cells. Since dying tumor cells may adversely affect DC function, it has been suggested that activating DCs with TLR agonists may be beneficial in eliciting anti-tumor immunity in immunotherapy for cancer treatment. It has also been suggested that the successful treatment of breast cancer with radiotherapy and chemotherapy requires activation of TLR4.

[0245] TLR agonists known in the art and 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; polyadenosine-polyuridylic acid (poly AU), a TLR3 agonist; polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (Hiltonol), a TLR3 agonist; bacterial flagellin TLR5 agonist; imiquimod, a TLR7 agonist; resiquimod, a TLR7 / 8 agonist; loxoribine, a TLR7 / 8 agonist; and unmethylated CpG dinucleotides (CpG-ODN), a TLR9 agonist.

[0246] Other TLR agonists known in the art and found to be useful in the present invention also include, but are not limited to, aminoalkyl glucosamine phosphate (AGP) bound to the TLR4 receptor, which is known to be used as a vaccine adjuvant and an immunostimulant for stimulating cytokine production, activating macrophages, promoting innate immune responses, and increasing the production of antibodies in immune animals. An example of a naturally occurring TLR4 agonist is bacterial LPS. An example of a semisynthetic TLR4 agonist is monophosphoryl lipid A (MPL). AGP and its immunomodulatory effects through TLR4 are disclosed in patent publications, such as WO2006 / 016997, WO 2001 / 090129 and / or U.S. Patent No. 6113918, and have been reported in the literature. Additional AGP derivatives are disclosed in U.S. Patent No. 7129219, U.S. Patent No. 6525028 and U.S. Patent No. 6911434. Some AGPs act as agonists of TLR4, while others are considered to be TLR4 antagonists.

[0247] In addition to the above-mentioned immunostimulants, the compositions of the present invention may further comprise other therapeutic agents, which, due to their adjuvant properties, can stimulate the immune system to respond to cancer antigens present on inactivated tumor cells. Such adjuvants include, but are not limited to, lipids, liposomes, inactivated bacteria (e.g., inactivated or attenuated Listeria) that induce innate immunity, compositions that mediate innate immune activation through (NOD)-like receptors (NLRs), retinoic acid-induced gene (RIG)-I-like receptors (RLRs) and / or C-type lectin receptors (CLRs). Examples of PAMPs include lipoproteins, lipopolypeptides, peptidoglycans, yeast polysaccharides, neisseria porins, flagellins, profilin, galactosylceramide, muramyl dipeptide. Peptidoglycans, lipoproteins, and lipoteichoic acid are cell wall components of gram-positive bacteria. Most bacteria express lipopolysaccharides, and MPL is an example. Flagellin refers to the 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 biologically active peptidoglycan motif shared by all bacteria.

[0248] Due to their adjuvant properties, TLR agonists are preferably used in combination with other vaccines, adjuvants and / or immunomodulators, and can be used in combination in a variety of combinations. Thus, in certain embodiments, the compounds of Formula I described herein that bind to STING and induce STING-dependent TBKI activation and inactivated tumor cells that express and secrete one or more cytokines that stimulate DC induction, recruitment and / or maturation, as described herein, can be administered together with one or more TLR agonists for therapeutic purposes.

[0249] Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that regulates anti-tumor immune responses by promoting the generation of regulatory T cells and blocking effector T cell activation, thereby promoting tumor growth by allowing cancer cells to avoid immune surveillance (Lemos 2016; Munn 2016). The other active ingredient (antitumor agent) for combined or co-administered with the compound of Formula I of the present invention is an IDO inhibitor. Epacadostat, ((Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-[2-(aminosulfonylamino)ethylamino]-1,2,5-oxadiazole-3-carboxamidine) is a highly potent and selective oral inhibitor of the IDO1 enzyme that can reverse tumor-related immunosuppression and restore effective anti-tumor immune responses. Epacadostat is disclosed in U.S. Patent No. 8034953.

[0250] Further examples of other therapeutic agents (anti-tumor agents) that are administered in combination or co-administered with a compound of Formula I are CD73 inhibitors and A2a and A2b adenosine antagonists.

[0251] The compounds of Formula I and pharmaceutically acceptable salts thereof may be used in combination with at least one other therapeutic agent for preventing or treating bacterial and viral infections. Examples of such agents include, but are not limited to, polymerase inhibitors, such as those disclosed in WO 2004 / 037818, and those disclosed in WO 2004 / 037818 and WO 2006 / 045613; JTK-003, JTK-019, NM-283, HCV-796, R-803, R1728, R1626, and those disclosed in WO 2006 / 018725, WO 2004 / 074270, WO 2003 / 095441, US 2005 / 0176701, WO 2006 / 020082, WO 2005 / 080388, WO 2004 / 064925, WO 2004 / 065367, WO 2003 / 007945, WO 02 / 04425、WO 2005 / 014543、WO 2003 / 000254、EP 1065213、WO 01 / 47883、WO 2002 / 057287、WO 2002 / 057245 and similar agents; replication inhibitors such as acyclovir, famciclovir, ganciclovir, cidofovir, lamivudine and similar agents; protease inhibitors such as the HIV protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and 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, amdosovir, and similar agents; xovir), elvucitabine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate / hemifumarate, and similar agents; non-nucleoside reverse transcriptase inhibitors (including agents with antioxidant activity, such as immunocal, oltipraz, etc.), such as nevirapine, delavirdine, efavirenz, loviramide, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, rilpivirine, and similar agents; 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 viraviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-427,857), TAK449, and in WO 02 / 74769, WO 2004 / 054974, WO 2004 / 055012, WO 2004 / 055010, WO 2004 / 055016, WO 2004 / 055011 and WO 2004 / 054581, and similar agents; pharmacokinetic enhancers, such as cobicistat; neuraminidase inhibitors, such as CS-8958, zanamivir, oseltamivir, peramivir, and similar agents; ion channel blockers, such as amantadine or rimantadine, and similar agents; interfering RNA and antisense oligonucleotides, such as ISIS-14803, and similar agents; antiviral agents with an undetermined mechanism of action, such as those disclosed in WO 2005 / 105761, WO 2003 / 085375, WO 2006 / 122011, ribavirin, and similar agents. The compounds of formula I and their pharmaceutically acceptable salts can also be used in combination with other therapeutic agents useful for treating Kaposi's sarcoma-associated herpes virus infections (KSHV and KSHV-associated), including but not limited to chemotherapeutic agents such as bleomycin, vinblastine, vincristine, cyclophosphamide, prednisone, alitretinoin and liposomal anthracyclines (e.g., doxorubicin, daunorubicin), immunotherapeutic agents (e.g., rituximab, tocilizumab, siltuximab) and others (e.g., paclitaxel and rapamycin). ;

[0252] In one embodiment of the invention, at least one other therapeutic agent is an antimycobacterial agent or a bactericidal antibiotic. The compound of formula I and its pharmaceutically acceptable salt can also be used in combination with at least one other therapeutic agent that can be used to treat TB infection (Mycobacterium tuberculosis) and tularemia (Franciseiia tularensis), including but not limited to first-line oral agents isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, rifabutin; injections, including kanamycin, amikacin, capreomycin, streptomycin; fluoroquinolones, including levofloxacin, moxifloxacin, ofloxacin; oral antibacterial agents, aminosalicylic acid, cycloserine, terizidone, thioamide, prothionamide; S Q-109PNU-100480, rifapentine, linezolid, PA-824, AZD5847, gatifloxacin, moxifloxacin, Sirturo (bedaquiline), delamanid (OPC-67683) and agents with unknown mechanisms of action in the treatment of drug-resistant TB, including clofazimine, linezolid, amoxicillin / clavulanic acid, thiosemicarbazone, imipenem / cilastatin, high-dose isoniazid, clarithromycin, ciprofloxacin. The compounds of formula I and their pharmaceutically acceptable salts can also be combined with antimycobacterial agents (e.g., isoniazid (INH), ehambutol (ehambutol) Rifampin and pyrazinamide (PZA)), bactericidal antibiotics (e.g. rifabutin Rifapentine Aminoglycosides Fluoroquinolones (levofloxacin, moxifloxacin, ofloxacin), thioamides (ethionamide), cyclosporine Para-aminosalicylic acid Cycloserine Kanamycin Streptomycin, viomycin, capreomycin ), Bedaquiline Fumarate Oxazolidinone PNU-100480 or delamanid (OPC-67683).

[0253] The compounds of formula I and their pharmaceutically acceptable salts may also be used in combination with at least one other therapeutic agent useful for treating Chlamydia, including but not limited to azithromycin, doxycycline, erythromycin, levofloxacin, and ofloxacin.

[0254] The compounds of the present invention may also be used in combination with at least one other therapeutic agent useful for treating Plasmodium infection, including but not limited to chloroquine, atovaquone-proguanil, artemether-lumefantrine, mefloquine, quinine, quinidine, doxycycline, clindamycin, artesunate, and primaquine.

[0255] In the treatment of amyotrophic lateral sclerosis (ALS), the compound of formula I or a pharmaceutically acceptable salt thereof can be used in combination with: a glutamate blocker (riluzole ), Quinidine Anticholinergics ( Scopolamine patch (Transderm )), sympathomimetics (pseudoephedrine), mucolytics (guaifenesin), or analgesics (tramadol Ketorolac Morphine; fentanyl patch

[0256] In the treatment of multiple sclerosis, the compound of formula I or a pharmaceutically acceptable salt thereof can be used in combination with: corticosteroids (prednisone, methylprednisolone), interferon β1-A Pegylated interferon beta-1A Glatiramer acetate Glatiramer acetate ( -generic equivalent of Copaxone); dimethyl fumarate Fingolimod ); teriflunomide Dafapidine Daclizumab (Zinbryta); Alemtuzumab Natalizumab Mitoxantrone hydrochloride

[0257] The compounds of the invention can also be used as adjuvants to improve the immune response to any given antigen and / or reduce the reactogenicity / toxicity in patients (particularly humans) in need thereof. Thus, the compounds of the invention can be used in conjunction with vaccine compositions to alter, in particular enhance, the immune response, for example by increasing the level or duration of protection and / or allowing a reduction in antigen dosage.

[0258] The compound of formula I and its pharmaceutically acceptable salt can be used in combination with one or more vaccines or immunogenic antigens for preventing or treating viral infection. Such vaccines or immune antigens include but are not limited to proteins or particles derived from pathogens, such as attenuated viruses, viral particles and viral proteins commonly used as immune substances. Examples of viruses and viral antigens include, but are not limited to, poliovirus, Coronavirus family and coronavirus, rhinovirus (all subtypes), adenovirus (all subtypes), hepatitis A, hepatitis B, hepatitis C, hepatitis D, human papillomavirus (including all subtypes), rabies virus, human T-cell lymphotropic virus (all subtypes), rubella virus, mumps virus, coxsackievirus A (all subtypes), coxsackievirus B (all subtypes), human enterovirus, herpesvirus (including cytomegalovirus, Epstein-Barr virus, human herpesvirus (all subtypes), herpes simplex virus, varicella-zoster virus), human immunodeficiency virus (HIV) (all subtypes), Epstein-Barr virus, reovirus (all subtypes), filovirus (including Marbur g virus and Ebola virus (all strains)), Arenaviruses (including lymphocytic choriomeningitis virus, Lassa virus, Junin virus and Machupo virus), Arboviruses (including West Nile virus), Dengue virus (all serotypes), Zika virus, Colorado tick fever virus, Sindbis virus, Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Poxviruses including (Orthopoxviruses (Variola virus, Monkeypox virus, Vaccinia virus, Cowpox virus), Yatapoxvirus (Tanapox virus, Yaba monkey tumor virus), Parapoxvirus, Molluscum poxvirus), Yellow fever, Hantaviruses (including Hantaan, Seoul, Dobrava, Sin Nombre, Puumala and Dobrava-like Saaremaa), human parainfluenza viruses and influenza viruses (all types), H1N1 influenza and swine influenza viruses, respiratory syncytial virus (all subgroups), rotaviruses (including human rotavirus AE, bovine rotavirus, rhesus rotavirus), polyomaviruses (including simian virus 40, JC virus, BK virus, Coltiviruses, eyach viruses, Caliciviruses), and Parvoviridae (including Dependovirus, Parvovirus and Erythrovirus).

[0259] Therefore, the present invention provides an immunogenic composition comprising an antigen or antigen composition and a compound of formula I or a pharmaceutically acceptable salt thereof. A vaccine composition comprising an antigen or antigen composition and a compound of formula I or a pharmaceutically acceptable salt thereof is further provided. The compound of formula I and its pharmaceutically acceptable salt may also be used in combination with: at least one other therapeutic agent (e.g., interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists and similar agents) that can be used to prevent or treat viral infections (e.g., immunotherapy); and therapeutic vaccines, antifibrotic agents, anti-inflammatory agents (e.g., corticosteroids or NSAIDs (non-steroidal anti-inflammatory agents)) and similar drugs.

[0260] Compounds that modulate STING, 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 mesalazine preparations, hydroxychloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologics, including anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrin agents, anti-IFNα, anti-CD20 or CD4 biologics, and other cytokine inhibitors or biologics directed against T cell or B cell receptors or interleukins.

[0261] 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, can be administered in combination with at least one other therapeutic agent, including a corticosteroid (e.g., prednisolone ( Orapred, Millipred, Omnipred, Econopred, Flo-Pred), immunosuppressants (such as methotrexate Dexamethasone Mycophenolate mofetil ), B cell therapy (Belimumab B cell inhibitors ( (anti-CD22), SBI-087 (anti-CD20), anti-BAFF antibody (LY2127399, A623), ), Azathioprine ), triamcinolone acetonide Kenalog- ), Hydroxychloroquine Thalidomide Immunoglobulin therapy Anti-interferon-α therapy AGS- IFN Kinoid), TLR7 and TLR9 blockers (IMO-3100), anti-cytokine therapy (anti-IL6 (CNTO-136), anti-interferon-γ (AMG811), immunomodulatory therapy (Lupuzor TM , Abatacept, AMG557, laquinimod, paquimod, leflunomide, anti-ICOS (Medi-570), anti-CD40 ligand antibody (CDP7657)) and / or platelet aggregation inhibitor (aspirin).

[0262] In the treatment of vasculitis and diseases associated with small and medium vessel inflammation, compounds that modulate STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, can be administered in combination with alkylating agents (cyclophosphamide, ), anti-rheumatic anti-CD20 antibody and anti-TNF inhibitors Combined administration.

[0263] In the treatment of psoriasis, compounds that modulate STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, may be administered in combination with ixekizumab, tirazumab (MK-3222) or secukinumab (AIN457). In one embodiment of the invention, 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 administered in combination with an inhaled corticosteroid (ICS), such as fluticasone propionate. Beclomethasone dipropionate Budesonide (Pulmicort), trocitinide Flunisolide Mometasone Acid Ciclesonide ), long-acting beta-agonists (LABAs, such as formoterol fumarate Salmeterol Xinafoate ), ICS and LABA combinations (e.g., fluticasone furoate and vilanterol (Breo ), formoterol / budesonide inhaler Beclomethasone dipropionate / formoterol and fluticasone propionate / salmeterol ), short-acting beta-agonists (SABAs), such as albuterol sulfate ( Proventil Ventolin Inhalation solution), levosalbuterol tartrate ( HFA), ipratropium / salbutamol Ipratropium bromide ( HFA), leukotriene modifiers (such as montelukast sodium Zafirlukast or Qiliutong and anti-IgE (eg, omalizumab ), methylxanthine bronchodilators (eg, theophylline ( Quibron- Slo- Slo- Theo- Theo- Uni- ), mast cell inhibitors (such as sodium cromoglycate Nedocromil sodium ), long-acting muscarinic antagonists (LAMA), such as mometasone furoate / formoterol fumarate dihydrate ).

[0264] Other agents that may be suitable for combination therapy in the treatment of asthma include protein tyrosine kinase inhibitors (masitinib), CRTH2 / D-prostaglandin receptor antagonists (AMG 853), indacaterol Epinephrine inhalation aerosol (E004), fluticasone furoate / fluticasone propionate, vinanterol inhalation / fluticasone furoate powder (Relovair TM ), Fluticasone Propionate / Formoterol Fumarate Dehydrating Agent reslizumab, salbutamol dry powder inhaler, tiotropium Formoterol / Budesonide Fluticasone furoate Vectura's VR506, lebrikizumab (RG3637), and a phosphodiesterase (PDE)-3 and (PDE)-4 inhibitor (RPL554) in combination.

[0265] In one embodiment of the invention, 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, a long-acting beta agonist, a short-acting beta agonist, and an inhaled corticosteroid. For example, in the treatment of COPD, a compound that modulates STING, particularly a compound of Formula I or a pharmaceutically acceptable salt thereof, can be administered in combination with a LABA (e.g., salmeterol xinafoate (Serevent), umeclidinium / vilanterol (Anoro ), Incrose ), Aformoterol tartrate Formoterol Fumarate Inhalation Powder Indacaterol Maleate or fluticasone propionate / efomoterol fumarate dehydrating agent ), long-acting inhaled anticholinergics (or muscarinic antagonists, such as tiotropium and aclidinium bromide Phosphodiesterase (PDE-r) inhibitors (eg, roflumilast, ), ICS / LABA combinations (e.g., fluticasone furoate and vilanterol (Breo ), Fluticasone Propionate / Salmeterol Budesonide / Formoterol Mometasone / Formoterol Ipratropium bromide / salbutamol sulfate Salbutamol / ipratropium bromide (Combivent )), SABA (such as ipratropium bromide and salbutamol sulfate ) and ICS (eg, budesonide and fluticasone propionate Beclomethasone dipropionate

[0266] Other agents that may be suitable for combination therapy in the treatment of COPD include SCH527123 (CXCR2 antagonist), glycopyrrolate (NVA237) ), glycopyrrolate and indacaterol maleate ((QVA149) ), glycopyrrolate and formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol Tiotropium bromide / Odatero and aclidinium / formoterol inhaler.

[0267] In one embodiment of the invention, 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 scleroderma, compounds that modulate STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, can be administered in combination with oral corticosteroids (e.g., prednisolone ( Orapred, Millipred, Omnipred, Econopred, Flo-Pred), immunosuppressants (such as methotrexate Cyclosporine Antithymocyte globulin Mycophenolate mofetil Cyclophosphamide FK506 (tacrolimus), thalidomide Chlorambucil Azathioprine ), calcium channel blockers (such as nifedipine or nicardipine Topical emollients (nitroglycerin ointment), ACE inhibitors (eg, lisinopril Diltiazem ( Cardizem Cardizem )), serotonin reuptake inhibitors (such as fluoxetine ), endothelin-1 receptor inhibitors (e.g. bosentan Epoprostenol ), antifibrotic agents (e.g. colchicine Para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO), and D-penicillamine Interferon alpha and interferon gamma (INF-g), proton pump inhibitors (eg, omeprazole Metoclopramide Lansoprazole Esomeprazole Pantoprazole Rabeprazole ) or imatinib ARG201 (arGentis Pharmaceutical), belimumab Tocilizumab

[0268] In the treatment of Sjögren's syndrome, compounds that modulate STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, may be administered in combination with: anti-rheumatic agents (hydroxychloroquine and ), cholinergic agonists JAK inhibitors ( and anti-TNF therapy In one embodiment of the invention, at least one other therapeutic agent is ciliary neurotrophic growth factor or a gene transfer agent. For example, in the treatment of retinitis pigmentosa, a compound that modulates STING, particularly a compound of Formula I or a pharmaceutically acceptable salt thereof, can be administered with ciliary neurotrophic growth factor (NT-501-CNTF) or a gene transfer agent. Combined administration.

[0269] In one embodiment of the invention, at least one other therapeutic agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent attenuated live influenza vaccine, an antiviral agent, or an inactivated influenza vaccine. For example, in the treatment of influenza, a compound that modulates STING, particularly a compound of Formula I or a pharmaceutically acceptable salt thereof, can be administered in combination with a trivalent (IIV3) inactivated influenza vaccine (e.g. ), quadrivalent (IIV4) inactivated influenza vaccine (e.g. Quadrivalent, Quadrivalent, Quadrivalent), trivalent recombinant influenza vaccine (e.g. ), quadrivalent live attenuated influenza vaccine (e.g. Quadrivalent), antiviral agents (such as oseltamivir Zanamivir Rimantadine or amantadine ),or Fludase, Preflucel or

[0270] In the treatment of staphylococcal infections, compounds that modulate STING, particularly compounds of Formula I or pharmaceutically acceptable salts thereof, may be administered in combination with antibiotics (e.g., β-lactam cephalosporins ( etc.), nafcillin Sulfonamides (sulfamethoxazole and trimethoprim Sulfasalazine Acetylsulfadiazine etc.) or vancomycin ).

[0271] In one embodiment of the invention, at least one other therapeutic agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, interferon gamma, an antihistamine, or an antibiotic. For example, in the treatment of atopic dermatitis, a compound that modulates STING, particularly a compound of Formula I or a pharmaceutically acceptable salt thereof, can be administered in combination with a topical immunomodulator or calcineurin inhibitor (e.g., pimecrolimus). or tacrolimus ointment ), topical corticosteroids (eg, hydrocortisone Betamethasone Fluticasone Triamcinolone acetonide Fluocinolone and clobetasol ), oral corticosteroids (such as hydrocortisone Methylprednisolone or prednisolone Immunosuppressants (eg, cyclosporine or interferon gamma (Alferon Intron A, Roferon- )), antihistamines (for itching, e.g. ), antibiotics (such as the penicillin derivative flucloxacillin or dicloxacillin Erythromycin ( T- Erythra- etc.)), nonsteroidal immunosuppressants (such as azathioprine Methotrexate Cyclosporine Mycophenolate mofetil ).

[0272] The compounds of the present invention can also be formulated as adjuvants with vaccines to regulate their activity. Such compositions may contain antibodies or antibody fragments or antigenic components, including but not limited to proteins, DNA, living or dead bacteria and / or viruses or virus-like particles, and 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 (e.g., CpG DNA or similar agents), cytokines (e.g., GM-CSF or IL-12 or similar agents). In another aspect of the present invention, a vaccine adjuvant comprising a compound of Formula I or a pharmaceutically acceptable salt thereof is provided. A vaccine composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and an antigen or antigenic composition is further provided.

[0273] Treatment

[0274] The compounds of the present invention can be used in therapeutic methods. A therapeutic method is also provided, which comprises administering a therapeutically effective amount of a compound of the present invention to a subject in need of treatment. The term "therapeutically effective amount" is an amount sufficient to show a benefit to the patient. This benefit can be at least an improvement in at least one symptom. The actual amount, rate of administration, and time course of administration will depend on the nature and severity of the condition to be treated. The prescription of treatment, such as the determination of dosage, is the responsibility of general practitioners and other doctors.

[0275] Application

[0276] The active compound or pharmaceutical composition comprising the active compound can be administered to the 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, for example, transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, an aerosol, e.g., through the mouth or nose); rectal; vaginal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, intravitreal, and intrasternal; by implantation of a reservoir, for example, subcutaneous, intravitreal, or intramuscular. The subject can be a eukaryote, an animal, a vertebrate, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a 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), ape (e.g., a gorilla, a chimpanzee, an orangutan, a gibbon), or a human.

[0277] In one embodiment for treating tumors, intratumoral injection may be used.

[0278] preparation

[0279] Although the active compound or combination of compounds can be administered alone, it is preferably provided as a pharmaceutical composition (e.g., 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 skilled in the art, and optionally other therapeutic or prophylactic agents.

[0280] Therefore, the present invention further provides a pharmaceutical composition as defined above, and a method for preparing a pharmaceutical composition, which comprises mixing at least one active compound as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers or other materials described herein.

[0281] As used herein, the term "pharmaceutically acceptable" 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 subjects (e.g., humans) without excessive toxicity, irritation, allergic response, or other problems or complications, 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.

[0282] Suitable carriers, excipients, etc. may be found in standard pharmaceutical texts, e.g. Remington Pharmaceutical Sciences , 18th edition, Mack Publishing Company, Easton, Pa., 1990.

[0283] The preparation can be conveniently present in unit dosage form and can be prepared by any method well known in the pharmaceutical field. Such a method includes the step of combining the active compound with a carrier constituting one or more auxiliary components. Typically, the preparation is prepared by uniformly and closely combining the active compound with a liquid carrier or a finely divided solid carrier or both, and then molding the product if necessary.

[0284] The formulation may be in the form of a liquid, solution, suspension, emulsion, elixir, syrup, tablet, lozenge, granules, powder, capsule, cachet, pill, ampoule, suppository, pessary, ointment, gel, paste, cream, spray, mist, foam, lotion, oil, pill, elixir or aerosol.

[0285] Formulations suitable for oral administration (e.g., by ingestion) can be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a pill; as a decoction; or as a paste.

[0286] Tablets can be made by conventional methods, for example, compression or molding, optionally using one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active compound in a free-flowing form (e.g., powder or granules) in a suitable machine, optionally mixed with one or more of the following items: binders (e.g., povidone, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropyl methylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silicon dioxide); disintegrants (e.g., sodium starch glycolate, cross-linked polyvidone, cross-linked sodium carboxymethylcellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); and preservatives (e.g., methylparaben, propylparaben, 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 may optionally be coated or scored and may be formulated to provide slow or controlled release of the active compound therein, for example using hydroxypropylmethylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach.

[0287] Preparations suitable for topical administration (e.g., transdermal, intranasal, ophthalmic, oral, and sublingual) can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. Alternatively, the preparation can include a patch or dressing, such as a bandage or adhesive plaster, impregnated with the active compound and optionally one or more adjuvants or diluents.

[0288] Formulations suitable for topical administration in the mouth include lozenges containing the active compound on a flavored basis, usually sucrose and acacia or tragacanth; pastilles containing the active compound on an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active compound in a suitable liquid carrier.

[0289] Formulations suitable for external 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.

[0290] Formulations suitable for nasal administration, where the carrier is a solid, include coarse powders having, for example, a particle size in the range of about 20 to about 500 microns, which are administered in the manner of snuff, i.e., rapid inhalation through the nasal passages from a powder container close to the nose. Suitable formulations, where the carrier is a liquid for administration as, for example, a nasal spray, nasal drops, or an aerosol by a nebulizer, include aqueous or oily solutions of the active compound.

[0291] Formulations suitable for administration by inhalation include those presented in the form of a pressurized aerosol spray, with the use of a suitable propellant, eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

[0292] Preparations suitable for topical application through the skin include ointments, creams and emulsions. When formulated into an ointment, the active compound can be optionally used with a paraffin or water-miscible ointment base. Alternatively, the active compound can be formulated into a cream with an oil-in-water cream base. If necessary, the aqueous phase of the cream base can include, for example, at least about 30% w / w of a polyol, i.e., an alcohol with two or more hydroxyl groups, such as propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. Topical preparations may desirably include compounds that enhance the absorption or penetration of the active compound through the skin or other affected areas. Examples of such transdermal enhancers include dimethyl sulfoxide and related analogs.

[0293] When formulated as an emulsion for external use, the oil phase may optionally comprise only an emulsifier (also referred to as an emulsion), or it may comprise a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier used as a stabilizer. It is also preferred to include both oil and fat. The emulsifier with or without a stabilizer together constitutes a so-called emulsifying wax, and the wax together with the oil and / or fat constitutes a so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

[0294] Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. Selecting suitable oil or fat for preparation is based on achieving desired cosmetic properties, because the solubility of active compound in most oils that may be used for pharmaceutical emulsion preparations may be very low. Therefore, emulsifiable paste should preferably be non-greasy, undyed and washable product, with suitable consistency to avoid leakage from pipe or other containers. Straight or branched mono- or di-alkyl esters can be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched esters called Crodamol CAP, and the latter three are preferred esters. According to desired performance, these can be used alone or in combination.

[0295] Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0296] Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0297] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active compound such carriers as are known in the art to be appropriate.

[0298] Formulations suitable for parenteral administration (e.g., by injection, including skin, subcutaneous, intramuscular, intravenous, and intradermal) include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions, which may contain antioxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents, as well as liposomes or exosomes or other microparticle systems, which are intended to be used to target the compound to blood components or one or more organs. Examples of suitable isotonic carriers for 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 formulation may be present in unit dose or multi-dose sealed containers, such as ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Ready-to-use injection solutions and suspensions can be prepared from sterile powders, granules and tablets. The formulation can be in the form of liposomes or exosomes or other particulate systems intended for targeting the active compound to blood components or one or more organs.

[0299] dose

[0300] Those skilled in the art will appreciate that the appropriate dose of the compound and the composition comprising the compound may vary from patient to patient. Determining the optimal dose generally involves a balance between the level of therapeutic benefit and any risk or harmful side effects. The dose level selected will depend on a variety of factors, including but not limited to the activity of the specific compound, the route of administration, the time 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 species, sex, age, weight, condition, general health and previous medical history of the patient. The amount of the compound and the route of administration will ultimately be determined by a doctor, veterinarian or clinician, although the dose is usually selected to achieve a local concentration at the site of action to achieve the desired effect without substantially causing harmful or adverse side effects.

[0301] Administration can be carried out in a single dose, continuously or intermittently (e.g., divided doses at appropriate time intervals) throughout the treatment process. Methods for determining the most effective mode of administration and dosage are well known to those skilled in the art and vary with the preparation used for treatment, the purpose of treatment, the target cell being treated, and the subject being treated. Single or multiple administrations can be performed, and dosage levels and patterns are selected by the treating physician, veterinarian, or clinician.

[0302] Typically, 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. When the active compound is a salt, ester, amide, prodrug, etc., the dosage is calculated based on the parent compound, so the actual weight used is increased proportionally.

[0303] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 100 mg, 3 times a day.

[0304] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 150 mg, twice a day.

[0305] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 200 mg, twice a day.

[0306] However, in one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 50 or about 75 mg, 3 or 4 times a day.

[0307] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 100 or about 125 mg, twice a day.

[0308] treat

[0309] As used herein, the term "treatment" in the context of treating a condition generally relates to treatment and therapy, whether human or animal (e.g., in veterinary applications), wherein some desired therapeutic effect is achieved, e.g., inhibiting progression of the condition, and includes reducing the rate of progression, halting the rate of progression, regression of the condition, improvement of the condition, and cure of the condition. Treatment as a preventative measure (i.e., prophylaxis, prevention) is also included.

[0310] As used herein, the term "therapeutically effective amount" relates to an amount of an active compound, or a material, composition or dosage comprising an active compound, which, when administered according to a desired treatment regimen, is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0311] Similarly, as used herein, the term "prophylactically effective amount" relates to an amount of an active compound, or a material, composition or dosage comprising an active compound, which, when administered according to the desired treatment regimen, is effective to produce some desired prophylactic effect, commensurate with a reasonable benefit / risk ratio.

[0312] Subjects / Patients

[0313] The subject / patient can be an animal, a mammal, a placental mammal, a marsupial (e.g., a kangaroo, a wombat), a monotreme (e.g., a platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a lagomorph (e.g., a rabbit), an avian (e.g., a bird), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a porcine (e.g., a pig), an ovine (e.g., a sheep), a bovine (e.g., a cow), 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.

[0314] Furthermore, the subject / patient may be in any developmental form thereof, such as a fetus. In a preferred embodiment, the subject / patient is a human.

[0315] General Synthesis Methods

[0316] The compounds of the present invention can be prepared using the procedures described in detail in the following general methods and use examples. The reaction conditions mentioned are illustrative and non-limiting, for example, a variety of synthetic methods can be used by those skilled in the art to synthesize the desired compounds, such as but not limited to the methods described in the literature (such as but not limited to March's Advanced Organic Chemistry: Reactions, Mechanisms and Structures, 7th Edition or Larock's Comprehensive Organic Transformations: Comprehensive Organic Transformations: A Guide to Functional Group Preparation).

[0317] Compounds of formula I as described above can be prepared by the synthetic strategies outlined below, wherein the above definitions apply. Thus, in any of the following general synthetic schemes, A 1 , A 2 , A 3 , 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 Pand Y are defined as any compound of the present invention as described herein, including formula (I) and any embodiments thereof.

[0318] General Synthesis 1

[0319]

[0320] Scheme 1a shows the synthesis of compounds having structure G4. In the presence of (a) a suitable acid (such as but not limited to acetic acid) or (b) sodium bisulfite or (c) sodium metabisulfite or (d) In the case of 1 , A 1 , A 2 , A 3 and A 4 The aldehyde G1 can be reacted with one equivalent of a substituent R 11 , A 11 , A 12 , A 13 and A 14 The aldehyde G2 is reacted with one equivalent of tetraphenylamine G3 to obtain a compound of type G4. In some examples, 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 ) reacts with one equivalent of tetraphenylamine G3 to obtain a compound of type G4. Tetraphenylamine can also be symmetrical (R C1 =R C11 , R C3 =R C13 , R C4 =R C14 In other examples, aldehydes G1 and G2 can be reacted with an equivalent amount of a dinitro / diphenylamine compound G5 using conditions such as, but not limited to, heating with sodium dithionite as shown in Scheme 1b.

[0321]

[0322] It will be appreciated by those skilled in the art that, as shown in Schemes 1a and 1b, the substituents R 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 C14 It may be a halogen atom or other suitable leaving group (e.g., boronic acid or boronic ester, -OH, -O-trifluoromethyl ether, -OC(O)allyl, etc.) to achieve transition-metal catalyzed transformations such as Ulmann, Negishi, Stille, Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig couplings, or for SnAr displacement to produce further examples of compound I type.

[0323] General Synthesis 2

[0324]

[0325] Compounds of structure G1 can be obtained by treating an appropriately substituted arene or heteroarene G6 with an alkyl lithium (such as, but not limited to, n-butyl lithium) or a lithium amide base (such as, but not limited to, lithium diisopropylamide), followed by quenching the resulting lithiated material with N,N-dimethylformamide. Compounds of structure G1 can also be obtained by bromination of intermediate G7 to form an alkyl bromide G8 using a suitable bromine source (such as, but not limited to, N-bromosuccinimide) in the presence of an initiator (such as, but not limited to, benzoyl peroxide). Oxidation of G8 can be carried out with a suitable oxidant (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 many other methods well known to those skilled in the art, such as, but not limited to, oxidation of benzyl alcohol, reaction with an organolithium compound, and reduction of an acid / ester / nitrile.

[0326] General Synthesis 3

[0327]

[0328] Scheme 3 shows a method by which compounds of formula G3 can be prepared, wherein "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, a mesylate, or a tosylate). In Scheme 3, "W" is defined as a primary amide C(=O)NH 2 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 , carboxylic acid-CO 2 H, activated acid (such as acyl halide or mixed anhydride) or nitrile -CN.

[0329] The first step to obtain a compound of formula G3 is to react a phenyl compound substituted with a suitable leaving group G9 with a diamine of type G10 and an equal amount of another phenyl compound substituted with a suitable leaving group G11 to give a bis-nitro substance G12. In some embodiments, the bis-nitro compound G12 will be symmetrical, wherein R C1 =R C11 , R C3 =R C13 , R C4 =R C14 . Alternatively, a G12-type compound can be obtained by first reacting a phenyl compound substituted with a suitable leaving group G9 with a diamine G13 monoprotected by a suitable protecting group (such as but not limited to a Boc group) to obtain an intermediate G14. Deprotection of the amine using, for example, acidic conditions yields an intermediate of type G15, which can then be reacted with a phenyl compound substituted with a suitable leaving group G11 to yield a dinitro intermediate G12. Reduction of the aromatic nitro group in compound G12 can be accomplished by methods well known to those skilled in the art, including but not limited to, using 10% Pd / C or Raney nickel in a hydrogen atmosphere, using iron or zinc in an acidic medium, or using sodium dithionite for catalytic hydrogenation to yield a tetraphenylamine compound of type G3.

[0330] Those skilled in the art will appreciate that the substituents R on compounds G3, G9, G11, G12, G143 and G15 C1 , R C3 and R C4 , R C11 , R C13 and R C14 It may be a halogen atom or other suitable leaving group (e.g., boronic acid or boronic ester, -OH, -O-trifluoromethanesulfonyl, -OC(O)allyl, etc.) to effect transition metal-catalyzed transformations such as Ulmann, Negishi, Stille, Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig couplings, or for SnAr shifts to produce further examples of compound I type.

[0331] General Synthesis 4

[0332]

[0333] The conditions for converting the diacid G16 to the diester G18 are obvious to those skilled in the art, but include an excess of a suitable nucleophile G17 and a catalyst such as concentrated sulfuric acid (for ester formation), as shown in Scheme 4a. Alternatively, G16 can be first 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 in the presence of a catalyst such as, but not limited to, 4-dimethylaminopyridine. The diamide analog of the diester G16 can be prepared by converting the diacid G16 in place of the nucleophile G17 using a suitably functionalized nucleophile under conditions obvious to those skilled in the art, including conditions similar to those described in Scheme 4a.

[0334] Diesters G18 can also be obtained by reacting diacid G16 with a suitable alkyl halide G19 in the presence of a suitable base such as, but not limited to, cesium carbonate as shown in Scheme 4b.

[0335]

[0336] General Synthesis 5

[0337]

[0338] Scheme 5 shows an alternative route to synthesize compounds having structure G4, where "W" is defined as the primary amide C(=O)NH 2 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 , carboxylic acid-CO 2 H, activated acid (e.g., acyl halide or mixed anhydride) or nitrile -CN. The nitro intermediate G14 can be reduced to the diphenylamine intermediate using the following conditions, such as but not limited to stirring over a heterogeneous catalyst (e.g., Pd / C) under a hydrogen atmosphere to give G190. In the presence of (a) a suitable acid (e.g., but not limited to acetic acid) or (b) sodium bisulfite or (c) sodium metabisulfite or (d) In the case of , the diphenylamine is condensed with the aldehyde intermediate G1 to provide an intermediate of type G20. Treatment of the mono-Boc protected material under acidic conditions releases the primary amine to provide a compound of type G21. In the presence of a base (such as but not limited to triethylamine), a second nucleophilic aromatic substitution can be carried out with a phenyl compound substituted with a suitable G11-type leaving group to provide G22. The 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 provide G23. In the presence of (a) a suitable acid (such as but not limited to acetic acid) or (b) sodium bisulfite (c) sodium metabisulfite or (d) In this case, the diphenylamine intermediate G23 can be condensed with an equal amount of G2-type aldehyde to obtain a G4-type bisbenzimidazole compound.

[0339] General Synthesis 6

[0340]

[0341] Compounds of formula G26 or G27 can be obtained via the common nitrile intermediate G24 (Scheme 6a). Compounds of the G24 type can be obtained using the chemistry described in General Synthesis 1 and General Synthesis 5, wherein R1 / R11 is substituted with a nitrile-CN group. Treatment of the appropriately substituted nitrile G24 with hydroxylamine hydrochloride can afford an N-hydroxyamidine intermediate of the type G25. Intermediate G25 is subsequently treated with a reagent that provides a carbonyl (C=O) equivalent, such as, but not limited to, carbonyldiimidazole, to afford a 5-oxo-4H-1,2,4-oxadiazol-3-yl derivative of the type G26. Alternatively, nitrile G24 can be used to form tetrazole compound G27 in a single step in the presence of a base, such as, but not limited to, triethylamine, and an azide source, such as sodium azide.

[0342]

[0343] Compounds of type G30 are regioisomers of G26 and can be prepared from acid G16. Coupling of acid G16 with a hydrazine substituted on one nitrogen atom with a suitable protecting group ("PG", such as, but not limited to, tert-butyloxycarbonyl (Boc)) using a coupling agent 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 affords protected intermediates of type G28. Removal of the protecting group using conditions well known to those skilled in the art affords compounds of type G29, which can be reacted with reagents providing carbonyl (C=O) equivalents such as, but not limited to, carbonyldiimidazole to afford 2-oxo-3H-1,3,4-oxadiazol-5-yl derivatives of type G30.

[0344] Further implementation plans

[0345] 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 .

[0346] A 1 -A 4 and A 11 -A 14

[0347] In some embodiments, A 1 CR A .

[0348] In other embodiments, A 1 is N.

[0349] In some embodiments, A 2 CR B .

[0350] In other embodiments, A 2 is N.

[0351] In some embodiments, A 3 CR C .

[0352] In other embodiments, A 3 is N.

[0353] In some embodiments, A 4 CR D .

[0354] In other embodiments, A 4 is N.

[0355] In some embodiments, A 1 , A 2 , A 3 and A 4 Two of them are N.

[0356] In other embodiments, A 1 , A 2 , A3 and A 4 One of them is N.

[0357] In other embodiments, A 1 , A 2 , A 3 and A 4 None of them is N, that is, A 1 , A 2 , A 3 and A 4 CR A , CR B , CR C and CR D .

[0358] In some embodiments, A 11 CR AA .

[0359] In other embodiments, A 11 is N.

[0360] In some embodiments, A 12 CR BB .

[0361] In other embodiments, A 12 is N.

[0362] In some embodiments, A 13 CR CC .

[0363] In other embodiments, A 13 is N.

[0364] In some embodiments, A 14 CR DD .

[0365] In other embodiments, A 14 is N.

[0366] In some embodiments, A 11 , A 12 , A 13 and A 14 Two of them are N.

[0367] In other embodiments, A 11 , A 12 , A 13 and A 14 One of them is N.

[0368] In other embodiments, A 11 , A 12 , A13 and A 14 None of them is N, that is, A 11 , A 12 , A 13 and A 14 CR AA , CR BB , CR CC and CR DD .

[0369] In some embodiments, the compound of Formula I is selected from compounds of Formula (IIIa)-(IIIe):

[0370]

[0371]

[0372] R A , R B , R C , R D , R AA , R BB , R CC and R DD (if present)

[0373] In some embodiments, R A , R B , R C , R D , R AA , R BB , R CC and R DD (if present) selected from H, F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. In some embodiments, R A , R B , R C , R D , R AA , R BB , R CC and R DD (if present) are independently selected from H, F, Cl and Br, preferably H, Cl and F.

[0374] In some embodiments, R A , R B , R C and R D one of (if any), and R AA , R BB , RCC and R DD One of (if present) is selected from H, F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0375] In other embodiments, R A , R B , R C and R D two of (if any), and R A , R B , R C , R D , R AA , R BB , R CC and R DD Two of (if present) are selected from H, F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0376] In a further embodiment, R A , R B , R C and R D three of (if any), and R A , R B , R C , R D , R AA , R BB , R CC and R DD Three of the above (if present) are selected from H, F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0377] In some embodiments, R A , R B , R C and R D one, two or three (if any), and R AA , R BB , R CC and R DDOne, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, and OMe. The remainder, if present, is H. In some of these embodiments, R A , R B , R C and R D one, two or three (if any), and R AA , R BB , R CC and R DD One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 and cyclopropyl and OMe. The remainder, if present, is H. In some of these embodiments, R A , R B , R C and R D one, two or three (if any), and R AA , R BB , R CC and R DD One, two or three (if present) are selected from H, F, Cl, Br, Me and CF 3 and OMe.

[0378] In some embodiments, R A , R B , R C and R D one of (if any), and R AA , R BB , R CC and R DD One, two or three (if present) are selected from F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0379] In other embodiments, R A , R B , R C and R D two of (if any), and R A , R B , R C , R D , R AA , R BB , R CC and R DDOne, two or three (if present) are selected from F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0380] In a further embodiment, R A , R B , R C and R D three of (if any), and R A , R B , R C , R D , R AA , R BB , R CC and R DD One, two or three (if present) are selected from F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0381] In some embodiments, R A , R B , R C and R D one, two or three (if any), and R AA , R BB , R CC and R DD One (if present) is selected from F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0382] In other embodiments, R A , R B , R C and R D one, two or three (if any), and R A , R B , R C , R D , R AA , R BB , R CC and R DDTwo of (if present) are selected from F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0383] In a further embodiment, R A , R B , R C and R D one, two or three (if any), 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 F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH. The remainder (if any) is H.

[0384] 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 For F.

[0385] In some embodiments, R B Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R BB Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R B and R BBSelected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R B and / or R BB Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, and OMe. In some embodiments, R B and / or R BB is 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 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 For Cl.

[0386] In some embodiments, R C Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R CC Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R C and R CC Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R C and / or R CC Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, and OMe. In some embodiments, R 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 RCC is H. In some embodiments, R C and / or R CC is F. In some embodiments, R C and / or R CC For Cl.

[0387] In some embodiments, R D Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R DD Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R D and R DD Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, CH 2 OH and CH 2 In some embodiments, R D and / or R DD Selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, and OMe. In some embodiments, R 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 For Cl.

[0388] In some embodiments, R A , R B , R C and R D 1 or 2 (if present) of R are halogen, and the rest are H. In these embodiments, preferred halogen atoms are Cl, Br and F, more preferably Cl and F, and most preferably F. In these embodiments, R A and R C 1 or 2 of them are halogen, and R B and R DFor H.

[0389] In some embodiments, R AA , R BB , R CC and R DD 1 or 2 (if present) of R are halogen, and the rest are H. In these embodiments, preferred halogen atoms are Cl, Br and F, more preferably Cl and F, and most preferably F. In these embodiments, R AA and R CC 1 or 2 of them are halogen, and R B and R D For H.

[0390] In some embodiments, A 1 , A 2 , A 3 and A 4 A combination selected from 1.1-1.30 in the following table:

[0391] combination <![CDATA[A 1 ]]> <![CDATA[A 2 ]]> <![CDATA[A 3 ]]> <![CDATA[A 4 ]]> 1.1 CF CH CH CH 1.2 CH CBr CH CH 1.3 CH CCl CH CH 1.4 CF CCl CH CH 1.5 CH CH CH CBr 1.6 CH CH CCl CH 1.7 CH CF CF CH 1.8 CH CH CH CH 1.9 CF CH CF CH 1.10 CF CH CCl CH 1.11 CBr CH CH CH 1.12 CCl CH CH CH 1.13 N CH CCl CH 1.14 CH CCl CCl CH 1.15 CH CF CH CH 1.16 CH CMe CH CH 1.17 CH N CH CH 1.18 CH CH CBr CH 1.19 CH CH <![CDATA[CCF 3 ]]> CH 1.20 CH CH CE CH 1.21 CH CH CF CH 1.22 CH CH CMe CH 1.23 CH CH C-OMe CH 1.24 CH CH CCl CCl 1.25 CH CH CH CF 1.26 CH CH CH C-OMe 1.27 CH CH CH N 1.28 CI CH CH CH 1.29 CH CH CCN CH 1.30 CBr CH CCl CH

[0392] In some embodiments, A 11 , A 12 , A 13 and A 14 A combination selected from 2.1-2.30 in the following table:

[0393]

[0394]

[0395] In some embodiments, A 1 , A 2 , A 3 , A 4 , A 11 , A 12 , A 13 and A 14 Select from combinations 3.1-3.8 in the following table:

[0396] combination <![CDATA[A 1 / A 11 ]]> <![CDATA[A 2 / A 12 ]]> <![CDATA[A 3 / A 13 ]]> <![CDATA[A 4 / A 14 ]]> 1 CF CH CH CH 2 CH CBr CH CH 3 CH CCl CH CH 4 CF CCl CH CH 5 CH CH CH CBr 6 CH CH CCl CH 7 CH CF CF CH 8 CH CH CH CH

[0397] Among them, combinations 1, 3, 4, 6 and 7 may be preferred.

[0398] In a further embodiment, A 1 , A 2 , A 3 , A 4 , A 11 , A 12 , A 13 and A 14Select from combinations 9-28 in the following table:

[0399]

[0400]

[0401] Among them, combinations 9 and 10 may be preferred.

[0402] In some embodiments, combinations 1, 3, 6, and 9 may be preferred.

[0403] In some embodiments, combinations 1 and 10 may be preferred.

[0404] In some embodiments, combination 10 may be preferred.

[0405] In some embodiments, Combination 1 may be preferred.

[0406] Y

[0407] In some embodiments, Y is (CH 2 ) n , wherein n is 2 to 3. In some embodiments, Y is (CH 2 ) 2 In some embodiments, Y is (CH 2 ) 3 In some embodiments, Y is (CH 2 ) 4 .

[0408] In other embodiments, Y is -CH 2 -CH=CH-CH 2 -.

[0409] R C1 , R C3 , R C4 , R C11 , R C13 and R C14

[0410] In some embodiments, R C1 , R C3 , R C4 , R C11 , R C13 and R C14 Both are H.

[0411] In other embodiments, R C1 , R C3 and R C4 Two of them and R C11 , R C13 and R C14Two of them are H, and the others are selected from defined groups (excluding H).

[0412] In other embodiments, R C1 , R C3 and R C4 One of the C11 , R C13 and R C14 One of the Rs is H, and the others are independently selected from the defined groups (excluding H).

[0413] In some embodiments, R C1 , R C3 and R C4 independently selected from H, Cl, F, Br, Me, OMe, cyano, CF 3 and CH 2 OH. In some of these embodiments, R C1 , R C3 and R C4 Independently selected from H, Cl, F, CF 3 , OMe and CH 2 OH. In other 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 other of these embodiments, R C1 , R C3 and R C4 Independently selected from H and OMe.

[0414] In some embodiments, R C11 , R C13 and R C14 independently selected from H, Cl, F, Br, Me, OMe, cyano, CF 3 and CH 2 OH. In some of these embodiments, R C11 , R C13 and R C14 Independently selected from H, Cl, F, CF 3 , OMe and CH 2 OH. In another 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 C4is independently selected from H, F and OMe. In other of these embodiments, R C11 , R C13 and R C14 Independently selected from H and OMe.

[0415] In some embodiments, R C1 It is OMe.

[0416] In some embodiments, R C11 It is OMe.

[0417] In some embodiments, R C3 For H.

[0418] In some embodiments, R C13 For H.

[0419] In some embodiments, R C4 It is H or F, preferably H.

[0420] In some embodiments, R C14 It is H or F, preferably H.

[0421] In some embodiments, R C1 and R C11 OMe, R C3 and R C13 is H, and R C4 and R C14 All are H or F, preferably H.

[0422] In some embodiments, R C1 , R C3 and R C4 Select from the following combinations 1-4:

[0423] combination <![CDATA[R C1 ]]> <![CDATA[R C3 ]]> <![CDATA[R C4 ]]> 1 H H H 2 H H F 3 OMe H H 4 OMe H F

[0424] In some embodiments, combinations 3 and 4 may be preferred.

[0425] In some embodiments, combination 3 may be preferred.

[0426] In some embodiments, R C11 , R C13 and R C14 Select from the following combinations 1-4:

[0427] combination <![CDATA[R C11 ]]> <![CDATA[R C13 ]]> <![CDATA[R C14 ]]> 1 H H H 2 H H F 3 OMe H H 4 OMe H F

[0428] In some embodiments, combinations 3 and 4 may be preferred.

[0429] In some embodiments, combination 3 may be preferred.

[0430] In some embodiments, R C1 , R C3 , R C4 , R C11 , R C13 and R C14 Select from the following combinations 1-4:

[0431] combination <![CDATA[R C1 / R C11 ]]> <![CDATA[R C3 / R C13 ]]> <![CDATA[R C4 / R C14 ]]> 1 H H H 2 H H F 3 OMe H H 4 OMe H F

[0432] In some embodiments, combinations 3 and 4 may be preferred.

[0433] In some embodiments, combination 3 may be preferred.

[0434] R 1 and R 11

[0435] In some embodiments, R 1 and R 11 Selected from C(=O)OH, C(=O)OCH 3 , F, Br, tetrazolyl and oxo-oxadiazolyl.

[0436] In some embodiments, R 1 and R 11 is selected from C(=O)OH, tetrazolyl and oxo-oxadiazolyl.

[0437] In some embodiments, R 1 and R 11 It is -C(=O)OH.

[0438] In other embodiments, R 1 and R 11 It is a tetrazolyl group.

[0439] In other embodiments, R 1 and R 11 is oxo-oxadiazolyl, for example 5-oxo-4H-1,2,4-oxadiazol-3-yl and 2-oxo-3H-1,3,4-oxadiazol-5-yl.

[0440] In other embodiments, R 1 and R 11 It is a triazole group.

[0441] In other embodiments, R 1 and R 11 is Br or F.

[0442] In some embodiments, R 1 and R 11 In these embodiments, RC1 Can be used with R C11 Same, R C3 Can be used with R C13 Same as R C4 Can be used with R C14 The same, and A 1 , A 2 , A 3 and A 4 Can be respectively with A 11 , A 12 , A 13 and A 14 In some embodiments, R 1 is tetrazolyl and R 11 It is C(=O)OH.

[0443] In some embodiments, R 1 and R 11 C(=O)OR P1 In these embodiments, R P1 Preferred is methyl.

[0444] Other Implementations

[0445] In some embodiments, the compound is a compound of formula (II):

[0446]

[0447] in:

[0448] Y is (CH 2 ) n , wherein n is 2 to 4;

[0449] R 1 and R 11 is selected from -C(=O)OH and tetrazolyl;

[0450] A 1 CR A or N;

[0451] A 2 CR B or N;

[0452] A 3 CR C or N;

[0453] A 4 CR D or N;

[0454] Among them A 1 , A 2 , A 3and A 4 No more than two of them can be N;

[0455] R A , R B , R C and R D One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH;

[0456] The rest of R A , R B , R C and R D (if present) is H;

[0457] A 11 CR AA or N;

[0458] A 12 CR BB or N;

[0459] A 13 CR CC or N;

[0460] A 14 CR DD or N;

[0461] Among them A 11 , A 12 , A 13 and A 14 No more than two of them can be N;

[0462] R AA , R BB , R CC and R DD One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH;

[0463] The rest of R AA , R BB , R CC and R DD (if present) is H;

[0464] R C1 , R C3 and R C4independently selected from H, Cl, F, Br, Me, OMe, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 Alkenyl and C 5 Heterocyclic group;

[0465] R C11 , R C13 and R C14 independently selected from H, Cl, F, Br, Me, OMe, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 Alkenyl and C 5 Heterocyclic group.

[0466] Example

[0467] As described herein, the following examples are provided only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0468] Abbreviations

[0469] 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).

[0470] For convenience, many compounds are referred to using well-known abbreviations, including but not limited to methanol (MeOH), deuterated methanol (MeOD-d 4 or CD 3 OD), ethanol (EtOH), isopropanol (i-PrOH), ethyl ether or diethyl ether (Et 2 O), ethyl acetate (EtOAc), acetic acid (AcOH), acetonitrile (MeCN or ACN), dichloromethane (DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), deuterated chloroform (CDCl 3 ), diethylamine (DEA), deuterated dimethyl sulfoxide (DMSO-d 6), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl), m-chloroperbenzoic acid (mCPBA), 1,1'-bis(diphenylphosphino)ferrocene (dppf), tert-butyloxycarbonyl (Boc, BOC), 2-(trimethylsilyl)ethoxymethyl (SEM), triethylamine (Et 3 N or TEA), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA or DIEA), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (PdCl 2 (dppf)), trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl 2 (PPh 3 ) 2 ), tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium(0)(Pd(PPh 3 ) 4 ), propylphosphonic anhydride (T3P), hexamethylphosphoramide (HMPA), 1,2-dichloroethane (DCE), chromium (VI) oxide (CrO 3 ), n-bromosuccinimide (NBS), potassium hydroxide (KOH), benzoyl peroxide (BPO), carbon tetrachloride (CCl 4 ), petroleum ether (Pet.Ether), potassium carbonate (K 2 CO 3 ), sodium sulfate (Na 2 SO 4 ), lithium diisopropylamine (LDA), azobisisobutyronitrile (AIBN), N-methylmorpholine N-oxide (NMO), benzoyl peroxide (BPO), 1,1'-carbonyldiimidazole (CDI) and 1-hydroxybenzotriazole (HOBt).

[0471] In addition, TLC means thin layer chromatography.

[0472] General Experiment Details

[0473] Unless otherwise stated, the following generalizations apply. 1H NMR spectra were recorded on a Bruker AVANCE III (400 MHz). The multiplicities of the signals are indicated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplet; tt, triplet of triplets; td, triplet of doublets; ddd, two doublets of doublets; br, broad; m, multiplet. All observed coupling constants J are reported in Hertz. Exchangeable protons are not always observed.

[0474] LCMS data were generated using the following conditions. Chlorine isotopes are reported as 35 Cl, bromine isotopes are reported as 79 Br or 81 Br or 79 Br / 81 Br both.

[0475] LC-MS method A (LCMS-A):

[0476] Device Information

[0477] LC model: Agilent 1200

[0478] (Pump type: binary pump, detector type: DAD)

[0479] MS model: Agilent G6110A quadrupole

[0480] LCMS parameters

[0481] LC: Column: Xbridge-C18, 2.5 μm, 2.1×30 mm

[0482] Column temperature: 30°C

[0483] Collection wavelength: 214nm, 254nm

[0484] Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

[0485] MS: Ion source: ES+ (or ES-) MS range: 50~900m / z

[0486] Fragmentation voltage: 60 Drying gas flow rate: 10L / min

[0487] Atomizer pressure: 35psi Drying gas temperature: 350℃

[0488] Vcap: 3.5kV

[0489] Gradient table:

[0490] Flow rate (mL / min) T(min) A(％) B(％) 0.5 0.0 70 30 0.5 0.2 70 30 0.5 1.8 5 95 0.5 2.4 5 95 0.5 2.6 70 30 0.5 3.5 70 30

[0491] Sample preparation

[0492] Dissolve the sample in methanol to a concentration of about 0.11 to 1 mg / mL, and then filter through a 0.22 μm syringe filter. (Injection volume: 1 to 10 μL)

[0493] LC-MS method B (LCMS-B):

[0494] Device Information

[0495] LC model: Agilent 1200

[0496] (Pump type: binary pump, detector type: DAD)

[0497] MS model: Agilent G6110A quadrupole

[0498] LCMS parameters

[0499] LC: Column: Xbridge-C18, 2.5 μm, 2.1×30 mm

[0500] Column temperature: 30°C

[0501] Collection wavelength: 214nm, 254nm

[0502] Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

[0503] MS: Ion source: ES+ (or ES-) MS range: 50~900m / z

[0504] Fragmentation voltage: 60 Drying gas flow rate: 10L / min

[0505] Atomizer pressure: 35psi Drying gas temperature: 350℃

[0506] Vcap: 3.5kV

[0507] Gradient table:

[0508] Flow rate (mL / min) T(min) A(％) B(％) 0.5 0.0 70 30 0.5 0.3 70 30 0.5 0.6 50 50 0.5 0.9 40 60 0.5 1.2 30 70 0.5 3.2 5 95 0.5 3.5 5 95 0.5 4.0 70 30 0.5 5.0 70 30

[0509] Sample preparation

[0510] Dissolve the sample in methanol to a concentration of about 0.11 to 1 mg / mL, and then filter through a 0.22 μm syringe filter. (Injection volume: 1 to 10 μL)

[0511] LC-MS method C (LCMS-C):

[0512] Device Information

[0513] LC model: Waters 2695alliance

[0514] (Pump type: quaternary pump, detector: 2996 photodiode array detector)

[0515] MS Model: Micromass ZQ

[0516] LCMS parameters

[0517] LC: Column: Xbridge-C18, 3.5 μm, 2.1×50 mm

[0518] Column temperature: 30°C

[0519] Collection wavelength: 214nm, 254nm

[0520] Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

[0521] MS: Ion source: ES+ (or ES-) MS range: 50~900m / z

[0522] Capillary voltage: 3kV Cone voltage: 3V Extraction voltage: 3V

[0523] Dry gas flow rate: 600L / hr Cone hole: 50L / hr

[0524] Desolvation temperature: 300°C

[0525] Source temperature: 100°C

[0526] Gradient table:

[0527] Flow rate (mL / min) T(min) A(％) B(％) 0.3 0.0 80 20 0.3 0.5 80 20 0.3 0.8 50 50 0.3 1.2 35 65 0.3 2.0 20 80 0.3 4.0 5 95 0.3 5.0 5 95 0.3 5.8 15 85 0.3 6.2 80 20 0.3 8.0 80 20

[0528] Sample preparation

[0529] Dissolve the sample in methanol to a concentration of about 0.11 to 1 mg / mL, and then filter through a 0.22 μm syringe filter. (Injection volume: 1 to 10 μL)

[0530] Other chromatograms

[0531] Analytical thin layer chromatography was performed on Merck silica gel 60F254 aluminum backing plates using fluorescence quenching under UV light or alkaline KMnO 4 Visualization was performed by immersion in water or ninhydrin.

[0532] Preparative thin layer chromatography (prep TLC) was performed using Tklst (China), special grade: (HPTLC): 8±2 μm>80%; (TLC): 10-40 μm. Model: GF254. Compounds were visualized by UV (254 nm).

[0533] Column chromatography was performed using Tklst (China), special grade, 100-200 mesh silica gel.

[0534] When necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods. Solutions of inorganic acids or bases were prepared as aqueous solutions unless otherwise stated.

[0535] Unless otherwise stated, solutions of hydrogen chloride, sodium hydroxide, potassium carbonate and sodium bicarbonate are aqueous solutions.

[0536] Intermediate preparation

[0537] (I) 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-aminobenzamide) (I4)

[0538]

[0539] (a) tert-Butyl (2-((4-carbamoyl-2-nitrophenyl)amino)ethyl)carbamate (I1)

[0540] 4-Chloro-3-nitrobenzamide (8.0 g, 39.9 mmol), tert-butyl (2-aminoethyl)carbamate (6.40 g, 39.9 mmol) and Et 3 A suspension of N (8.1 g, 79.8 mmol) in NMP (80 mL) was stirred at 4 °C. 2 Heat at 150°C overnight. Add water (500 mL) followed by petroleum ether / EtOAc (5:1, 300 mL) and collect the resulting precipitate 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-d 6 )δ8.65(s,1H),8.44(t,J=5.8Hz,1H),8.05–7.92(m,2H),7.27(s,1H),7.14(d,J=9. 1Hz, 1H), 7.04 (t, J = 5.8Hz, 1H), 3.46-3.45 (m, 2H), 3.20-3.19 (m, 2H), 1.35 (s, 9H).

[0541] (b) 4-((2-aminoethyl)amino)-3-nitrobenzamide hydrochloride (I2)

[0542] 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 (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 HNMR (400 MHz, DMSO-d 6 )δ8.65(d,J=2.1Hz,1H),8.42(s,1H),8.25(s,2H),8.05(dd,J=9.0,2.2Hz,1H),7.25(d,J=9.0Hz,1H),5.62(br s,3H),3.76-3.74(m,2H),3.01-2.97(m,2H).

[0543] (c) 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-nitrobenzamide)(I3)

[0544] 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 Et 3 A suspension of N (20.6 g, 203 mmol) in NMP (80 mL) was stirred at 4 °C. 2 The mixture was heated at 150°C overnight. 4-((2-aminoethyl)amino)-3-nitrobenzamide hydrochloride (I2) (800 mg, 3.57 mmol) and Et 3 N (3.0 g, 29.6 mmol), and the mixture was stirred under N 2 The mixture was heated at 150°C overnight. The mixture was cooled to room temperature, diluted with petroleum 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-d 6 )δ8.62(s,4H),7.99-7.95(m,4H),7.30-7.28(m,4H),3.70-3.64(m,4H).

[0545] (d) 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-aminobenzamide) (I4)

[0546] A suspension of 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-nitrobenzamide)(I3)(12 g, 30.9 mmol) and 10% Pd / C (2.0 g) in DMF (200 mL) was stirred at 4 000 rpm for 1 00 min. 2 Heat at 100°C overnight under atmosphere. Filter the mixture and concentrate the filtrate 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.44(s,2H),7.13(d,J=8.2Hz,2H),7.11(s,2H),6.74(s,2H),6.46(d,J=8.0Hz,2H),5.05(s,2H),4.58(s,4H),3.41–3.36(m,4H).

[0547] (ii) 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide)I13

[0548]

[0549] (a) Methyl 4-fluoro-2-hydroxybenzoate (I5)

[0550] 4-Fluoro-2-hydroxybenzoic acid (50.0 g, 320.3 mmol) and concentrated H 2 SO 4 A mixture of 40 mL, 672.7 mmol) in MeOH (600 mL) was stirred under N 2 The mixture was poured into water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic extracts were washed with water (500 mL x 2), brine (500 mL), and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum 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-d 6 )δ10.8(s,1H),7.83(dd,J=8.9,6.8Hz,1H),6.90–6.70(m,2H),3.88(s,3H).

[0551] (b) Methyl 4-fluoro-2-hydroxy-3-nitrobenzoate (I6)

[0552] In N 2 At 0°C, methyl 4-fluoro-2-hydroxybenzoate I5 (50.0 g, 294.0 mmol) was added to concentrated H 2 SO 4 Concentrated HNO was added dropwise to the solution (100 mL) 3 (20 mL, 382.1 mmol), and the mixture was allowed to warm 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 x 3). The combined organic extracts were washed with water (1.5 L x 2), brine (1.5 L), and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (100% petroleum ether) to give a mixture of the title compound and uncharacterized regioisomers (50 g, ~3.75:1 uncharacterized regioisomer / title compound). The mixture was used in the next step without further purification or characterization. LCMS-A (ES-API): rt 1.57 min (minor) m / z 216.0 [M+H] + and rt 1.68min (major) m / z 216.1 [M+H] + .

[0553] (c) Methyl 4-fluoro-2-methoxy-3-nitrobenzoate (I7)

[0554] Methyl 4-fluoro-2-hydroxy-3-nitrobenzoate (containing a major uncharacterized regioisomer) I6 (50.0 g), CH 3 I (99.0 g, 697 mmol) and K 2 CO 3 A mixture of (64.1 g, 465 mml) in DMF (200 mL) was stirred at N 2 The mixture was poured into water (1.0 L), extracted with EtOAc (1.0 L x 3), and the combined organic extracts were washed with water (1.0 L x 2), brine (1.0 L), and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=100:1 to 40:1) and 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] + .1 H NMR (400 MHz, DMSO-d 6 )δ8.12(dd,J=9.1,6.5Hz,1H),7.50(t,J=9.0Hz,1H),3.93(s,3H),3.91(s,3H).

[0555] (d) Methyl 4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methoxy-3-nitrobenzoate (I8)

[0556] 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 Et 3 A mixture of N (5.3 g, 52.4 mmol) in NMP (100 mL) was stirred at 4 °C for 2 h. 2 The mixture was poured into water (500 mL), extracted with EtOAc (500 mL×3), and the combined organic extracts were washed with water (500 mL×2), brine (500 mL), and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=100:1 to 10:1) to give 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-d 6 )δ7.79(d,J=9.2Hz,1H),6.96(t,J=5.5Hz,1H),6.74(d,J=9.2Hz,1H),6.70(t, J=5.7Hz,1H),3.79(s,6H),3.27–3.21(m,2H),3.11–3.06(m,2H),1.37(s,9H).

[0557] (e) Methyl 4-((2-aminoethyl)amino)-2-methoxy-3-nitrobenzoate hydrochloride (I9)

[0558] A mixture of methyl 4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methoxy-3-nitrobenzoate I8 (9.5 g, 25.7 mmol) and 3M HCl in dioxane (200 mL) was stirred at N 2The mixture was stirred at room temperature 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-d 6 )δ7.81(dd,J=9.2,3.8Hz,1H),6.82–6.71(m,2H),3.79(s,3H),3.75(s,3H),3.31–3.28(m,4H).

[0559] (f) 4,4'-(Ethane-1,2-diylbis(azadiyl))bis(2-methoxy-3-nitrobenzoic acid methyl ester) (I10)

[0560] 4-((2-aminoethyl)amino)-2-methoxy-3-nitrobenzoic acid methyl ester hydrochloride I9 (5.5 g, 18.0 mmol), 4-fluoro-2-methoxy-3-nitrobenzoic acid methyl ester I7 (4.68 g, 20.4 mmol) and Et 3 A solution of N (6.2 g, 61.3 mmol) in NMP (100 mL) was stirred for 2 h. 2 Heat at 80°C for 16 h. Pour the mixture into water (600 mL) and collect the resulting precipitate by filtration to give the title compound (8.0 g, 82%) as a yellow solid. LCMS-C (ES-API): rt 4.75 min, m / z 477.1 [MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δ7.76(d,J=9.2Hz,2H),6.77–6.74(m,4H),3.78(s,6H),3.77(s,6H),3.40(br s,4H).

[0561] (g) 4,4'-(Ethane-1,2-diylbis(azadiyl))bis(2-methoxy-3-nitrobenzoic acid) (I11)

[0562] A mixture of 4,4'-(ethane-1,2-diylbis(azadiyl))bis(methyl 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 2M HCl aqueous solution. 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-d 6 )δ12.6(br s,2H),7.77(d,J=9.1Hz,2H),6.74(d,J=9.3Hz,2H),6.69(t,J=5.5Hz,2H),3.78(s,6H),3.44(br s,4H).

[0563] (h) 4,4'-(Ethane-1,2-diylbis(azadiyl))bis(2-methoxy-3-nitrobenzamide)(I12)

[0564] 4,4'-(ethane-1,2-diylbis(azadiyl))bis(2-methoxy-3-nitrobenzoic acid) I11 (3.4 g, 7.6 mmol), NH 4 A mixture of Cl (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 under N 2 The mixture was stirred at room temperature 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.63(d,J=9.0Hz,2H),7.42(br s,4H),6.77(d,J=9.1Hz,2H),6.60(t,J=4.8Hz,2H),3.77(s,6H),3.39–3.36(m,4H).

[0565] (I) 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13)

[0566] A mixture of 4,4'-(ethane-1,2-diylbis(azadiyl))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 4 ℃ for 1 h. 2 Stir at room temperature for 3 days under atmosphere (3 MPa). Filter the mixture and concentrate the filtrate under reduced pressure to give the title compound (120 mg). Wash the filter cake with DMSO and freeze-dry the filtrate to give another title compound (680 mg). Combine the separated solids 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-d 6 )δ7.39(br s,2H),7.11(d,J=8.4Hz,2H),7.10(br s,2H),6.37(d,J=8.5Hz,2H),5.23(br s,2H),4.42(br s,4H),3.66(s,6H),3.35(br s,4H).

[0567] Example

[0568] Example 1: 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid)

[0569]

[0570] (a) Methyl 2-(bromomethyl)-5-chlorobenzoate (A1)

[0571] To methyl 5-chloro-2-methylbenzoate (5.0 g, 27.1 mmol) in CCl 4 To the solution in 4% ethanol (50 mL), NBS (5.3 g, 29.8 mmol) and AIBN (2.2 g, 13.5 mmol) were added, and the mixture was stirred under N 2 The mixture was poured into water, extracted with EtOAc, and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by column chromatography (petroleum ether) to give the title compound (3.0 g, 34%) as a colorless oil.1 H NMR (400 MHz, DMSO-d 6 )δ7.85(d,J=2.2Hz,1H),7.69–7.62(m,2H),4.99(s,2H),3.88(s,3H).

[0572] (b) 5-chloro-2-formylbenzoic acid methyl ester (A2)

[0573] 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 stirred under N 2 The mixture was poured into water (30 mL), extracted with EtOAc (30 mL x 3), and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum 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-d 6 )δ10.3(s,1H),7.93–7.83(m,3H),3.92(s,3H).

[0574] (c) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(methyl 3-chlorobenzoate) (A3)

[0575] Methyl 5-chloro-2-formylbenzoate A2 (83 mg, 0.42 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) I13 (80 mg, 0.21 mmol) and NaHSO 3 A mixture of (44 mg, 0.42 mmol) in DMF (4 mL) was stirred under N 2 The mixture was heated at 100°C 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-d 6)δ7.80(d,J=2.3Hz,2H),7.71(s,2H),7.68(d,J=8.6Hz,2H),7.45(s,2H),7.28(dd,J=8.2,2. 3Hz, 2H), 7.06 (d, J = 8.6Hz, 2H), 6.79 (d, J = 8.2Hz, 2H), 4.36 (s, 6H), 4.25 (s, 4H), 3.61 (s, 6H).

[0576] (d) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-chlorobenzoic acid)(1)

[0577] 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) were mixed in EtOH / H 2 The mixture in 4% HCl (5 mL / 5 mL) was heated at 80 ° C for 3 h. Most of the EtOH was removed under reduced pressure and the pH of the residue was adjusted to 4-5 with 1M HCl aqueous solution. 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-d 6 )δ7.80(d,J=2.3Hz,2H),7.71(s,2H),7.64(d,J=8.6Hz,2H),7.44(s,2H),7.14(dd,J=8 .4,1.2Hz,2H),6.94(d,J=8.6Hz,2H),6.63(d,J=8.2Hz,2H),4.39(s,6H),4.27(s,4H).

[0578] Example 2-2,2'-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (2)

[0579]

[0580] (a) Dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoate (A4)

[0581] 4,4'-(Ethane-1,2-diylbis(azadiyl))bis(3-aminobenzamide) I4 (500 mg 1.52 mmol), methyl 2-formylbenzoate (499 mg 3.04 mmol) and NaHSO 3 A solution of (316 mg 3.04 mmol) in DMF (30 mL) was stirred under N 2 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-d 6 )δ8.18(d,J=1.0Hz,2H),8.01(br s,2H),7.89(dd,J=7.9,1.3Hz,2H),7.65(dd,J=8.5,1.6Hz,2H),7.54–7.43(m,2H),7.28(br s,2H),7.22(d,J=8.5Hz,2H),7.21–7.16(m,2H),6.52(d,J=7.5Hz,2H),4.26(s,4H),3.53(m,6H).

[0582] (b) 2,2'-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (2)

[0583] 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 stirred at N 2 The mixture was heated at 50°C 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] + . 1 H NMR (400 MHz, DMSO-d 6)δ8.22(s,2H),8.08(br s,2H),7.91(d,J=7.5Hz,2H),7.67(d,J=8.5Hz,2H),7.52(t,J=7.4Hz,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).

[0584] Example 3-2,2'-(Ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoic acid) (3)

[0585]

[0586] (a) Methyl 4-bromo-2-formylbenzoate (A5)

[0587] 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, extracted with EtOAc, and the organic layer was washed with saturated NaHCO 3 Wash with aqueous solution and 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum 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-d 6 )δ10.4(s,1H),8.01–7.95(m,2H),7.85(d,J=8.2Hz,1H),3.90(s,3H).

[0588] (b) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(methyl 4-bromobenzoate) (A6)

[0589] To a solution of methyl 4-bromo-2-formylbenzoate A5 (200 mg, 0.82 mmol) and 4,4′-(ethane-1,2-diylbis(azadiyl))bis(3-aminobenzamide) I4 (135 mg, 0.41 mmol) in DMF (9 mL) was added NaHSO 3 (85 mg, 0.82 mmol), and the mixture was stirred under N2 The mixture was heated at 120°C overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, brine, and purified by Na 2 SO 4 Dry, filter and concentrate 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-d 6 )δ8.25(s,2H),7.97(br s,2H),7.82(d,J=8.4Hz,2H),7.76–7.73(m,4H),7.32(d,J=8.5Hz,2H),7.27(br s,2H),6.82(s,2H),4.31(s,4H),3.58(s,6H).

[0590] (c) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-1H-benzo[d]imidazole-1,2-diyl))bis(4-bromobenzoic acid)(3)

[0591] To a solution of 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, the residue was diluted with water, acidified to pH 3-4 with 2M aqueous HCl solution, and 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.26(s,2H),8.00(br s,2H),7.83(d,J=8.0Hz,2H),7.75–7.65(m,4H),7.37–7.21(m,4H),6.79(br s,2H),4.39(s,4H).

[0592] Example 4-2,2'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (4)

[0593]

[0594] (a) Dimethyl 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoate (A7)

[0595] Methyl 2-formylbenzoate (197 mg, 1.20 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) I13 and NaHSO 3 A mixture of (52 mg, 0.50 mmol) in DMF (20 mL) was stirred under N 2 The mixture was heated at 120°C overnight under atmosphere. The mixture was diluted with water and partitioned with EtOAc, resulting in the formation of a precipitate. The precipitate was collected by filtration and triturated with DCM / MeOH=20 / 1, 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.91(d,J=7.9Hz,2H),7.70(br s,2H),7.61(d,J=8.6Hz,2H),7.56-7.51(m,2H),7.46(br s, 2H), 7.34 (t, J = 8.4Hz, 2H), 6.86 (d, J = 8.6Hz, 2H), 6.70 (d, J = 7.2Hz, 2H), 4.36 (s, 6H), 4.22 (s, 4H), 3.56 (s, 6H).

[0596] (b) 2,2'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))dibenzoic acid (4)

[0597] A mixture of 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-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] + . 1H NMR (400 MHz, DMSO-d 6 )δ7.94(d,J=7.9Hz,2H),7.70(br s,2H),7.56(d,J=8.6Hz,2H),7.51(t,J=7.8Hz,2H),7.45(br s, 2H), 7.27 (t, J = 7.5Hz, 2H), 6.69 (d, J = 8.7Hz, 2H), 6.54 (d, J = 7.6Hz, 2H), 4.37 (s, 6H), 4.18 (s, 4H).

[0598] Example 5-2-(2-(1H-tetrazolyl-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazolyl-5-yl)phenyl)-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (5)

[0599]

[0600] (a) 2-(1H-tetrazolyl-5-yl)benzaldehyde (A8)

[0601] To a solution of 5-phenyl-1H-tetrazole (5.0 g, 34.2 mmol) in THF (100 mL) was added sec-butyl lithium (1.3 M, 54.0 mL, 69.0 mmol) dropwise at -78 °C under nitrogen, 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 and purified by MgSO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=5:1-4:1) to give the title compound (4.0 g, 67%) as a white solid. LCMS-B (ES-API): rt 1.03 min; m / z 175.0 [M+H] + .

[0602] (b) 2-(2-(1H-tetrazolyl-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazolyl-5-yl)phenyl)-5-carbamoyl-1H-benzo[d]imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (5)

[0603] 2-(1H-tetrazolyl-5-yl)benzaldehyde A8 (500 mg, 2.88 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-aminobenzamide) I4 (472 mg, 1.44 mmol) and NaHSO 3 A solution of (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 [MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δ8.15(d,J=1.6Hz,2H),7.97(br s,2H),7.91(d,J=7.8Hz,2H),7.66(dd,J=8.4,1.7Hz,2H),7.54(t,J=7.6Hz,2H),7.28(br s,2H),7.14-7.12(m,4H),6.63(d,J=7.4Hz,2H),4.20(s,4H).

[0604] Example 6-1,1'-(Ethane-1,2-diyl)bis(2-(2-(2H-tetrazolyl-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (6)

[0605]

[0606] 4,4'-(Ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) I13 (50 mg, 0.13 mmol), 2-(2H-tetrazolyl-5-yl)benzaldehyde A8 (45 mg, 0.26 mmol) and NaHSO 3 A mixture of (40 mg, 0.39 mmol) in DMF (5 mL) was heated at 120 ° C overnight under nitrogen. 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, 1% HCO 2 Gradient elution with aqueous H-ACN solution at a flow rate of 15 mL / min) gave the title compound (4 mg, 4%) as a white solid. LCMS-C (ES-API): rt 2.36 min; m / z 697.1 [M+H] + .1 H NMR (400 MHz, DMSO-d 6 )δ7.95(d,J=7.6Hz,2H),7.69(br s,2H),7.59-7.55(m,4H),7.44(br s, 2H), 7.25 (t, J = 7.6Hz, 2H), 6.76 (d, J = 7.6Hz, 2H), 6.69 (d, J = 8.6Hz, 2H), 4.28 (s, 6H), 4.08 (s, 4H).

[0607] Example 7-2,2'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoic acid) (7)

[0608]

[0609] (a) Methyl 2-(bromomethyl)-4-chlorobenzoate (A9)

[0610] To methyl 4-chloro-2-methylbenzoate (2.0 g, 10.8 mmol) in CCl 4 To the solution in 40 mL, NBS (2.0 g, 11.9 mmol) and AIBN (1.0 g, 5.42 mmol) were added, and the mixture was stirred under N 2 The mixture was poured into water and extracted with EtOAc, and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=100:1) to give the title compound (2.3 g, 82%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d 6 )δ7.85(d,J=2.2Hz,1H),7.69-7.62(m,2H),4.99(s,2H),3.88(s,3H).

[0611] (b) Methyl 4-chloro-2-formylbenzoate (A10)

[0612] 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 stirred under N 2 NMO (1.0 g, 8.73 mmol) and THF (15 mL) were added, and the mixture was heated under N 2The mixture was poured into water (40 mL), extracted with EtOAc (40 mL x 3), and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=200:1 to 150:1 to 120:1) to give 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-d 6 )δ10.4(s,1H),7.94-7.81(m,3H),3.91(s,3H).

[0613] (c) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(methyl 4-chlorobenzoate) (A11)

[0614] Methyl 4-chloro-2-formylbenzoate (A10) (0.100 g, 0.50 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (0.098 g, 0.25 mmol) and NaHSO 3 A mixture of (0.052 g, 0.50 mml) in DMF (4 mL) was stirred under N 2 The mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3), and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was triturated with MeOH to give 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-d 6 )δ7.89(d,J=8.5Hz,2H),7.68-7.66(m,4H),7.58(dd,J=8.5,2.1Hz,2H),7.45(d,J=1.9Hz,2H),6.98(d,J=8.6Hz,2H),6.80(br s,2H),4.38(s,6H),4.29(s,4H),3.60(s,6H).

[0615] (d) 2,2'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(4-chlorobenzoic acid)(7)

[0616] 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) were mixed in EtOH / H 2 The mixture in 4% paraformaldehyde (5% paraformaldehyde) (5 mL / 5 mL) was stirred at room temperature overnight. The mixture was poured into water (10 mL) and washed with EtOAc (10 mL×3). The aqueous phase was adjusted to pH 4-5 with 1M HCl aqueous solution, 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-d 6 )δ13.2(br s,2H),7.91(d,J=8.5Hz,2H),7.67(d,J=2.0Hz,2H),7.60(d,J=8.6Hz,2H),7.5 2(dd,J=8.5,1.8Hz,2H),7.43(d,J=2.0Hz,2H),6.80(d,J=8.6Hz,2H),6.56(br s,2H),4.41(s,6H),4.27(s,4H).

[0617] 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)

[0618]

[0619] (a) 4,5-Dichloro-2-(methoxycarbonyl)benzoic acid (A12)

[0620] A solution of 5,6-dichloroisobenzofuran-1,3-dione (5 g, 23 mmol) in methanol (50 mL) was heated to reflux for 5 h. 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] + . 1H NMR (400 MHz, DMSO-d 6 )δ8.00(s,1H),7.96(s,1H),3.81(s,3H).

[0621] (b) 5,6-Dichloroisobenzofuran-1(3H)-one (A13)

[0622] At 0°C, 4,5-dichloro-2-(methoxycarbonyl)benzoic acid (A12) (1.0 g, 4.0 mmol) and Et 3 A solution of N (1.1 mL, 8.0 mmol) in anhydrous THF (20 mL) was added dropwise with ClCO 2 Et (654 mg, 6.0 mmol). The mixture was stirred for 40 min and then filtered. The filtrate was diluted with anhydrous THF (10 mL) and water (0.36 mL) was added, followed by the addition of NaBH 4 (303 mg, 8.0 mmol), and the mixture was stirred until TLC analysis showed that all the starting materials were 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-d 6 )δ8.14(s,1H),8.05(s,1H),5.41(s,2H).

[0623] (c) 3-Bromo-5,6-dichloroisobenzofuran-1(3H)one (A14)

[0624] 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 stirred at N 2 The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=100:1 to 50:1) to give the title compound (545 mg, 68%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.19(s,1H),8.11(s,1H),7.99(s,1H).

[0625] (d) 4,5-Dichloro-2-formylbenzoic acid (A15)

[0626] 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-d 6 )δ11.1(br s,2H),8.09(s,1H),7.96(s,1H).

[0627] (e) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-dichlorobenzoic acid)(8)

[0628] 4,5-Dichloro-2-formylbenzoic acid (A15) (0.100 g, 0.459 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (0.089 g, 0.23 mmol) and NaHSO 3 A mixture of (0.119 g, 1.15 mmol) in DMF (3 mL) was stirred at N 2 The mixture was concentrated by freeze drying and the residue was purified by preparative HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, gradient elution with 0.1% formic acid in ACN aqueous solution, flow rate 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.96(s,2H),7.66(s,2H),7.65(d,J=8.6Hz,2H),7.43(br s,2H),6.94(d,J=8.6Hz,2H),6.88(brs,2H),4.41(s,6H),4.31(s,4H).

[0629] Example 9-1,1'-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(2H-tetrazolyl-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (9)

[0630]

[0631] (a) 5-Chloro-2-(dimethoxymethyl)benzonitrile (A16)

[0632] 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 stirred under N 2 The mixture was heated at 80°C overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with saturated NaHCO 3 The mixture was washed with aqueous solution, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum 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-d 6 )δ8.01(d,J=2.2Hz,1H),7.75(dd,J=8.4,2.2Hz,1H),7.58(d,J=8.4Hz,1H),5.50(s,1H),3.26(s,6H).

[0633] (b) 5-(5-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A17)

[0634] To a solution of 5-chloro-2-(dimethoxymethyl)benzonitrile (A16) (1.0 g, 4.73 mmol) in NMP (20 mL) was added Et 3 N.HCl (1.95 g, 14.2 mmol) and NaN 3 (1.54 g, 23.6 mmol), and the mixture was stirred under N 2 The mixture was heated at 110°C for 3 h. Most of the NMP was removed by freeze drying, 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-d 6)δ7.85(d,J=2.2Hz,1H),7.68(d,J=8.4Hz,1H),7.62(dd,J=8.4,2.2Hz,1H),6.07(s,1H),3.22(s,6H).

[0635] (c) 4-Chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A18)

[0636] 5-(5-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A17) (1.1 g) and 2M H 2 SO 4 A mixture of aqueous solution (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 and brine, and purified by Na 2 SO 4 Dry, filter and concentrate 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.7(s,1H),8.08(d,J=2.2Hz,1H),7.86(d,J=8.4Hz,1H),7.58(dd,J=8.4,2.1Hz,1H).

[0637] (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)

[0638] To a solution of 4-chloro-2-(2H-tetrazol-5-yl)benzaldehyde (A18) (0.100 g, 0.481 mmol) in DMF (6 mL) was added 4,4′-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (0.093 mg, 0.240 mmol) and NaHSO 3 (0.050 mg, 0.481 mmol), and the mixture was stirred under N 2The mixture was heated at 80°C 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, gradient elution with ACN aqueous solution containing 0.1% formic acid, flow rate 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-d 6 )δ7.95(s,2H),7.73(s,2H),7.62(d,J=8.5Hz,2H),7.41(s,2H),6.98(d,J=7.7 Hz, 2H), 6.72 (d, J = 8.4Hz, 2H), 6.56 (d, J = 8.0Hz, 2H), 4.38 (s, 6H), 3.88 (s, 4H).

[0639] Example 10-2,2'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (10)

[0640]

[0641] (a) Ethyl 3-fluoro-2-methylbenzoate (A19)

[0642] To a solution of 3-fluoro-2-methylbenzoic acid (5.0 g, 32.5 mmol) in DMF (80 mL) was added K 2 CO 3 (13.5 g, 97.5 mmol) and EtI (7.6 g, 48.8 mmol), and the mixture was stirred under N 2 The mixture was diluted with water, extracted with EtOAc, and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum 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-d 6)δ7.61(d,J=7.2Hz,1H),7.43–7.30(m,2H),4.30(q,J=7.1Hz,2H),2.39(d,J=2.3Hz,3H),1.31(t,J=7.1Hz,3H).

[0643] (b) Ethyl 2-(bromomethyl)-3-fluorobenzoate (A20)

[0644] Ethyl 3-fluoro-2-methylbenzoate (A19) (5.4 g, 29.7 mmol) was reacted in CCl 4 To a solution of 1% ethyl acetate (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, extracted with EtOAc, and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel chromatography (petroleum ether / EtOAc=1:0 to 100:1) to give the title compound (6.2 g, 86%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ7.75-7.71(m,1H),7.57-7.49(m,2H),4.95(d,J=1.7Hz,2H),4.35(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0645] (c) Ethyl 3-fluoro-2-formylbenzoate (A21)

[0646] To a solution of ethyl 2-(bromomethyl)-3-fluorobenzoate (A2O) (6.2 g, 23.8 mmol) in THF (20 mL) was added NMO (11.2 g, 95.4 mmol), and the mixture was heated at reflux overnight. The mixture was diluted with water, extracted with EtOAc, and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel chromatography (petroleum 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-d 6 )δ10.3(s,1H),7.79-7.72(m,1H),7.69-7.57(m,2H),4.34(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H).

[0647] (d) 2,2'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(ethyl 3-fluorobenzoate) (A22)

[0648] 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(azadiyl))bis(3-amino-2-methoxybenzamide (I13) (0.872 g, 2.25 mmol) and NaHSO 3 (0.930 g, 8.98 mmol) and the mixture was heated at 100°C overnight. Ethyl 3-fluoro-2-formylbenzoate (A21) (0.100 g, 0.51 mmol) was further added and the mixture was heated at 100°C overnight. The mixture was diluted with water, extracted with EtOAc, and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The solid grey residue was washed with petroleum ether / EtOAc=10:1 (50 mL×2) to give the title compound (1.1 g, 75%) as a grey solid. LCMS-B (ES-API): rt 3.12 min, m / z 741.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.84(d,J=8.6Hz,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 = 6.4Hz, 6H).

[0649] (e) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-fluorobenzoic acid) (10)

[0650] A solution of 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 h. 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, gradient elution with 0.1% formic acid in ACN aqueous solution, flow rate 15.0 mL / min) to give the title compound (17 mg, 2%) as a white solid. LCMS-B(ES-API):rt 2.49min,m / z 685.2[M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ13.2(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).

[0651] 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)

[0652]

[0653] (a) 2-Amino-5-chloro-3-fluorobenzoic acid (A23)

[0654] 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 at N 2 The mixture was stirred at room temperature overnight. DCM (60 mL) was added and the mixture was washed with water (2×60 mL). During the second wash, a precipitate formed, which was collected by filtration and washed with water, then dried in vacuo 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-d 6)δ7.51-7.50(m,1H),7.44(dd,J=11.2,2.5Hz,1H).

[0655] (b) 2-Bromo-5-chloro-3-fluorobenzoic acid (A24)

[0656] To a solution of 2-amino-5-chloro-3-fluorobenzoic acid (A23) (4.0 g, 0.021 mol) in ACN (100 mL) was added 40% aqueous HBr (16.9 g, 0.083 mol) dropwise at 0°C over 10 min. Then, NaNO was added dropwise over 1 h. 2 (1.6 g, 0.023 mol) in water (20 mL) and the mixture was stirred at 0 ° C for 5 min. CuBr (3.6 g, 0.025 mol) was then added in portions 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 in vacuo 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-d 6 )δ14.0(br s,1H),7.81(dd,J=8.6,2.4Hz,1H),7.66(dd,J=2.4,1.4Hz,1H).

[0657] (c) 5-Chloro-3-fluoro-2-formylbenzoic acid (A25)

[0658] 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 dropwise i-PrMgCl (2 M THF solution, 16.0 mL, 0.032 mol) at -30 °C, and the mixture was stirred for 2 h. DMF (6 mL) was then added, and the mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was removed under reduced pressure, and the residue was diluted with 1 M HCl aqueous solution 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-d 6)δ8.48(br s,1H),7.91(dd,J=8.8,1.5Hz,1H),7.80(d,J=1.5Hz,1H),6.85(br s,1H).

[0659] (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)

[0660] 5-Chloro-3-fluoro-2-formylbenzoic acid (A25) (0.800 g, 3.95 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (0.767 g, 1.97 mmol) and NaHSO 3 A mixture of (0.205 g, 1.97 mmol) in DMF (20 mL) was stirred under N 2 Heat at 60°C overnight. Add water (30 mL), collect the resulting precipitate by filtration, and purify by preparative HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, gradient elution with ACN aqueous solution containing 0.1% formic acid, flow rate 15.0 mL / min) to obtain 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-d 6 )δ7.76-7.63(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).

[0661] 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)

[0662]

[0663] (a) 4-Chloro-3-fluoro-2-formylbenzoic acid (A26)

[0664] In N 2To a solution of diisopropylamine (695 mg, 6.87 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 3.0 mL, 7.5 mmol) at -78 °C, 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 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 mixture was heated to 40 °C with saturated NH 4 The reaction mixture was quenched with aqueous Cl solution and washed with EtOAc. The aqueous phase was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether to petroleum ether / EtOAc=1:1 to DCM / MeOH=10:1) to give the title compound (1.0 g) as a white solid. LCMS analysis showed that it was a mixture of about 1:5 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): title compound rt 2.99 min, m / z 203.0, 205.0 [M+H] + .

[0665] (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)

[0666] To a solution of a ~1:5 mixture of 4-chloro-3-fluoro-2-formylbenzoic acid / 4-chloro-3-fluorobenzoic acid (A26) (104 mg) and 4,4′-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (100 mg, 0.26 mmol) in DMF (8 mL) was added NaHSO 3 (107 mg, 1.03 mmol), and the mixture was stirred under N 2 The mixture was heated at 120°C overnight. The mixture was purified by preparative HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, gradient elution with CAN aqueous solution containing 0.1% formic acid, flow rate 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-d 6)δ7.77(d,J=8.6Hz,2H),7.68(d,J=3.0Hz,2H),7.63-7.59(m,4H),7.42(br s,2H),7.03(d,J=8.5Hz,2H),4.50-4.47(m,2H),4.37(s,6H),4.24-4.21(m,2H).

[0667] Example 13-6,6'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid methyl ester) (13) and 6,6'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid) (14)

[0668]

[0669] (a) Methyl 5-bromo-2-(bromomethyl)benzoate (A27)

[0670] 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) were dissolved in CCl 4 The mixture in N 2 The mixture was heated at 80°C 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 x 3). The combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel chromatography (petroleum ether / EtOAc=120:1 to 80:1) to give the title compound (1.01 g, 75%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ7.98(d,J=2.2Hz,1H),7.80(dd,J=8.3,2.2Hz,1H),7.56(d,J=8.3Hz,1H),4.98(s,2H),3.88(s,3H).

[0671] (b) Methyl 5-bromo-2-formylbenzoate (A28)

[0672] 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 stirred at 4 °C for 2 h. 2 Heat at reflux overnight. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum 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-d 6 )δ10.3(s,1H),8.06(d,J=2.0Hz,1H),8.00(dd,J=8.5,2.2Hz,1H),7.80(d,J=8.3Hz,1H),3.91(s,3H).

[0673] (c) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(methyl 3-bromobenzoate) (13)

[0674] A mixture of methyl 5-bromo-2-formylbenzoate (A28) (100 mg, 0.41 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (81.6 mg, 0.21 mmol) and NaHSO 3 A mixture of (21.9 mg, 0.21 mmol) in DMF (5 mL) was stirred at N 2 Heat at 120°C overnight. Add water (20 mL), collect the resulting precipitate by filtration and dry in vacuo 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-d 6)δ7.94(d,J=2.1Hz,2H),7.72-7.69(m,4H),7.46-7.41(m,4H),7.11(d,J= 8.7Hz, 2H), 6.77 (d, J = 8.0Hz, 2H), 4.36 (s, 6H), 4.25 (s, 4H), 3.61 (s, 6H).

[0675] (d) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3-bromobenzoic acid)(14)

[0676] To a solution of 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(methyl 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 2M aqueous HCl. The resulting precipitate was collected by filtration and dried in vacuo 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.95(d,J=2.0Hz,2H),7.72(br s,2H),7.65(d,J=8.6Hz,2H),7.45(br s,2H),7.33(dd,J=8.0,1.6Hz,2H),6.98(d,J=8.6Hz,2H),6.60(d,J=8.2Hz,2H),4.37(s,6H),4.25(s,4H).

[0677] 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)

[0678]

[0679] (a) 4,5-Difluoro-2-formylbenzoic acid (A29)

[0680] In N 2To a solution of 2-bromo-4,5-difluorobenzoic acid (500 mg, 2.11 mmol) in THF (5 mL) was added n-BuLi (2.5 M hexane solution, 1.70 mL, 4.22 mmol) dropwise at -78 °C, 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 heated with saturated NH 4 The mixture was quenched with aqueous Cl solution and 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] + .

[0681] (b) 6,6'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,4-difluorobenzoic acid)(15)

[0682] 4,5-Difluoro-2-formylbenzoic acid (A29) (16 mg, 0.086 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (23 mg, 0.07 mmol) and NaHSO 3 A mixture of (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, gradient elution with ACN aqueous solution containing 0.1% formic acid, 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-d 6 )δ7.81(dd,J=8.3,4.9Hz,2H),7.68(d,J=2.0Hz,2H),7.60(d,J=7.9Hz,2H),7.49-7. 38(m,4H),7.08(d,J=7.7Hz,2H),4.48-4.46(m,2H),4.34(s,6H),4.23-4.22(m,2H).

[0683] 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)

[0684]

[0685] (a) 3,5-Difluoro-2-formylbenzoic acid (A30)

[0686] To a solution of 2-bromo-3,5-difluorobenzoic acid (500 mg, 2.11 mmol) in anhydrous THF (10 mL) was added i-PrMgCl (2M THF solution, 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, the residue was diluted with 0.5 M aqueous HCl, extracted with DCM, and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel chromatography (petroleum ether / EtOAc=100:0 to 100:1) to give 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 HNMR (400 MHz, DMSO-d 6 )δ8.44(br s,1H),7.75(td,J=9.3,2.1Hz,1H),7.62(dd,J=7.0,2.1Hz,1H),6.82(br s,1H).

[0687] (b) 2,2'-(ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(3,5-difluorobenzoic acid) (16)

[0688] 3,5-Difluoro-2-formylbenzoic acid (A30) (130 mg, 0.70 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (136 mg, 0.35 mmol) and NaHSO 3 A solution of (73 mg, 0.70 mmol) in DMF (8 mL) was stirred at N 2The mixture was heated at 120°C for 16 h. The mixture was concentrated under reduced pressure until a precipitate was formed, which was collected by filtration and purified by preparative HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, gradient elution with ACN aqueous solution containing 0.1% formic acid, flow rate 15.0 mL / min) to obtain 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-d 6 )δ7.76-7.62(m,4H),7.60-7.50(m,2H),7.47(d,J=2.8Hz,2H),7.30-7.06(m, 2H),7.26(d,J=8.6Hz,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-d 6 )δ7.75(d,J=8.6Hz,2H),7.66-7.51(m,4H),7.38-7.16(m,4H),7.20(d,J=8.6Hz,2H),4.43-4.24(m,10H).

[0689] 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)

[0690]

[0691] (a) 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-carboxylic acid tert-butyl ester) (A31)

[0692] 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 hydrazinecarboxylate (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 N 2The 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), and then purified by Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave the title compound (410 mg, >100%) as a yellow oil which was used in the next step without further purification.

[0693] (b) 1,1'-(Ethane-1,2-diyl)bis(2-(4-chloro-2-(hydrazinecarbonyl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) dihydrochloride (A32)

[0694] A mixture of 2,2'-(2,2'-(ethane-1,2-diethylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(5-chlorobenzoyl))bis(hydrazine-1-carboxylate) (A31) (410 mg, assuming quantitative yield from the previous step, 0.42 mmol) and 3M HCl in dioxane solution (6 mL) was stirred at room temperature for 4 h. 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] + .

[0695] (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)

[0696] 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, assuming quantitative yield in the previous step, 0.095 mmol), CDI (59 mg, 0.36 mmol) and Et 3 A mixture of N (37 mg, 0.36 mmol) in DMF (4 mL) was stirred at 4 ℃ for 2 h. 2 The mixture was poured into water (20 mL), extracted with EtOAc (15 mL x 3), and the combined organic extracts were washed with water (15 x 2 mL), brine (15 mL), and then purified by Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by preparative HPLC (Agilent, BOSTON, 250×2.12 mm, 10 μm column, gradient elution with ACN water containing 0.1% formic acid, flow rate 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-d 6 )δ12.6(br s,2H),7.71(br s,2H),7.66(d,J=1.8Hz,2H),7.60(d,J=8.6Hz,2H),7.46(br s, 2H), 7.05 (d, J = 6.8Hz, 2H), 6.96 (d, J = 8.6Hz, 2H), 6.64 (d, J = 8.3Hz, 2H), 4.38 (s, 6H), 4.21 (s, 4H).

[0697] 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)

[0698]

[0699] (a) 4,5-Difluoro-2-methoxybenzoic acid (A33)

[0700] 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, CDCl 3 )δ7.99(dd,J=10.5,9.1Hz,1H),6.90(dd,J=11.2,6.0Hz,1H),4.05(s,3H).

[0701] (b) 4,5-Difluoro-2-methoxybenzamide (A34)

[0702] To a solution of 4,5-difluoro-2-methoxybenzoic acid (A33) (16.5 g, 85 mmol) in anhydrous DCM (300 mL) was added DMF (10 drops) and (COCl) at 0°C. 2(15 mL, 17 mmol), 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 anhydrous DCM (30 mL) and cooled to 0 °C. Concentrated NH 4 OH aqueous solution (26-28% aqueous solution, 70 mL), 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.76(dd,J=11.5,9.6Hz,1H),7.70(br s,1H),7.66(br s,1H),7.32(dd,J=12.7,6.5Hz,1H),3.89(s,3H).

[0703] (c) 4,5-Difluoro-2-methoxy-3-nitrobenzamide (A35)

[0704] 4,5-difluoro-2-methoxybenzamide (A34) (12.0 g, 64.2 mmol) was added to concentrated H 2 SO 4 Add KNO (150 mL) dropwise 3 (9.74 g, 96.3 mmol) in concentrated H 2 SO 4 (5 mL) and the reaction temperature was maintained at 0°C. After the addition was complete, TLC analysis showed that the starting material was consumed. The mixture was diluted with water, extracted with EtOAc, and the combined organic extracts were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH=1:0 to 200:1 to 100:1) to give 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-d 6 )δ7.99(br s,1H),7.96(dd,J=10.4,8.8Hz,1H),7.92(br s,1H),3.89(s,3H).

[0705] (d) 4,4'-(ethane-1,2-diylbis(azadiyl))bis(5-fluoro-2-methoxy-3-nitrobenzamide) (A36)

[0706] To a solution of 4,5-difluoro-2-methoxy-3-nitrobenzamide (A35) (2.5 g, 10.8 mmol) in DMF (13 mL) was added K 2 CO 3 (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-d 6 )δ7.56(br s,2H),7.54(br s,2H),7.47(d,J=13.9Hz,2H),6.27-6.20(m,2H),3.75(s,6H),3.34-3.33(m,4H).

[0707] (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)

[0708] To a solution of 4,4'-(ethane-1,2-diylbis(azadiyl))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 Na 2 S 2 O 4(0.214 g, 1.23 mmol). The flask was equipped 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 overnight at 50°C under vacuum, and then purified by preparative HPLC (Agilent, YMC-C18, 150×20 mm, 5 μm column, gradient elution with 0.1% TFA in ACN aqueous solution 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-d 6 )δ7.78(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).

[0709] Example 19-1,1'-(Ethane-1,2-diyl)bis(2-(5-chloro-2-(2H-tetrazolyl-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (42)

[0710]

[0711] (a) 4-Chloro-2-(dibromomethyl)benzonitrile (A37)

[0712] 4-Chloro-2-methylbenzonitrile (10.0 g, 66.0 mmol), NBS (35.2 g, 198 mmol) and BPO (1.60 g, 6.60 mmol) were dissolved in CCl 4 The solution in (200 mL) was heated to N 2 The mixture was heated at reflux for 24 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=500:1 to 200:1) to give the title compound (13.0 g, 64%) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ8.02(d,J=8.4Hz,1H),7.91(d,J=2.2Hz,1H),7.70(dd,J=8.3,2.1Hz,1H),7.40(s,1H).

[0713] (b) 4-Chloro-2-formylbenzonitrile (A38)

[0714] To a solution of 4-chloro-2-(dibromomethyl)benzonitrile A37 (10.0 g, 32.3 mmol) in acetonitrile (75 mL) was added AgNO 3 (16.5 g, 97.0 mmol) in water (17 mL) and the mixture was heated at reflux for 20 min and then cooled to room temperature. The precipitate was removed by filtration and washed with DCM (3×200 mL). The combined filtrate was washed with water (100 mL) and 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=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] + .

[0715] (c) 4-Chloro-2-(dimethoxymethyl)benzonitrile (A39)

[0716] 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 under reflux for 16 h. The mixture was concentrated under reduced pressure, and the residue was washed with saturated NaHCO 3 The aqueous solution was diluted and extracted with EtOAc. The organic extract was purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum 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] + .

[0717] (d) 5-(4-chloro-2-(dimethoxymethyl)phenyl)-2H-tetrazole (A40)

[0718] 4-Chloro-2-(dimethoxymethyl)benzonitrile (3.00 g, 14.2 mmol), Et 3 N.HCl (2.73 g, 19.9 mmol) and NaN 3 A mixture of (2.76 g, 42.5 mmol) in DMF (40 mL) was stirred under N 2Heat at 110°C for 16 h. Pour the mixture into water (200 mL) and wash with EtOAc (100 mL×3). The aqueous layer was lyophilized 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] - .

[0719] (e) 5-Chloro-2-(2H-tetrazolyl-5-yl)benzaldehyde (A41)

[0720] 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 H 2 SO 4 Aqueous solution (36 mL, 70.6 mmol) was added 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 and brine, and then purified by Na 2 SO 4 Dry, filter and concentrate 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 HNMR (400 MHz, DMSO-d 6 )δ10.3(s,1H),7.98(d,J=2.0Hz,1H),7.97-7.96(m,2H).

[0721] (f) 1,1'-(Ethane-1,2-diyl)bis(2-(5-chloro-2-(2H-tetrazolyl-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide)(42)

[0722] 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) I13 (200 mg, 0.51 mmol), 5-chloro-2-(2H-tetrazolyl-5-yl)benzaldehyde A41 (236 mg, 0.58 mmol) and A solution of (380 mg, 0.61 mmol) in DMF (6 mL) was stirred at N 2The mixture was stirred at room temperature for 2 h. The mixture was poured into water (30 mL), 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-d 6 )δ7.91(d,J=8.4Hz,2H),7.67-7.65(m,4H),7.61(d,J=8.1Hz,2H),7.45(br s,2H),6.93-6.91(m,4H),4.29(s,6H),4.17(s,4H).

[0723] Example 20-1,1'-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(2H-tetrazolyl-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (43)

[0724]

[0725] (a) 2-Bromo-3,5-difluorobenzonitrile (A42)

[0726] 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) was added concentrated H 2 SO 4 (14.1 g, 143.8 mmol). 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), and then washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel chromatography (petroleum ether / EtOAc=200:1 to 100:1) to give the title compound (7.2 g, 92%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ7.98–7.94(m,1H),7.92(dd,J=8.9,2.8Hz,1H).

[0727] (b) 3,5-Difluoro-2-vinylbenzonitrile (A43)

[0728] 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(PPh 3 ) 4 (2.65 g, 2.29 mmol), and the mixture was stirred under N 2 The mixture was poured into water (400 mL), extracted with EtOAc (200 mL×3), and the combined organic extracts were washed with water (100×2 mL), brine (100 mL), and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel chromatography (petroleum 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-d 6 )δ7.86–7.72(m,2H),6.77(dd,J=17.8,11.8Hz,1H),6.05(d,J=17.8Hz,1H),5.82(d,J=11.7Hz,1H).

[0729] (c) 5-(3,5-difluoro-2-vinylphenyl)-1H-tetrazole (A44)

[0730] 3,5-Difluoro-2-vinylbenzonitrile A43 (2.00 g, 12.1 mmol), t 3 N.HCl (2.34 g, 18.8 mmol) and NaN 3 A solution of (2.36 g, 36.3 mmol) in DMF (40 mL) was stirred at N 2 The mixture was heated at 110°C for 16 h. The mixture was poured into water (400 mL) and washed with EtOAc (250 mL×3). The aqueous phase was lyophilized 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] + .

[0731] (d) 2,4-difluoro-6-(1H-tetrazolyl-5-yl)benzaldehyde (A45)

[0732] 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 stirred for 2 h.3 The gas was bubbled 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 give 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-d 6 )δ10.1(s,1H),7.78–7.70(m,1H),7.67(d,J=8.9Hz,1H).

[0733] (e) 1,1'-(Ethane-1,2-diyl)bis(2-(2,4-difluoro-6-(2H-tetrazolyl-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide)(43)

[0734] 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) I13 (160 mg, 0.41 mmol), 2,4-difluoro-6-(1H-tetrazolyl-5-yl)benzaldehyde A45 (190 mg, 0.90 mmol) and A solution of (304 mg, 0.49 mmol) in DMF (8 mL) was stirred at N 2 The mixture was stirred at room temperature for 1 h. The mixture was poured into water (50 mL) and the resulting precipitate was collected by filtration. The product was purified by preparative HPLC (Agilent, BOSTON 250×2.12 mm, 10 μm column, 1% HCO 2 The residue was purified by gradient elution with aqueous ACN solution at a flow rate of 20.0 mL / min to afford the title compound (5 mg, 2%) as a gray solid. LCMS-B (ES-API): rt 2.57 min, m / z 769.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.73–7.66(m,4H),7.59(d,J=8.4Hz,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).

[0735] 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)

[0736]

[0737] (a) 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-carboxylic acid tert-butyl ester) (A46)

[0738] To a solution of 2,2'-(ethane-1,2-diethylbis(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 (50% w / w EtOAc solution, 2.23 g, 3.5 mmol), tert-butyl carbamate (370 mg, 2.8 mmol) and Et 3 N (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 showed that the reaction was incomplete. The residue was dissolved in THF (2.5 mL) and added (50% w / w EtOAc solution, 2.23 g, 3.5 mmol), tert-butyl carbamate (370 mg, 2.8 mmol) and Et 3 N (1.4 g, 14.0 mmol) was added and the mixture was heated at 80 °C for 7 h. The solvent was removed under reduced pressure. LCMS analysis showed that the reaction was incomplete. The residue was dissolved in THF (2.5 mL) and added (50% w / w EtOAc solution, 2.23 g, 3.5 mmol), tert-butyl carbamate (370 mg, 2.8 mmol) and Et 3 N (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 showed that the reaction was incomplete. The residue was dissolved in THF (2.5 mL) and added (50% w / w EtOAc solution, 2.23 g, 3.5 mmol), tert-butyl carbamate (370 mg, 2.8 mmol) and Et 3N (1.4 g, 14.0 mmol), 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] + .

[0739] (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)

[0740] 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 4M solution of HCl in dioxane (20 mL), and the mixture was then stirred at room temperature for 2 h. 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-d 6 )δ12.3(s,2H),10.4(s,2H),7.77-7.74(m,6H),7.39-7.34(m,8H),5.00-4.00(m,10H).

[0741] (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)

[0742] 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 to be 0.10 mmol) in DMF (1 mL) was added CDI (64.9 mg, 0.40 mmol) and Et 3N (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, gradient elution with ACN aqueous solution containing 0.1% formic acid, flow rate 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-d 6 )δ12.7(brs,2H),7.81–7.73(m,3H),7.69–7.51(m,6H),7.17(d,J=8.4Hz,2 H),6.85(s,1H),4.56(d,J=9.6Hz,2H),4.39(s,6H),4.18(d,J=9.6Hz,2H). 1 H NMR (400 MHz, 60 °C, DMSO-d 6 )δ12.6(s,2H),7.66–7.56(m,7H),7.34(s,2H),7.13(d,J=8.8Hz,2H),6.87(s,1H),4.50(s,2H),4.35(s,6H),4.18(s,2H).

[0743] 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)

[0744]

[0745] (a) 2-Bromo-4-chloro-6-fluorobenzaldehyde (A48)

[0746] In N 2To a solution of 1,2-dibromo-5-chloro-3-fluorobenzene (2.0 g, 6.94 mmol) in anhydrous THF (10 mL) was added i-PrMgCl (2M THF solution, 3.81 mL, 7.63 mmol) at -65°C 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 and purified by Na 2 SO 4 After drying, filtering and concentrating under reduced pressure, the residue was purified by silica gel chromatography (petroleum ether) to give the title compound (800 mg, 50%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ10.20(d,J=1.2Hz,1H),7.45(t,J=1.7Hz,1H),7.13(dd,J=10.0,2.0Hz,1H).

[0747] (b) 1,1'-(Ethane-1,2-diyl)bis(2-(2-bromo-4-chloro-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide)(45)

[0748] 2-Bromo-4-chloro-6-fluorobenzaldehyde (A48) (1.34 g, 5.67 mmol), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (1.0 g, 2.57 mmol) and NaHSO 3 A mixture of (670 mg, 6.44 mmol) in DMF (16.8 mL) was heated at 80 °C overnight. The mixture was cooled to room temperature, 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] + .

[0749] (c) 1,1'-(Ethane-1,2-diyl)bis(2-(4-chloro-2-cyano-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (A49)

[0750] A solution 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 cooled to room temperature, 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 give the title compound (330 mg, 54%) as a brown solid. LCMS-C (ES-API): rt 3.49 min, m / z 715.06 [M+H] + .

[0751] (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)

[0752] 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), Et 3 N.HCl (150 mg, 1.09 mmol) and NaN 3 A mixture of (141.7 mg, 2.18 mmol) in DMF (2.4 mL) was stirred under N 2 The mixture was heated at 80°C overnight. The mixture was returned 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 chromatographed on silica gel (DCM / MeOH, 5:1, containing 2.5% v / v concentrated NH 4 OH aqueous solution), and then by preparative HPLC (Agilent, YMC-C18, 150×20 mm, 5.0 μm column, gradient elution with 0.1% TFA in MeOH aqueous solution, flow rate of 15.0 mL / min) to obtain 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-d 6 )δ7.96–7.63(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).

[0753] 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)

[0754]

[0755] 4,4'-(Ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (100 mg, 0.26 mmol), 4-chloro-2-(2H-tetrazolyl-5-yl)benzaldehyde (A18) (54 mg, 0.26 mmol), 5-chloro-3-fluoro-2-formylbenzoic acid (A25) (52 mg, 0.26 mmol) and NaHSO 3 A mixture of (80 mg, 0.78 mmol) in DMF (8.0 mL) was stirred under N 2 Heat at 120°C for 16 h under atmosphere. Cool the mixture to room temperature, pour into water (40 mL), and collect the resulting precipitate by filtration. Preparative HPLC (Agilent 10prep-C18, 10 μm, 250×21.3 mm column, gradient elution with ACN aqueous solution containing 0.1% formic acid, flow rate 20 mL / min) gave 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-d 6 )δ7.97(d,J=1.6Hz,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).

[0756] Example 24: 1,1'-(Ethane-1,2-diyl)bis(2-(2-fluoro-6-(2H-tetrazolyl-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (48)

[0757]

[0758] (a) 2-(Bromomethyl)-3-fluorobenzonitrile (A50)

[0759] 3-Fluoro-2-methylbenzonitrile (4.4 g, 32.6 mmol) was added in CCl 4 To the solution in (45mL) was added NBS (29.0g, 163mmol) and BPO (0.8g, 3.3mmol), and the mixture was heated at reflux overnight. The mixture was returned 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 (petroleum ether / EtOAc=200:1 to 50:1) to give the title compound (5.2g, 74%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ7.82(dd,J=7.6,0.8Hz,1H),7.70-7.60(m,2H),4.74(d,J=0.8Hz,2H).

[0760] (b) 3-Fluoro-2-formylbenzonitrile (A51)

[0761] 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, extracted with EtOAc, and the organic extract was purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound (540 mg, 75%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.3(s,1H),7.94–7.85(m,2H),7.85–7.77(m,1H).

[0762] (c) 1,1'-(ethane-1,2-diyl)bis(2-(2-cyano-6-fluorophenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide) (A52)

[0763] 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(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (592 mg, 1.52 mmol) and NaHSO 3(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-d 6 )δ7.70(br s,2H),7.66-7.64(m,4H),7.55(br s,2H),7.44-7.41(m,4H),7.07(d,J=8.7Hz,2H),4.65(s,4H),4.42(s,6H).

[0764] (d) 1,1'-(Ethane-1,2-diyl)bis(2-(2-fluoro-6-(2H-tetrazolyl-5-yl)phenyl)-4-methoxy-1H-benzo[d]imidazole-5-carboxamide)(48)

[0765] 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 Et 3 N.HCl (97 mg, 0.705 mmol) and NaN 3 (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, gradient elution with ACN aqueous solution containing 0.1% formic acid, 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 2.445 min; m / z 733.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.03(d,J=7.8Hz,1H),7.83(d,J=7.9Hz,2H),7.70–7.58(m,4H),7.56–7.37(m,4H),6.96 (d,J=8.2Hz,2H),6.49(d,J=8.4Hz,1H),4.40–4.25(m,2H),4.19(s,6H),4.09–3.99(m,2H).

[0766] 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)

[0767]

[0768] (a) Methyl 2-bromo-3-fluorobenzoate (A53)

[0769] To a solution of 2-bromo-3-fluorobenzoic acid (5.00 g, 22.9 mmol) in MeOH (40 mL) was added concentrated H 2 SO 4 (3.0 mL), and the mixture was heated at reflux overnight. The mixture was diluted with water, extracted with DCM, and the organic layer was washed with brine and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound (4.8 g, 90%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ7.71–7.49(m,3H),3.88(s,3H).

[0770] (b) 2-Bromo-3-fluorobenzohydrazide (A54)

[0771] 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% aqueous solution, 16.0 g, 329 mmol), and the mixture was heated at 55°C for 3 h. The mixture was returned to room temperature, poured into ice water, and the resulting precipitate was collected by filtration and dried in vacuo 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-d 6 )δ9.64(br s,1H),7.52–7.40(m,2H),7.20(ddd,J=6.9,2.0,0.8Hz,1H),4.53(br s,2H).

[0772] (c) 5-(2-Bromo-3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (A55)

[0773] To a solution of 2-bromo-3-fluorobenzohydrazide (A54) (3.2 g, 13.7 mmol) in DMF (26.0 mL) was added Et3 N (4.2 g, 41.2 mmol) and CDI (6.7 g, 41.2 mmol) were added and the mixture was heated at 40°C for 3 h. The mixture was poured into water and extracted with DCM. The organic extract was washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=5:1) to give the title compound (1.5 g, 43%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.9(br s,1H),7.67–7.59(m,3H).

[0774] (d) 5-(3-Fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A56)

[0775] 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(PPh 3 ) 4 (265.8 mg, 0.23 mmol), and the mixture was stirred under N 2 The mixture was poured into water (20 mL), extracted with EtOAc (9 mL×3), and the combined organic extracts were washed with water (9 mL×2) and brine (9 mL), and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=50:1 to 10:1) to give 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-d 6 )δ12.7(br s,1H),7.60–7.56(m,1H),7.51–7.44(m,2H),6.99(dd,J=17.9,11.8Hz,1H),5.78(ddd,J=17.9,2.6,1.6Hz,1H),5.67(dt,J=11.8,1.8Hz,1H).

[0776] (e) 2-Fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A57)

[0777] 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 stirred at 4 °C. 3 The gas was bubbled until the light blue color persisted. Dimethyl sulfide (746 mg, 12.0 mmol) was added, the mixture was returned 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 [MH] -

[0778] (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)

[0779] 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(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (120 mg, 0.41 mmol) and A solution of (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), the resulting precipitate was collected by filtration and purified by preparative HPLC (Agilent YMC-C18, 5 μm, 150×20 mm column, gradient elution with ACN aqueous solution containing 0.1% formic acid, 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 about 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-d 6 )δ7.90–7.62(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).

[0780] 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)

[0781]

[0782] (a) Methyl 2-bromo-5-chloro-3-fluorobenzoate (A58)

[0783] To a solution of 2-bromo-5-chloro-3-fluorobenzoic acid (A24) (4.0 g, 15.8 mmol) in DMF (52 mL) was added CH 3 I (4.5 g, 31.6 mmol) and K 2 CO 3 (6.4 g, 47.4 mmol), and the mixture was stirred at room temperature for 30 min. The mixture was diluted with water, extracted with EtOAc, and the organic layer was washed with brine and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel chromatography (petroleum 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 )δ7.87(dd,J=8.6,2.4Hz,1H),7.70(dd,J=2.3,1.5Hz,1H),3.88(s,3H).

[0784] (b) 2-Bromo-5-chloro-3-fluorobenzohydrazide (A59)

[0785] 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% aqueous solution, 5.6 g, 89.5 mmol), and the mixture was heated at 55° C. for 2 h. The mixture was returned to room temperature, poured into ice water, and the resulting precipitate was collected by filtration and dried in vacuo to give the title compound (1.4 g, 93%) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ9.71(br s,1H),7.74(dd,J=8.7,2.4Hz,1H),7.34(dd,J=2.4,1.3Hz,1H),4.55(br s,2H).

[0786] (c) 5-(2-Bromo-5-chloro-3-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (A60)

[0787] 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 Et 3 N (1.6 g, 15.7 mmol), and the mixture was stirred under N 2 The mixture was cooled to room temperature, poured into water and extracted with DCM. The organic extract was washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum 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-d 6 )δ7.90(dd,J=8.6,2.4Hz,1H),7.70(dd,J=2.0,1.2Hz,1H).

[0788] (d) 5-(5-Chloro-3-fluoro-2-vinylphenyl)-1,3,4-oxadiazol-2(3H)-one (A61)

[0789] 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(PPh 3 ) 4 (375.3 mg, 0.325 mmol), and the mixture was stirred under N 2 The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether to petroleum 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.9(s,1H),7.76(dd,J=10.9,2.1Hz,1H),7.76(dd,J=2.0,0.8Hz,1H),6.98(dd,J=18.0,12.0Hz,1H),5.82-5.68(m,2H).

[0790] (e) 4-Chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A62)

[0791] 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 bubbled with O 3 Gas until light blue persists. Dimethyl sulfide (490 mg, 7.9 mmol) was then added, and the mixture was returned 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 [MH] - .

[0792] (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)

[0793] A solution of 4-chloro-2-fluoro-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzaldehyde (A62) (crude product from the previous step, 200 mg), 4,4'-(ethane-1,2-diylbis(azadiyl))bis(3-amino-2-methoxybenzamide) (I13) (87.5 mg, 0.23 mmol) and A solution of (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, freeze-dried, and the residue was purified by silica gel chromatography (DCM and DCM / MeOH=10:1) and then by preparative HPLC (Agilent YMC-C18, 5 μm, 150×20 mm column, gradient elution with ACN aqueous solution containing 0.1% formic acid, flow rate of 15.0 mL / min) to give the title compound (7.2 mg, 1.1%, over 2 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-d 6)δ7.73(br s,2H),7.64(s,2H),7.55–7.46(m,4H),7.06(d,J=8.6Hz,2H),6.89(br s,2H),4.50–4.39(m,2H),4.33(s,6H),4.15–4.04(m,2H).

[0794] Further Embodiments

[0795] The following exemplified compounds were prepared by similar methods.

[0796]

[0797]

[0798]

[0799]

[0800]

[0801] Determination

[0802] The compounds disclosed herein were tested for activity as STING modulators in the following assays. Each detection method is designed to test different aspects of the potential interaction of a compound with STING. Therefore, compounds are considered active as long as they show binding or modulation in any one (or more) of these assays.

[0803] Protein production and purification

[0804] 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 encoding amino acid residues 149 to 345 (Swiss Prot Q86WV6) of human STING (WT) for expression in E. coli, human STING (HAQ) and human STING (R232H) were synthesized by GenScriptUSA Inc (Piscataway, New Jersey, USA). They 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 of the three allelic variants are listed below:

[0805] His-TEV–hSTING (WT)

[0806] MGHHHHHHGTENLYFQGSE149 KGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGS 345

[0807] His-TEV–hSTING(R232H)

[0808] MGHHHHHHGTENLYFQGSE 149 KGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGS 345

[0809] His-TEV–hSTING(HAQ)

[0810] MGHHHHHHGTENLYFQGSE 149 KGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTADRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCQTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGS 345

[0811] To produce recombinant human STING protein, the expression plasmid encoding the above construct was transformed into Escherichia coli BL21DE3 strain and grown in 2×1L volume of Terrific broth (TB) supplemented with 100 μg / ml ampicillin at 37°C with shaking until OD600 reached 0.8. The culture was then cooled to 16°C, protein expression was induced by adding isopropyl β-D-1-thiogalactopyranoside to a final concentration of 0.5 mM, and the culture was shaken overnight for another 16 h. After expression, the cell culture was centrifuged at 5000×g for 20 min, and the cell pellet was frozen at -70°C.

[0812] Protein purification was initiated by thawing cell pellets in lysis buffer (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 2 mM MgCl2, 10 mM imidazole, 0.5 mg / ml lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, complete protease inhibitor tablets, EDTA-free [Roche]) using a ratio of 7 ml buffer per 1 g of cells. Cells were further lysed by passing through an ice-cold Avestin C5 cell disruptor three times and then centrifuged 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 (25mMTris-HCl pH 8.0, 300mM NaCl, 5mM DTT, 20mM imidazole), and the bound His-TEV-hSTING protein was eluted with IMAC elution buffer (25mM Tris-HCl pH 8.0, 300mM NaCl, 5mM DTT, 250mM imidazole). The IMAC eluted protein was further purified by a HiLoad 26 / 60 Superdex 75 column pre-equilibrated in storage buffer (25mM Tris-HCl, pH 8.0, 150mM NaCl, 5mM DTT 0.02% [w / v] sodium azide). Finally, the hSTING protein was concentrated to ≥2mg / ml using an Amicon Ultra centrifugal filter device (Utra-15 MWCO 10kDa), quickly frozen in liquid nitrogen and stored in a -70°C freezer.

[0813] Differential Scanning Fluorescence (DSF)

[0814] Differential scanning fluorimetry (DSF) is a rapid screening method for identifying low molecular weight ligands that bind and stabilize (or sometimes destabilize) purified proteins (Niesen 2007). DSF monitors the thermal unfolding of proteins in the presence of a fluorescent dye, typically using a real-time PCR instrument. The temperature at which the protein unfolds is measured by the increase in fluorescence of the dye, which has an affinity for the hydrophobic parts of the protein that are gradually exposed during the unfolding process. The fluorescence of the dye is quenched in an aqueous environment, but increases when the dye binds to hydrophobic sites on the unfolded protein. Plotting the fluorescence intensity as a function of temperature generates an S-shaped curve that can be described by a two-state transition. The inflection point (Tm) of the transition curve is calculated using simple equations, such as the Boltzmann equation.

[0815] The thermal stability of STING protein (with and without bound ligand) was measured using a previously described method (Seabrook & Newman, 2013), and samples were tested in triplicate using 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 mixture dilution 1:1200) and compound (final concentration 100 μM). The sealed plate was placed in a Bio-Rad CFX96 / C1000 thermal cycler and FRET scanning mode (λ excitation at 490 nm, read at λ emission at 570 nm). Melting curves were recorded from 20°C to 100°C in increments of 0.5°C every 30 seconds, and readings were taken at each increment. Data were analyzed using the “Meltdown analysis” protocol described by Rosa (2015). The melting temperature (Tm) obtained for STING protein alone (1% [v / v] DMSO) was subtracted from the Tm obtained for protein incubated with ligand. m ) to generate the ΔT listed in the table below m DSF data for each compound were generated for three different STING protein variants: human STING (WT), human STING (HAQ), and human STING (R232H).

[0816]

[0817]

[0818] Surface Plasmon Resonance (SPR)

[0819] The binding interaction of the ligand to the STING protein was quantified using surface plasmon resonance (SPR) with minimally biotinylated STING protein immobilized on the surface of a streptavidin chip. In this way, a highly active STING protein surface was obtained that was not affected by the low pH required for the amine coupling method. Purified huSTING protein was minimally biotinylated using a previously described method (Chhabra 2012). Briefly, approximately 20 nmol of recombinant STING protein in 1× TBS buffer (25 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM DTT) was incubated with EZ-LinkTM Sulfo-NHS-LC-LC-biotin (Thermofisher Scientific, cat#21338) at a molar ratio of 1:0.6 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, 5% [v / v] glycerol. The protein peak containing the biotinylated huSTING protein was collected and stored in aliquots at -80°C.

[0820] Streptavidin was immobilized simultaneously in all four channels of a CM5 sensor chip docked to a Biacore instrument (Biacore S200 or Biacore T200, GE Healthcare) as described previously (Zender 2013). The SPR binding buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 2% [v / v] DMSO) was added at 8 °C in a single channel at a constant flow rate of 2 μL / min until the desired capture level was reached, typically 3000 to 7000 RU (1 RU = 1 pg / mm 2 ).

[0821] All binding experiments were performed at 8 °C in SPR binding buffer. To determine binding affinity, compound interactions with immobilized STING protein were analyzed using dose-effect experiments. Fresh 10 mM DMSO compound solutions were diluted directly into SPR binding buffer to a concentration typically of 50 μM and then further diluted 2- or 3-fold to reach a 5- or 7-point concentration series range. Each ligand concentration series was injected at a constant flow rate of 60 μL / min with an association time of 90 s and a dissociation time of 180 s. These were modified for compounds with longer residence times to allow the curve to reach steady state or to allow the compound to completely dissociate before subsequent injections. Where appropriate, tighter binding compounds (approximately KD < 1 uM) were tested using a single-cycle kinetic format (Karlsson 2006) with longer association and dissociation times (typically 450 s and 1800 s, respectively).

[0822] Scrubber 2 (www.biologic.com.au) was used for data processing, where the signal was referenced to a blank surface (streptavidin + D-biotin) and further corrected for DMSO refractive index changes and then “double referenced” using buffer-blank injections (Papalia 2006). Responses were fit to either a 1:1 steady-state affinity model or a 1:1 kinetic model (including a mass transport component) available in Scrubber.

[0823] Example <![CDATA[SPR(HAQ)K D (μM)]]> 1 16.6 2 67 3 >10 4 28.6 5 19.3 6 11.9 9 2.66 10 0.183 11 0.078 15 6.34 16 0.166 17 0.416 18 0.144 19.1 0.002 20 12.8 21 1.09 22 0.002 23 0.002 24 22 25 19.3 26 32.5 29.1 0.936 30 90 31 55 32 90 33 78 34 26 35 35 37 0.200 38 >100 39 300 40 64

[0824] Example <![CDATA[SPR(HAQ)K D (μM)]]> 41 83 42 14.8 43 0.096 44 0.423 45 28.9 46 0.025 48 0.030 49 0.031 50 0.014

[0825] Example <![CDATA[SPR(WT)K D (μM)]]> 1 200 2 80 3 700 4 >10 5 30 6 40 9 40 10 5.86 11 1.08 15 1000 16 1.52 17 9.5 18 2.01 19.1 0.034 20 96 21 5.380 22 0.077 23 0.043 24 102 25 250 26 >40 29.1 33 30 126 31 88 32 >80 33 107 34 74 35 >100 36 58 38 >100 40 180 41 200 42 139.1 43 1.79 44 11.1 45 29.6

[0826] Example <![CDATA[SPR(WT)K D (μM)]]> 46 0.413 48 0.512 49 0.755 50 0.359

[0827] THP-1 reporter cell line assay

[0828] THP-1STING Lucia ISG cells (InvivoGen#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 seeded at a density of 7 × 105 cells / mL and maintained at 37°C / 5% CO 2 The cells were passaged every 3-4 days. The selection pressure was maintained by adding 100 μg / mL Zeocin every second time.

[0829] Assay conditions: Cells were harvested and resuspended in fresh growth medium at a concentration of 5×105 cells / mL. 20 μL of this cell preparation was dispensed per well into a 384-well cell culture plate (Greiner, #781098X) and incubated at 37°C / 5% CO 2 Incubate for 2 hours.

[0830] Starting with a 10 mM compound stock solution in DMSO, concentration effect curves (typically 11 doses) were prepared by 2.5-fold serial dilutions. Compound dilutions were transferred to the cell culture plate using a needle tool (0.1 μL transfer), with control wells matched to DMSO. Positive control wells received ML RR S2 CDA (Med Chem Express HY12885B) in 5 μL of culture medium at a final concentration of 40 μM. All other wells received only an additional 5 μL of culture medium to balance the volume. Plates were incubated at 37°C / 5% CO 2 Incubate for 24 hours.

[0831] For the detection step, QUANTI-Luc (InvivoGen #rep-qlc1) was prepared according to the manufacturer's instructions and 10 μL per well was added to the culture plate. The plate was shaken for 10 seconds on an orbital shaker and placed in the dark at room temperature for 2 minutes before reading luminescence on a Perkin Elmer Envision plate reader.

[0832] Data Analysis: Luminescence raw data were normalized to % activity relative to the signals of positive control wells and negative control wells not treated with compound. The following formula was used to calculate the normalized % activity of the raw signal:

[0833] Activity % = (sample – negative) / (positive – negative)

[0834] THP-1STING Lucia ISG Cell EC 50 The activity of the human HAQ isoform of STING can be assessed. To assess the activity of compounds against the WT human STING isoform, an equivalent method was performed, where the cells used were THP-1-Dual KI-hSTING-R232 (InvivoGen #thpd-r232).

[0835]

[0836]

[0837] Description of the Invention

[0838] 1. Compounds of formula I:

[0839]

[0840] in:

[0841] Y is (CH 2 ) n , wherein n is 2 to 4, or -CH 2 -CH=CH-CH 2 -;

[0842] R 1 and R 11 independently selected from -C(=O)OH, -C(=O)OR P1 , Br, F, tetrazolyl, oxo-oxadiazolyl and (2H-triazol-4-yl), wherein R P1 is selected from methyl and ethyl;

[0843] A 1 CR A or N;

[0844] A 2 CR B or N;

[0845] A 3 CR C or N;

[0846] A 4 CR D or N;

[0847] Among them A 1 , A 2 , A 3 and A 4 No more than two of them can be N;

[0848] R A , R B , R C and R D One, two or three (if present) are selected from H, F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH;

[0849] The rest of R A , R B , R C and R D (if present) is H;

[0850] A 11 CR AA or N;

[0851] A12 CR BB or N;

[0852] A 13 CR CC or N;

[0853] A 14 CR DD or N;

[0854] Among them A 11 , A 12 , A 13 and A 14 No more than two of them can be N;

[0855] R AA , R BB , R CC and R DD One, two or three (if present) are selected from H, F, Cl, Br, I, Me, Et, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH;

[0856] The rest of R AA , R BB , R CC and R DD (if present) H;

[0857] R C1 , R C3 and R C4 independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 Alkenyl and C 5 Heterocyclic group;

[0858] R C11 , R C13 and R C14 independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 Alkenyl and C 5 Heterocyclic group;

[0859] or a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and / or N-oxide thereof.

[0860] 2. A compound according to statement 1, wherein 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 .

[0861] 3. A compound according to statement 1 or 2, wherein A 1 CR A .

[0862] 4. A compound according to statement 1 or 2, wherein A 1 is N.

[0863] 5. A compound according to any one of statements 1 to 4, wherein A 2 CR B .

[0864] 6. A compound according to any one of statements 1 to 4, wherein A 2 is N.

[0865] 7. A compound according to any one of statements 1 to 6, wherein A 3 CR C .

[0866] 8. A compound according to any one of statements 1 to 6, wherein A 3 is N.

[0867] 9. A compound according to any one of statements 1 to 6, wherein A 4 CR D .

[0868] 10. A compound according to any one of statements 1 to 6, wherein A 4 is N.

[0869] 11. A compound according to statement 1 or 2, wherein A 1 CR A , A 2 CR B , A 3 CR C , and A 4 CR D .

[0870] 12. A compound according to statement 1 or 2, wherein A 1 , A 2 , A 3 and A 4 One of them is N.

[0871] 13. A compound according to statement 1 or 2, wherein A 1 , A 2 , A 3 and A 4 Two of them are N.

[0872] 14. A compound according to any one of statements 1 to 13, wherein A 11 CR AA .

[0873] 15. A compound according to any one of statements 1 to 13, wherein A 11 is N.

[0874] 16. A compound according to any one of statements 1 to 15, wherein A 12 CR BB .

[0875] 17. A compound according to any one of statements 1 to 15, wherein A 12 is N.

[0876] 18. A compound according to any one of statements 1 to 17, wherein A 13 CR CC .

[0877] 19. A compound according to any one of statements 1 to 17, wherein A 13 is N.

[0878] 20. A compound according to any one of statements 1 to 19, wherein A 14 CR DD .

[0879] 21. A compound according to any one of statements 1 to 19, wherein A 14 is N.

[0880] 22. A compound according to any one of statements 1 to 13, wherein A 11 CR AA , A 12 CR BB , A 13 CR CC , and A 14 CR DD .

[0881] 23. A compound according to any one of statements 1 to 13, wherein A 11 , A 12 , A 13 and A 14 One of them is N.

[0882] 24. A compound according to any one of statements 1 to 13, wherein A 11 , A 12 , A 13 and A 14 Two of them are N.

[0883] 25. A compound according to any one of statements 1 to 13, wherein the compound is of formula IIIb:

[0884]

[0885] 26. A compound according to any one of statements 1 to 13, wherein the compound is of formula IIIc:

[0886]

[0887] 27. A compound according to any one of statements 1 to 13, wherein the compound is of formula IIId:

[0888]

[0889] 28. A compound according to any one of statements 1 to 13, wherein the compound is of formula IIIe:

[0890]

[0891] 29. A compound according to any one of statements 1 to 28, wherein R A , R B , R C and R D One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano and OMe, and the remainder (if present) are H.

[0892] 30. A compound according to any one of statements 1 to 28, wherein R A , R B , R C and R D One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl and OMe, and the remainder (if present) is H.

[0893] 31. A compound according to any one of statements 1 to 28, wherein R A , R B , R C and R D One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 and OMe, with the remainder (if any) being H.

[0894] 32. A compound according to any one of statements 1 to 31, wherein R A (if present) selected from H and F.

[0895] 33. A compound according to any one of statements 1 to 32, wherein R B (if present) is selected from H, F and Cl.

[0896] 34. A compound according to statement 33, wherein R B (if present) is selected from H and Cl.

[0897] 35. A compound according to any one of statements 1 to 34, wherein R C (if present) is selected from H, F and Cl.

[0898] 36. A compound according to any one of statements 1 to 35, wherein R D (if present) is selected from H, F and Cl.

[0899] 37. A compound according to statement 11, wherein R A , R B , R C and R D Choose from one of the following combinations:

[0900] combination <![CDATA[R A ]]> <![CDATA[R B ]]> <![CDATA[R C ]]> <![CDATA[R D ]]> 1 F H H H 2 H Br H H 3 H Cl H H 4 F Cl H H 5 H H H Br 6 H H Cl H 7 H F F H 8 H H H H 9 CF CH CF CH 10 CF CH CCl CH 11 CBr CH CH CH 12 CCl CH CH CH 13 N CH CCl CH 14 CH CCl CCl CH 15 CH CF CH CH 16 CH CMe CH CH 17 CH N CH CH 18 CH CH CBr CH 19 CH CH <![CDATA[CCF 3 ]]> CH 20 CH CH CE CH 21 CH CH CF CH 22 CH CH CMe CH 23 CH CH C-OMe CH 24 CH CH CCl CCl 25 CH CH CH CF 26 CH CH CH C-OMe 27 CH CH CH N 28 CI CH CH CH 29 CH CH CCN CH 30 CBr CH CCl CH

[0901] 38. A compound according to statement 37, wherein R A , R B , R C and R D Selected from combinations 1, 3, 6 and 9.

[0902] 39. A compound according to any one of statements 1 to 38, wherein R AA , R BB , R CC and R DD One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano and OMe, and the remainder (if present) are H.

[0903] 40. A compound according to any one of statements 1 to 38, wherein R AA , R BB , R CC and R DD One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl and OMe, and the remainder (if present) is H.

[0904] 41. A compound according to any one of statements 1 to 38, wherein R AA , R BB , R CC and R DD One, two or three (if present) are selected from H, F, Cl, Br, Me, CF 3 and OMe, with the remainder (if any) being H.

[0905] 42. A compound according to any one of statements 1 to 41, wherein R AA (if present) selected from H and F.

[0906] 43. A compound according to any one of statements 1 to 42, wherein R BB (if present) is selected from H, F and Cl.

[0907] 44. A compound according to statement 43, wherein R BB (if present) is selected from H and Cl.

[0908] 45. A compound according to any one of statements 1 to 44, wherein R CC (if present) is selected from H, F and Cl.

[0909] 46. ​​A compound according to any one of statements 1 to 45, wherein R DD (if present) is selected from H, F and Cl.

[0910] 47. A compound according to statement 22, wherein R AA , R BB , R CC and R DD Choose from one of the following combinations:

[0911] combination <![CDATA[R AA ]]> <![CDATA[R BB ]]> <![CDATA[R CC ]]> <![CDATA[R DD ]]> 1 F H H H 2 H Br H H 3 H Cl H H 4 F Cl H H 5 H H H Br 6 H H Cl H 7 H F F H 8 H H H H 9 CF CH CF CH 10 CF CH CCl CH 11 CBr CH CH CH 12 CCl CH CH CH 13 N CH CCl CH 14 CH CCl CCl CH 15 CH CF CH CH 16 CH CMe CH CH 17 CH N CH CH 18 CH CH CBr CH 19 CH CH <![CDATA[CCF 3 ]]> CH 20 CH CH CE CH 21 CH CH CF CH 22 CH CH CMe CH 23 CH CH C-OMe CH 24 CH CH CCl CCl 25 CH CH CH CF 26 CH CH CH C-OMe 27 CH CH CH N 28 CI CH CH CH 29 CH CH CCN CH 30 CBr CH CCl CH

[0912] 48. A compound according to statement 47, wherein R AA , R BB , R CC and R DD Selected from combinations 1, 3, 6 and 9.

[0913] 49. A compound according to any one of statements 1 to 48, wherein R C1 , R C3 and R C4 independently selected from H, Cl, F, Br, Me, OMe, cyano, CF 3 and CH 2 OH.

[0914] 50. A compound according to any one of statements 1 to 49, wherein R C1 , R C3 and R C4 Independently selected from H, Cl, F, CF 3 , OMe and CH 2 OH

[0915] 51. A compound according to any one of statements 1 to 50, wherein R C1 , R C3 and R C4 Independently selected from H, F and OMe.

[0916] 52. A compound according to any one of statements 1 to 51, wherein R C1 , R C3 and R C4 Two of them are H, and the others are selected from the defined groups except H.

[0917] 53. A compound according to any one of statements 1 to 52, wherein R C1 , R C3 and R C4 One of the R and R is H, and the other two R and R are independently selected from the groups defined above except H.

[0918] 54. A compound according to any one of statements 1 to 52, wherein R C1 , R C3 and R C4 For H.

[0919] 55. A compound according to any one of statements 1 to 48, wherein:

[0920] R C1 is H;

[0921] R C3 is H; and

[0922] R C4 For F.

[0923] 56. A compound according to any one of statements 1 to 48, wherein:

[0924] R C1 OMe;

[0925] R C3 is H; and

[0926] R C4 It is H or F.

[0927] 57. A compound according to any one of statements 1 to 56, wherein R C11 =R C1 , R C13 =R C3 And R C14 =R C4 .

[0928] 58. A compound according to any one of statements 1 to 56, wherein R C11 , R C13 and R C14 independently selected from H, Cl, F, Br, Me, OMe, cyano, CF 3 and CH 2 OH.

[0929] 59. A compound according to any one of statements 1 to 56, wherein R C11 , R C13 and R C14 Independently selected from H, Cl, F, CF 3 , OMe and CH 2 OH.

[0930] 60. A compound according to any one of statements 1 to 56, wherein R C11 , R C13 and R C14 Independently selected from H, F and OMe.

[0931] 61. A compound according to any one of statements 1 to 60, wherein R C11 , R C13 and R C14 Two of them are H, and the other one is selected from the defined groups other than H.

[0932] 62. A compound according to any one of statements 1 to 60, wherein R C11 , R C13 and R C14 One of the R and R is H, and the other two R and R are independently selected from the groups defined above except H.

[0933] 63. A compound according to any one of statements 1 to 60, wherein R C11 , R C13 and R C14 For H.

[0934] 64. A compound according to any one of Statements 1 to 56, wherein:

[0935] R C11 is H;

[0936] R C13 is H; and

[0937] R C14 For F.

[0938] 65. A compound according to any one of statements 1 to 56, wherein:

[0939] R C11 OMe;

[0940] R C13 is H; and

[0941] R C14 For H.

[0942] 66. A compound according to any one of Statements 1 to 65, wherein Y is (CH 2 ) n , where n is 2 to 3.

[0943] 67. A compound according to any one of Statements 1 to 65, wherein Y is (CH 2 ) 2 .

[0944] 68. A compound according to any one of Statements 1 to 65, wherein Y is (CH 2 ) 3 .

[0945] 69. A compound according to any one of Statements 1 to 65, wherein Y is (CH 2 ) 4 .

[0946] 70. A compound according to any one of statements 1 to 65, wherein Y is -CH 2 -CH=CH-CH 2 -.

[0947] 71. A compound according to any one of statements 1 to 70, wherein R 1 and R 11 Selected from -C(=O)OH, -C(=O)OR P1 , tetrazolyl, oxo-oxadiazolyl and (2H-triazol-4-yl), wherein R P1 Selected from methyl and ethyl.

[0948] 72. A compound according to any one of statements 1 to 71, wherein R 1 and R 11 is selected from C(=O)OH, tetrazolyl and oxo-oxadiazolyl.

[0949] 73. A compound according to statement 71 or 72, wherein R 1 and R 11 It is C(=O)OH.

[0950] 74. A compound according to statement 71 or 72, wherein R 1 and R 11 Tetrazolyl

[0951] 75. A compound according to statement 71 or 72, wherein R 1 and R 11 It is oxo-oxadiazolyl.

[0952] 76. A compound according to any one of Statements 1 to 76, wherein the compound is selected from any one of Compounds 1-52.

[0953] 77. A compound according to any one of statements 1-75, wherein the compound is selected from any one of compounds 1-51.

[0954] 78. A compound according to any one of statements 1-77, wherein the compound is in the form of a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph or N-oxide, or a combination thereof in any ratio.

[0955] 79. A compound as defined in any one of statements 1 to 78 for use in a method of treatment.

[0956] 80. A pharmaceutical composition comprising a compound as defined in any one of Statements 1 to 78 and a pharmaceutically acceptable excipient.

[0957] 81. A method of treating or preventing a disease ameliorated by modulation of STING, the method comprising administering to a patient in need of treatment a compound as defined in any one of Statements 1 to 78 or a pharmaceutical composition according to Statement 80.

[0958] 82. Use of a compound as defined in any one of Statements 1 to 78 in the manufacture of a medicament for the treatment or prevention of a disease ameliorated by modulation of STING.

[0959] 83. A compound as defined in any one of statements 1 to 78, or a pharmaceutical composition according to statement 78, for use in the treatment or prevention of a disease ameliorated by modulation of STING.

[0960] References

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

Claims

1. Compounds of formula I: (I)： in: Y is (CH2) n , wherein n is 2 to 4, or -CH2-CH=CH-CH2-; R 1 and R 11 independently selected from -C(=O)OH, -C(=O)OR P1 , Br, F, tetrazolyl, oxo-oxadiazolyl and , where R P1 is selected from methyl and ethyl; A 1 CR A or N; A 2 CR B or N; A 3 CR C or N; A 4 CR D or N; Among them A 1 , A 2 , A 3 and A 4 No more than two of them are N; R A , R B , R C and R D one, two or three, if present, are selected from H, F, Cl, Br, I, Me, Et, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; The rest of R A , R B , R C and R D , if it exists, it is H; A 11 CR AA or N; A 12 CR BB or N; A 13 CR CC or N; A 14 CR DD or N; Among them A 11 , A 12 , A 13 and A 14 No more than two of them are N; R AA , R BB , R CC and R DD one, two or three, if present, are selected from H, F, Cl, Br, I, Me, Et, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; The rest of R AA , R BB , R CC and R DD , if it exists, it is H; R C1 , R C3 and R C4 independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C 2-4 Alkenyl and 5-membered heterocyclic group; R C11 , R C13 and R C14 independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C 2-4 Alkenyl and 5-membered heterocyclic group; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein 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 .

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A 1 CR A , A 2 CR B , A 3 CR C , and A 4 CR D .

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A 11 CR AA , A 12 CR BB , A 13 CR CC , and A 14 CR DD .

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Formula IIIb, IIIc, IIId and IIIe: (IIIb), (IIIc), (IIId), (3rd) 6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R A , R B , R C and R D One, two or three, if present, are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano and OMe, and the rest, if present, are H.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A 1 , A 2 , A 3 and A 4 Select from combination 1-30:

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R AA , R BB , R CC and R DD One, two or three, if present, are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano and OMe, and the rest, if present, are H.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A 11 , A 12 , A 13 and A 14 Select from combination 1-30:

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R C11 =R C1 , R C13 =R C3 and R C14 =R C4 .

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 and R C4 Selected from combination 1-4:

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R C11 , R C13 and R C14 Selected from combination 1-4:

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is (CH2)2.

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 11 is selected from C(=O)OH, tetrazolyl and oxo-oxadiazolyl.

15. The compound according to claim 1, selected from: 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-tetrazolyl-5-yl)phenyl)-1-(2-(2-(2-(2H-tetrazolyl-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-tetrazolyl-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) 6,6'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(methyl 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) 6,6'-(Ethane-1,2-diylbis(5-carbamoyl-4-methoxy-1H-benzo[d]imidazole-1,2-diyl))bis(methyl 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) 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-cyanobenzoic acid methyl ester (52) or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. Use of a compound as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease that is ameliorated by regulating STING.

18. The use according to claim 17, wherein the disease is selected from one or more of the group consisting of: a) Cancer; b) Autoimmune diseases; c) Inflammatory diseases; d) neurodegenerative diseases; and e) Cell proliferative diseases.

19. The use according to claim 17 or 18, wherein: a) the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, uterine cancer, ovarian cancer, stomach cancer, colon cancer, breast cancer, esophageal cancer, small intestine cancer, intestinal cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, urethra cancer, prostate cancer, penis cancer, testicular cancer, ureter cancer, bladder cancer, kidney cancer or liver cancer; rectal cancer; cancer of the anal region; fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, renal pelvis, renal cell cancer; soft tissue sarcoma; myxoma; rhabdomyomas; fibromas; lipoma; teratoma; bile duct carcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatocarcinoma; fibrosarcoma; chondrosarcoma; myeloma; myeloproliferative disorders, including myeloproliferative neoplasms; chronic or acute leukemia; lymphocytic lymphoma; primary CNS lymphoma; CNS neoplasms; spinal cord axial tumors; squamous cell carcinoma; synovial sarcoma; malignant pleural mesothelioma; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hamartoma; mesothelioma; Hodgkin's disease, or a combination of one or more of the foregoing cancers; b) the autoimmune disease is selected from STING-associated vasculitis of infancy (SAVI); Aicardi Goutieres syndrome (AGS); lupus pernio; ataxia telangiectasia (also known as Louis-Bar syndrome); retinal vasculopathy with 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 Sjögren'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; Behcet's disease; spondylitis; giant cell arteritis; polymyalgia rheumatica; Raynaud's phenomenon; primary biliary cirrhosis; primary angiitis of the central nervous system; microscopic polyangiitis; neuromyelitis optica and mixed connective tissue disease; c) The inflammatory disease is selected from the group consisting of musculoskeletal inflammation; vascular inflammation; neuroinflammation; digestive system inflammation; ocular inflammation; reproductive system inflammation; autoimmune conditions with an inflammatory component, such conditions including universal acute disseminated alopecia, Behcet's disease, Chagas disease, STING-associated vasculitis of infancy (SAVI), Aicardi Goutieres syndrome (AGS), lupus pernio, ataxia telangiectasia (also known as Louis-Bar syndrome), retinal vasculopathy with leukodystrophy (RCVL), ANCA-associated vasculitis, chronic fatigue syndrome, autonomic dysfunction, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes mellitus, giant cell arteritis, goodpasture syndrome, Graves disease, Guillain-Barre syndrome, Hashimoto disease, Henoch-Schonlein purpura, Kawasaki disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, myoclonus syndrome, optic neuritis, ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter 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; contact hypersensitivity reactions, including contact dermatitis caused by poison ivy; urticaria; skin allergies; respiratory allergies, including hay fever, allergic rhinitis; and gluten-sensitive enteropathy (celiac disease); appendicitis; dermatitis; dermatomyositis; endocarditis; fibrositis; gingivitis; glossitis; hepatitis; hidradenitis suppurativa; iritis; laryngitis; mastitis; myocarditis; nephritis; otitis media; pancreatitis; mumps; Pericarditis; peritonitis; pharyngitis; pleurisy; pneumonia; prostatitis; pyelonephritis; stomatitis; transplant rejection; serum sickness; graft-versus-host disease; acute pancreatitis; chronic pancreatitis; acute respiratory distress syndrome; Sezary syndrome; congenital adrenal hyperplasia; non-suppurative thyroiditis; hypercalcemia associated with cancer; pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme; exfoliative dermatitis; seborrheic dermatitis; seasonal or perennial allergic rhinitis; bronchial asthma; contact dermatitis; atopic dermatitis; allergic drug reactions; Allergic conjunctivitis; keratitis; herpes zoster ophthalmicus; iritis and iridocyclitis; chorioretinitis; optic neuritis; Symptomatic sarcoidosis; chemotherapy for fulminant or disseminated pulmonary tuberculosis; idiopathic thrombocytopenic purpura in adults; secondary thrombocytopenia in adults; acquired (autoimmune) hemolytic anemia; leukemia and lymphoma in adults; acute leukemia in children; local enteritis; autoimmune vasculitis; multiple sclerosis; chronic obstructive pulmonary disease; solid organ transplant rejection; sepsis; d) the neurodegenerative disease is selected from multiple sclerosis; Huntington's disease; Alzheimer's disease; Parkinson's disease; and amyotrophic lateral sclerosis (ALS); e) the cell proliferative disease is selected from arthritis including rheumatoid arthritis and restenosis; fibrotic diseases including cirrhosis and atherosclerosis; mesangial cell proliferative diseases including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, proliferative retinopathy, organ transplant rejection and glomerulopathy; and metabolic disorders including psoriasis, diabetes, chronic wound healing; and / or f) The infectious disease is selected from infectious diseases originating from bacteria, including tuberculosis, chlamydia infection and tularemia infection; parasitic protozoan infections, including malaria; DNA virus infections, including herpesviridae, papillomaviridae, adenovirus and hepatoviridae; RNA virus infections, including retroviridae, flaviviridae, orthomyxoviridae and coronaviridae; and influenza, wherein the herpesviridae includes herpes simplex virus-1, Kaposi sarcoma-associated virus and Epstein-Barr virus, the papillomaviridae includes human papillomavirus, the hepatoviridae includes hepatitis B virus, the retroviridae includes human immunodeficiency virus, the flaviviridae includes dengue virus, hepatitis C virus, the orthomyxoviridae includes influenza virus, the coronaviridae includes human coronavirus and SARS coronavirus, which includes SARS-CoV-2.

20. The use according to claim 19, wherein the organ to be transplanted and rejected is selected from one or more of kidney, liver, heart, lung, pancreas including islet cells, bone marrow, cornea, small intestine, skin allograft, skin homograft and heart valve xenograft.

21. The use of claim 17 or 18, wherein the disease is selected from one or more of the group consisting 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 diseases including sepsis.

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