Benzothiophene, thienopyridine and thienopyrimidine derivatives for modulation of STING

Abstract

Compounds of formula (I) TIFF2022541043000089.tif4571 [Wherein W is O or NH, A 1 is CR A or N and A 2 is CR B or N and A 3 is CR C or N and A 4 is CR D or N, where A 1 , A 2 , A 3 , and A 4 Not more than two of the N1 is H or Me, and R C2 and R C3 One of them is C(=O)NH2, and the other is H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl; R C1 and R C4 are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl].

Description

[Technical field]

[0001] The present invention relates to substituted benzothiophenes, thienopyridines and thienopyrimidines and their use as pharmaceutical agents, particularly in the treatment of diseases ameliorated by modulation of STING. [Background technology]

[0002] 2. Background of the Invention Vertebrates are constantly threatened by microbial invasion and have evolved mechanisms of immune defense to eliminate infectious pathogens. In mammals, this immune system includes two branches: innate immunity and adaptive immunity. The innate immune system is the first line of defense initiated by pattern recognition receptors (PRRs) that detect pathogen-derived ligands and damage-associated molecular patterns (Takeuchi 2010). A growing number of these receptors have been identified, including Toll-like receptors (TLRs), C-type lectin receptors, retinoic acid-inducible gene I (RIG-I)-like receptors and NOD-like receptors (NLRs), as well as double-stranded DNA sensors. Activation of PRRs leads to the upregulation of genes involved in inflammatory responses, including type 1 interferons, proinflammatory cytokines and chemokines, which suppress pathogen replication and facilitate adaptive immunity.

[0003] The adaptor protein STING (stimulator of interferon genes), also known as TMEM 173, MPYS, MITA and ERIS, has been identified as a central signaling molecule in the innate immune response to cytoplasmic nucleic acids (Ishikawa 2008, WO2013 / 166000). Activation of STING mediates the IRF3 pathway and NF-. K It results in upregulation of the B pathway, leading to the induction of type 1 interferons, including interferon-β, and other cytokines. STING is critical for the response to cytoplasmic DNA of pathogen or host origin, and to unusual nucleic acids called cyclic dinucleotides (CDNs).

[0004] CDNs were first identified as bacterial second messengers responsible for the control of numerous responses in prokaryotic cells. Bacterial CDNs, such as c-di-GMP, are symmetric molecules characterized by two 3',5' phosphodiester linkages. [ka] [ka]

[0005] Recently, direct activation of STING by bacterial CDNs was confirmed by X-ray crystallography (Burdette 2013), and as a result, bacterial CDNs and their analogues have attracted interest as potential vaccine adjuvants (Libanova 2012, WO2007 / 054279, WO2005 / 087238).

[0006] More recently, the response to cytoplasmic DNA has been elucidated and shown to involve the generation of a novel mammalian CDN signaling molecule, identified as cGAMP, by an enzyme called cyclic GMP-AMP synthase (cGAS, previously known as C6orfl50 or MB21D1), which in turn activates STING. Unlike bacterial CDNs, cGAMP is an asymmetric molecule characterized by its mixed 2',5' and 3',5' phosphodiester linkages (Gao 2013A). The interaction of cGAMP(II) with STING has also been demonstrated by X-ray crystallography (Cai 2014).

[0007] Interferons were first described (Isaacs 1957) as substances capable of protecting cells against viral infection. In humans, type I interferons are a family of related proteins encoded by genes located on chromosome 9 that code for at least 13 isoforms of interferon alpha (IFNα) and one isoform of interferon beta (IFNβ). Recombinant IFNα was the first approved biological therapeutic and has become an important treatment in viral infections and cancer. Interferons are known to be potent modulators of the immune response acting on cells of the immune system as well as direct antiviral activity on cells.

[0008] Administration of small molecule compounds that can modulate innate immune responses, including activation or inhibition of type I interferon production and other cytokines, may be an important strategy for the treatment or prevention of human diseases, including viral infections and autoimmune diseases. This type of immunomodulatory strategy has the potential to identify compounds that may be useful not only in infectious diseases, but also in cancer (Zitvogel 2015), allergic diseases (Moisan 2006), neurodegenerative diseases such as amyotrophic lateral sclerosis and multiple sclerosis (Lemos 2014, Cirulli 2015, Freischmidt 2015), other inflammatory conditions such as irritable bowel disease (Rakoff-Nahoum 2004), and as vaccine adjuvants (Persing 2002, Dubensky 2013).

[0009] 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, Orthomyxoviruses and Paramyxoviruses, and Rhabdoviridae have evolved mechanisms to inhibit STING-mediated type I interferon production and evade host immune control (Holm 2016, Ma 2015, Wu 2015, Liu 2016, Chen 2014, Lau 2013, Ding 2013, Nitta 2013, Sun 2012, Aguirre 2012, Ishikawa 2009). Thus, small molecule activation of STING may be beneficial for the treatment of these infectious diseases.

[0010] In contrast, increased and prolonged type I IFN production is associated with a variety of chronic infections, including mycobacteria (Collins 2015, Wassermann 2015, Watson 2015), Francisella (Storek 2015, Jin 2011A), Chlamydia (Prantner 2010), Plasmodium (Sharma 2011), and HIV (Herzner 2015, Gao 2013B). Similarly, excessive type I interferon production is found in patients with complex autoimmune diseases. Genetic evidence in humans and support from studies in animal models support the hypothesis that inhibition of STING leads to a reduction in type I interferons that drive autoimmune diseases (Crow 2006, Stetson 2008). Thus, inhibitors of STING provide treatment for patients with chronic type I interferon and proinflammatory cytokine production associated with infections or combined autoimmune diseases. Allergic diseases are associated with a Th2-dominated immune response to allergens. Th2 responses are associated with elevated IgE levels and, due to their effect on mast cells, promote hypersensitivity to allergens resulting in symptoms seen, for example, in allergic rhinitis and asthma. In healthy individuals, the immune response to allergens is more balanced with a combination of Th2 / Th1 and regulatory T cell responses. It has been shown that induction of type 1 interferon leads to a reduction of Th2-type cytokines in the local environment and promotes Th1 / Treg responses. In this context, for example, induction of type 1 interferon by activation of STING may be beneficial in the treatment of allergic diseases, such as asthma and allergic rhinitis (Huber 2010).

[0011] Compounds that bind to STING and act as agonists have been shown to induce type 1 interferon and other cytokines when incubated with human PBMC. Compounds that induce human interferon can be useful in treating various disorders, for example, treating allergic diseases and other inflammatory conditions, such as allergic rhinitis and asthma, treating infectious diseases, neurodegenerative diseases, precancerous syndromes and cancer, and can also be useful as immunogenic compositions or vaccine adjuvants. Compounds that bind to STING can act as antagonists and can be useful, for example, in treating autoimmune diseases. It is envisioned that targeting STING with activators or inhibitors can be a promising approach for preventing and treating diseases and conditions, including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes, in which modulation of type 1 IFN pathway is beneficial, as well as immunogenic compositions or vaccine adjuvants.

[0012] Skin cancer and various cutaneous viral infections involve immune privileged environments, and activation of local immune responses to the lesions can be a local therapeutic approach. STING agonists can be used to treat viral warts, superficial skin cancers, and premalignant actinic keratoses. Due to the dual mechanism of action, STING activation (e.g., via microneedle patch delivery or topical formulations) can be used to control HPV directly through antiviral type I interferon production, and indirectly by enhancing adaptive immune responses downstream of innate immune activation. STING agonists can activate innate immune responses in the lesions and drive anti-HPV T cell responses.

[0013] Recent evidence indicates that spontaneous activation of the STING pathway in tumor-resident dendritic cells leads to type I IFN production and adaptive immune responses against tumors. Furthermore, activation of this pathway in antigen-presenting cells (APCs) within the tumor microenvironment drives subsequent priming of T cells against tumor-associated antigens (Corrales 2015). International patent applications WO2014 / 093936, WO2014 / 189805, WO2013 / 185052, WO2015 / 077354 and WO2015 / 185565 disclose certain cyclic dinucleotides and their use in inducing immune responses via activation of STING.

[0014] Additionally, non-CDN compounds have been described as active agonists of STING.

[0015] Applications WO2019 / 069269, WO2019 / 069270, WO2017 / 175156 and WO2017 / 175147, and Ramanjulu 2018 describe certain amido- and diamido-benzimidazole compounds and their use in modulating STING.

[0016] Applications WO2019 / 027858 and US2018 / 0093964 describe certain benzo[b]thiophene compounds and their use as agonists of STING. WO2019 / 195063 describes aza-benzothiophene compounds, and WO2019 / 195124 describes benzothiophenes and related compounds and their use as agonists of STING. WO2019 / 219820 describes benzothiophenes, thienopyridines and thienopyrimidines as modulators of STING.

[0017] Applications WO2018 / 234808, WO2018 / 234807, GB2563642A, WO2018 / 234805 describe certain arylamide compounds and their use as modulators of STING.

[0018] STING has known polymorphisms, including an allele encoding a histidine at position 232 that is refractory to bis-3',5' (canonical) CDNs but not 2',5'-3',5' (non-canonical, mixed-linkage) CDNs (Diner 2013; Jin 2011B). Single nucleotide polymorphisms in the STING gene have been reported to affect responsiveness to 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). The compounds of the invention modulate the activity of STING and therefore may provide beneficial therapeutic impact in the prevention and treatment of diseases, disorders and / or conditions in which modulation of STING (stimulator of interferon genes) is beneficial, such as inflammation, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes, and also as vaccine adjuvants. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Publication No. 2013 / 166000 [Patent Document 2] International Publication No. 2007 / 054279 [Patent Document 3] International Publication No. 2005 / 087238 [Patent Document 4] International Publication No. 2014 / 093936 [Patent Document 5] International Publication No. 2014 / 189805 [Patent Document 6] International Publication No. 2013 / 185052 [Patent Document 7] International Publication No. 2015 / 077354 [Patent Document 8] International Publication No. 2015 / 185565 [Patent Document 9] International Publication No. 2019 / 069269 [Patent Document 10] International Publication No. 2019 / 069270 [Patent Document 11] International Publication No. 2017 / 175156 [Patent Document 12] International Publication No. 2017 / 175147 [Patent Document 13] International Publication No. 2019 / 027858 [Patent Document 14] US Patent Application Publication No. 2018 / 0093964 [Patent Document 15] International Publication No. 2019 / 195063 [Patent Document 16] International Publication No. 2019 / 195124 [Patent Document 17] International Publication No. 2019 / 219820 [Patent Document 18] International Publication No. 2018 / 234808 [Patent Document 19] International Publication No. 2018 / 234807 [Patent Document 20] GB 2563642 [Patent Document 21] International Publication No. 2018 / 234805 Summary of the Invention [Means for solving the problem]

[0020] Summary of the Invention A first aspect of the present invention is a compound represented by formula I: [ka] To provide a compound of [In the formula, W is O or NH; R1 teeth, (i) H, (ii) C 3~6 Cycloalkyl, (iii) methyl, and ester C optionally substituted with a group selected from 3~7 Heterocyclyl, and (iv) alkoxy, amino, Amides, Acylamide, Acyloxy, Alkyl carboxyl esters, Alkylcarbamoyl, Alkyl carbamoyl esters, Phenyl, phosphonate esters, C optionally substituted with a group selected from methyl and oxo 3~7 Heterocyclyl, and Naturally occurring amino acids, optionally N-substituted with a group selected from methyl, acetyl and boc. Linear or branched C optionally substituted with a group selected from 1~4 Alkyl is selected from A 1 CR A or N, A 2 CR B or N, A 3 CR C or N, A 4 CR D or N, Here, A 1 , A 2 , A 3 , and A 4 may be N, R A , R B , R C and R Done or two of (when present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CHOMe and OH; R A , R B , R C and R D the remainder, if any, are H; R N1 is H or Me, R C2 and R C3 One of them is C(=O)NH2, and the other is H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl; R C1 and R C4 are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl.

[0021] A second aspect of the invention provides a compound of the first aspect for use in a method of treatment. The second aspect also provides a pharmaceutical composition comprising a compound of the first aspect and a pharma- ceutically acceptable excipient.

[0022] A third aspect of the invention provides a method of treating or preventing a disease ameliorated by modulation of STING, comprising administering to a patient in need of treatment a compound of the first aspect of the invention or a pharmaceutical composition of the second aspect of the invention. The third aspect of the invention also provides the use of a compound of the first aspect of the invention in the manufacture of a medicament for treating or preventing a disease ameliorated by modulation of STING, and a compound of the first aspect of the invention or a pharmaceutical composition thereof for use in treating or preventing a disease ameliorated by modulation of STING. The present invention provides, for example, the following items. (Item 1) Formula I:

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[0023] definition C 3~6 Cycloalkyl: The term "C 3~6 "Cycloalkyl," as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic hydrocarbon compound having 3 to 6 carbon atoms. 3~6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), and cyclohexyl (C6).

[0024] C 3~7 Heterocyclyl: The term "C 3~7 "Heterocyclyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a monocyclic heterocyclic compound and having 3 to 7 ring atoms, of which 1 to 2 atoms are heteroatoms selected from oxygen or nitrogen.

[0025] In this context, prefixes (e.g., C 3~7 ) indicates the number of ring atoms, whether carbon atoms or heteroatoms, or range of number of ring atoms.

[0026] C 3~7 Examples of heterocyclyl groups include, but are not limited to, N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), pyrrole (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), pyridine (C6), azepine (C7), azepane (C7); N2: Diazirine (C3) diazetidine (C4), imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole e) (C5), imidazole (C5), pyrazole (C5), piperazine (C6), pyrazine (C6), pyrimidine (C6), pyridazine (C6), diazepine (C7), diazepane (C7); O1: oxetane (C4), tetrahydrofuran (C5), oxane (C6); O2: dioxetane (C4), dioxolane (C5), dioxane (C6), dioxole (C5); N1O1: Tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), isoxazole (C5), oxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6) Examples of the groups include groups derived from

[0027] C 1~4 Alkyl: The term "C 1~4 "Alkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having from 1 to 4 carbon atoms.

[0028] Examples of saturated alkyl groups include, but are not limited to, Me: methyl (C1), Et: ethyl (C2), Pr: propyl (C3), and Bu: butyl (C4).

[0029] Examples of saturated straight chain alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), nPr: n-propyl (C3), and nBu: n-butyl (C4).

[0030] Examples of saturated branched alkyl groups include, but are not limited to, iPr: iso-propyl (C3, -C(CH3)2), iBu: iso-butyl (C4), sBu: sec-butyl (C4), and tBu: tert-butyl (C4).

[0031] C 2~4 Alkenyl: The term "C 2~4 "Alkenyl," as used herein, pertains to an alkyl group having from 2 to 4 carbon atoms and having one or more carbon-carbon double bonds.

[0032] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (1-methylvinyl, -C(CH3)=CH2) and butenyl (C4).

[0033] C 1~4 Fluoroalkyl: The term "C 1~4 "Fluoroalkyl," as used herein, refers to a C substituted with one or more fluorine atoms. 1~4 Concerning alkyl groups.

[0034] Alkoxy: -OR, where R is C as defined above. 1~4 Alkoxy is -OC 1~4Examples of alkoxy groups include, but are not limited to, methoxy (OMe, C1), ethoxy (OEt, C2), propyloxy (C3), and butyloxy (C4).

[0035] Alkylcarbamoyl: -NHC(=O)OR, where R is C as defined above. 1~4 Examples of alkylcarbamoyl groups include, but are not limited to, -N(H)C(=O)OCH3, -N(H)C(=O)OCH2CH3, and -N(H)C(=O)OC(CH3)3.

[0036] Alkyl carbamoyl ester: -OC(=O)NRR', where R and R' are independently H and C as defined above. 1~4 Examples of alkylcarbamoyl ester groups include, but are not limited to, -OC(=O)N(CH3)2, and -OC(=O)N(H)CH3.

[0037] Alkyl carboxyl ester: -OC(=O)OR, where R is C as defined above. 1~4 Examples of alkyl carboxyl ester groups include, but are not limited to, -OC(=O)OCH3, -OC(=O)OCH2CH3, -OC(=O)OC(CH3)3, and -OC(=O)OCH(CH3)2.

[0038] Amino: -N(R)R', where R and R' are independently H and C as defined above. 1~4 Examples of amino groups include, but are not limited to, -NH2, -N(H)CH3, -N(H)C(CH3)2, -N(CH3)2, and -N(CH2CH3)2.

[0039] Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide, aminoacyl): -C(=O)N(R)R', where R and R' are independently H and C as defined above. 1~4 Examples of amido groups include, but are not limited to, -C(=O)NH2, -C(=O)N(H)CH3, -C(=O)N(CH3)2, -C(=O)N(H)CH2CH3, and -C(=O)N(CH2CH3)2.

[0040] Acylamide: -N(R)C(=O)R', where R and R' are independently H and C(=O) as defined above. 1~4 Examples of acylamido groups include, but are not limited to, -N(H)C(=O)CH2CH3, -N(H)C(=O)CH3 and -N(CH3)C(=O)CH3.

[0041] Phenyl: -C6H5, where phenyl itself can be one or more C 1~4 Alkyl group, one or more C 1~4 Fluoroalkyl groups, one or more C 1~4 and optionally substituted with an alkoxy group, one or more halo substituents, and one or more cyano substituents.

[0042] Benzyl: -CH2-phenyl, where phenyl is as defined above.

[0043] Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, where R is an ester substituent, e.g., C as defined above. 1~4 Alkyl group, C 3~7 Heterocyclyl or phenyl groups, preferably C 1~4 Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh.

[0044] Acyloxy (reverse ester): -OC(=O)R, where R is an acyloxy substituent, e.g., C, as defined above. 1 4 Alkyl group, C 3~7 Heterocyclyl or phenyl, preferably C 1~4 (C is an alkyl group). Examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, and -OC(=O)Ph. Further examples of acyloxy groups include, but are not limited to, methyl ester (C1), ethyl ester (C2), propyl ester (C3), and butyl ester (C4).

[0045] Naturally occurring amino acid: The term "naturally occurring amino acid" as used herein refers to a monovalent moiety obtained by removing a hydrogen atom from a carboxyl or amino group on one of the amino acid compounds commonly found in nature (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine). The amino acid is particularly selected from isoleucine, leucine and valine, and most particularly valine.

[0046] In each of these groups, the carbon atom attached to both the carboxyl and amino groups is known as the α-carbon, and the carboxyl and amino groups attached thereto are the α-carboxyl and α-amino groups. Naturally occurring amino acids are optionally substituted with protecting groups on the α-amino group or any other amino group on the moiety, including, but not limited to, acetyl, methyl, and tertbutyl carbamate (boc) groups.

[0047] Phosphonate ester: -P(O)(OR)OR', where R and R' are independently C as defined above.1~4 An example of a phosphonate ester includes, but is not limited to, -P(O)(OEt)2. Cyano: -C≡N. Pivaloyloxymethyl: Formula [ka] Based on. Other forms included

[0048] Unless otherwise specified, the above includes well-known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO - ), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group also includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of an amino group, such as a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-O - ), a salt or solvate thereof, as well as conventional protected forms. salt

[0049] It may be convenient or desirable to prepare, purify, and / or handle corresponding salts of the active compounds, e.g., pharma- ceutically acceptable salts. Examples of pharma-ceutically acceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0050] For example, a compound may have an anionic or potentially anionic functional group (e.g., -COOH is -COO - In the case of a compound having an acid group, which may be a cation, a salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions, such as Na + and K. + , alkaline earth cations, e.g. Ca2+ and Mg 2+ , as well as other cations, such as Al +3 Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + ) are examples of some suitable substituted ammonium ions, including ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + It is.

[0051] The compound is cationic or has a functional group that can be cationic (e.g., -NH2 is -NH3 + In the case of a compound having an acid salt such as ethyl acetate, a salt can 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.

[0052] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, trifluoroacetic, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. solvate

[0053] It may be convenient or desirable to prepare, purify, and / or handle the corresponding solvate of active compound.The term "solvate" is used herein in its conventional sense to refer to the complex of solute (e.g., active compound, salt of active compound) and solvent.When solvent is water, solvate can be conveniently called hydrate, for example, monohydrate, dihydrate, trihydrate, etc. Isomers

[0054] Certain compounds of the present invention may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0055] The term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0056] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0057] "Diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures, such as electrophoresis and chromatography.

[0058] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0059] The definitions and rules of stereochemistry used herein generally follow those of SP 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 may exist in different stereoisomeric forms. It is intended that all stereoisomers of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane polarized light by a compound, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0060] It should be noted that, except as discussed below with respect to tautomeric forms, structural (or constitutional) isomers (i.e., isomers that differ simply in the connections between atoms, rather than in the positions of the atoms in space) are specifically excluded from the term "isomer" as used herein. For example, a reference to a methoxy group, -OCH3, should not be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may include structural isomeric forms that fall within that class as well (e.g., C 1~7 Alkyl includes n-propyl and iso-propyl, butyl includes n-, iso-, sec-, and tert-butyl, and methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

[0061] The above exclusion does not relate to tautomeric forms, e.g., keto-, enol-, and enolate forms, as found in, for example, the following tautomeric pairs: keto / enol (exemplified below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hyroxyazo, and nitro / aci-nitro. [ka]

[0062] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible by a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0063] In particular, the compounds of the present invention are N1 is H, which relates to the tautomerism exemplified below. [ka]

[0064] It should be noted that the term "isomer" specifically includes compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 H(T), and C may be in any isotopic form, including 12 C. 13 C, and 14 C may be in any isotopic form, including 16 O and 18 It may be in any isotopic form, including O, etc.

[0065] Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, including, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 Various isotopically labeled compounds of the present invention, such as compounds containing radioactive isotopes, e.g. 3 H, 13 C, and 14C is incorporated. Such isotope-labeled compounds can be useful in 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 assays, or in radiation treatment of patients. The therapeutic compounds of the present invention labeled or substituted with deuterium can have improved DMPK (drug metabolism and pharmacokinetic) properties in terms of distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium can result in certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, resulting from increased metabolic stability. 18 F-labeled compounds may be useful for PET or SPECT studies. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations below, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. In addition, heavier isotopes, particularly deuterium (i.e., 2 Substitution with H or D) can result in certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced required dosage or improved therapeutic index. In this context, it is understood that deuterium is considered as a substituent. The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a specific isotope is meant to represent any stable isotope of that atom.

[0066] Unless otherwise specified, reference to a particular compound includes all such isomeric forms, including (fully or partially) racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are either known in the art or readily obtained by adapting the methods taught herein or known methods in a known manner. Treatment indications

[0067] The compounds disclosed herein can provide therapeutic benefit in a number of disorders, particularly in the treatment or prevention of diseases that are ameliorated by modulation of STING.

[0068] One aspect of the present invention provides a method for treating or preventing STING-mediated diseases and disorders that benefit from agonistic effects on STING.Exemplary diseases / disorders include, but are not limited to, cancer and infectious diseases (e.g., diseases caused by viruses, such as HIV, HBV, HCV, HPV, and influenza, and bacteria).Another aspect of the present invention provides the use of STING agonists as vaccine adjuvants.

[0069] In one embodiment, the present invention provides the compound of the present invention for use in therapy.The present invention also provides the compound of formula I or its pharmaceutically acceptable salt for use in therapy.The present invention provides the compound of formula I or its pharmaceutically acceptable salt for use in the treatment of STING-mediated disease or disorder.

[0070] The present invention also provides a compound of formula I or a pharma- ceutically acceptable salt thereof for use as a vaccine adjuvant.Therefore, an immunogenic composition or a vaccine adjuvant comprising a compound of formula I or a pharma- ceutically acceptable salt thereof is also provided.In a further embodiment of the present invention, a composition comprising a compound of formula I or a pharma- ceutically acceptable salt thereof and one or more immunostimulants is provided.

[0071] In another embodiment, the invention provides a compound of the invention for use in the treatment of a STING-mediated disease or disorder and / or for use as an immunogenic composition or vaccine adjuvant.In another embodiment, the invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof for use in ameliorating organ injury or damage sustained as a result of a STING-mediated disease or disorder.

[0072] The invention further provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a STING-mediated disease or disorder.The invention further provides the use of a compound of formula I or a salt thereof, particularly a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a STING-mediated disease or disorder, such as the diseases and disorders described herein.

[0073] The present invention further provides the use of a compound of formula I or a salt thereof, particularly a pharma- ceutically acceptable salt thereof, in the manufacture of a vaccine.Furthermore, the present invention provides the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of an immunogenic composition comprising an antigen or an antigenic composition for the treatment or prevention of a disease.Furthermore, the present invention provides the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a vaccine composition comprising an antigen or an antigenic composition for the treatment or prevention of a disease.

[0074] In another embodiment, the present invention is directed to a method of treating a STING-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound of the present invention to a human in need thereof.In another embodiment, the present invention is directed to a method of treating a STING-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound of formula I or a salt, particularly a pharma- ceutically acceptable salt thereof, to a human in need thereof. infectious disease

[0075] The compounds of the present invention can be used to treat infectious diseases, which are any disease caused by or occurring concomitantly with infection from a pathogen. A pathogen is broadly defined as any organism that is foreign to the human tissue environment. Common pathogens that cause disease include bacteria (many such as TB), viruses (many such as HBV, HIV, influenza) and parasitic protozoa (such as P falciparum, which 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 infection by DNA or RNA viruses. The compounds of the present invention can be used to treat infectious diseases from DNA virus families: Herpesviridae (Herpes simplex virus type 1, Kaposi's sarcoma-associated virus and Epstein-Barr virus), Papillomaviridae (human papillomavirus), Adenovirus and Hepadnaviridae (Hepatitis B virus). Examples of RNA virus families include Retroviridae (human immunodeficiency virus), Flaviviridae (dengue virus, hepatitis C virus), Orthomyxoviridae (influenza), and Coronaviridae (human coronavirus and SARS coronavirus). cancer

[0076] As used herein, the terms "cancer", "neoplasm" and "tumor" are used interchangeably and refer to cells that have undergone malignant transformation, either in the singular or plural form, that render the cells pathological to the host organism. Primary cancer cells can be easily distinguished from non-cancerous cells by well-established techniques, particularly histological examination. The definition of cancer cells, as used herein, includes not only primary cancer cells, but also any cells derived from a cancer cell ancestor. Cancer cells include metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to types of cancer that typically manifest as solid tumors, a "clinically detectable" tumor is one that is detectable by procedures such as computed tomography (CT) scans, magnetic resonance imaging (MRI), x-rays, ultrasound, or palpation during a physical examination, based on tumor burden, and / or by expression of one or more cancer-specific antigens in samples that can be obtained from a patient. The tumor may be a hematopoietic (or hematologic or hematological or blood-related) cancer, such as a cancer derived from blood cells or immune cells, which may be referred to as a "liquid tumor." Specific examples of clinical conditions based on hematological tumors include leukemias, such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies, such as multiple myeloma, MGUS and Waldenstrom's macroglobulinemia; lymphomas, such as non-Hodgkin's lymphoma, Hodgkin's lymphoma, etc.

[0077] The cancer may be any cancer in which there is an abnormal number of blast cells or unwanted cell proliferation, or which is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myeloblastic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia, and megakaryocytic (or megakaryoblastic) leukemia. These leukemias can be collectively referred to as acute myeloid (or myeloblastic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPDs), including, but not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndromes or MDS), which can be referred to as refractory anemia (RA), refractory anemia with blasts (RAEB), and refractory anemia with blasts in transformation (RAEBT), and myelofibrosis with or without myeloid metaplasia of unknown etiology (MFS).

[0078] 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's lymphoma (B-NHL). B-NHL can be indolent (or low grade), intermediate grade (or aggressive) or high grade (highly aggressive). Indolent B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL), including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with hairy lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHL includes mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHL includes Burkitt lymphoma (BL), Burkitt-like lymphoma, small noncleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-associated (or AIDS-associated) lymphoma, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphocytic (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL can also include T-cell non-Hodgkin's lymphoma (T-NHL), including, but not limited to, T-cell non-Hodgkin's lymphoma, not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome.

[0079] Hematopoietic cancers also include Hodgkin lymphomas (or diseases), including classical Hodgkin lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte predominant (LP) Hodgkin lymphoma, nodal LP Hodgkin lymphoma, and lymphocytopenic Hodgkin lymphoma. Hematopoietic cancers also include plasma cell disorders or cancers, such as multiple myeloma (MM), including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes, and natural killer cells. Tissues containing hematopoietic cells, referred to herein as "hematopoietic cell tissues," include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as the spleen, lymph nodes, mucosa-associated lymphoid tissues (e.g., gut-associated lymphoid tissue), tonsils, Peyer's patches, and appendix, as well as other mucosa-associated lymphoid tissues, such as the bronchial lining.

[0080] Examples of cancer diseases and conditions in which the compounds of the invention may have potentially beneficial anti-tumor effects include, but are not limited to, cancer of the lung, bone, pancreas, skin, head, neck, uterus, ovary, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid, parathyroid, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinoma of the fallopian tube, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; soft tissue sarcoma; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatocellular carcinoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphoma; primary CNS lymphoma; CNS neoplasms; spinal axis tumors; squamous cell carcinoma; synovial sarcoma; malignant pleural mesothelioma; brain stem glioma; pituitary adenoma; bronchial adenoma; chondroitin hamartoma; mesothelioma; Hodgkin's disease, or a combination of one or more of the foregoing cancers.

[0081] Suitably, the present invention relates to a method for treating a variety of tumors including brain (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovary, pancreas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, islet cell adenoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastoma, The present invention relates to a method for treating or reducing the severity of cancer selected from the group consisting of: chronic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharangeal cancer, oral cavity cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

[0082] In some embodiments, the compounds of the present invention can be used to treat solid or liquid tumors.In some embodiments, the compounds of the present invention can be used to treat sarcoma, breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (RCC), lymphoma, squamous cell carcinoma of the head and neck (SCCHN), hepatocellular carcinoma (HCC), and / or non-Hodgkin's lymphoma (NHL).Suitably, the present invention relates to a method for treating or reducing the severity of pre-cancerous syndromes in mammals, including humans, where the pre-cancerous syndromes are selected from cervical intraepithelial neoplasia, monoclonal gammopathy of undetermined significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithelial (intraductal) neoplasia (PIN), ductal carcinoma in situ (DCIS), colonic polyps, and severe hepatitis or cirrhosis.

[0083] In one embodiment, the human has a solid tumor. In one embodiment, the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, ovarian cancer, and pancreatic cancer. In one embodiment, the human has one or more of colorectal cancer (CRC), esophageal, cervical, bladder, breast, head and neck, ovarian, melanoma, renal cell carcinoma (RCC), EC squamous cell, non-small cell lung cancer, mesothelioma, and prostate cancer. In another embodiment, the human has a liquid tumor, such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myelogenous leukemia.

[0084] In one embodiment, the compounds of the present invention may be useful in the treatment of skin cancer (e.g., non-melanoma skin cancer, squamous cell carcinoma, basal cell carcinoma) or actinic keratosis. In addition to the field effect to clear superficial skin cancer, the compounds of the present invention may prevent the development of secondary skin cancers and premalignant actinic keratosis in treated patients. autoimmune disease

[0085] Associated autoimmune diseases include, but are not limited to, STING-associated vasculitis of infancy (SAVI), Aicardi-Goutieres syndrome (AGS), lupus pernio, ataxia-telangiectasia (ATTA), and vasculitis of infancy (STING-associated vasculitis of infancy). telanogiectasia (also called Louis-Bar syndrome), retinal vasculopathy with cerebral leukodystrophy (RCVL), systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, psoriasis, diabetes mellitus including insulin-dependent diabetes mellitus (IDDM), dermatomyositis, human immunodeficiency virus (HIV), AIDS, polymyositis, systemic sclerosis (scleroderma), and 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 (microscopy polyangiitis, Behçet's disease, spondylitis, giant cell arteritis, polymyalgia rheumatica, Raynaud's phenomenon, primary biliary cirrhosis, primary vasculitis of the central nervous system microscopic polyangiitis, neuromyelitis optica, and mixed connective tissue disease. inflammation

[0086] Inflammation represents a group of vascular, cellular and neurological responses to trauma. Inflammation can be characterized as the migration of inflammatory cells, such as monocytes, neutrophils and granulocytes, into tissues. It is usually associated with reduced endothelial barrier function and edema into tissues. Inflammation can be classified as either acute or chronic. Acute inflammation is the body's initial response to a harmful stimulus and is accompanied by increased migration of plasma and leukocytes from the blood into the injured tissue. A cascade of biochemical events propagates and develops an inflammatory response involving the local vasculature, immune system and various cells within the injured tissue. Long-term inflammation, known as chronic inflammation, leads to a progressive migration of cell types present at the site of inflammation and is characterized by the concomitant destruction and healing of tissues by the inflammatory process.

[0087] Inflammation can be beneficial when it occurs as part of an immune response to infection or as an acute response to trauma, and is usually self-limited. However, inflammation can be harmful under various conditions. This includes the generation of excessive inflammation in response to infectious agents, which can lead to significant organ damage and death (e.g., in the setting of sepsis). Furthermore, chronic inflammation is generally harmful and underlies a number of chronic diseases, causing severe and irreversible damage to tissues. In such situations, the immune response is often directed against self-tissues (autoimmunity), but chronic responses to foreign entities can also lead to bystander damage to self-tissues.

[0088] The goal of anti-inflammatory treatment is therefore to reduce this inflammation, inhibit autoimmunity if present, and allow physiological processes or healing and tissue repair to proceed.

[0089] The compounds of the invention can be used to treat inflammation in any tissue or organ of the body, including musculoskeletal inflammation, vascular inflammation, neurogenic inflammation, gastrointestinal inflammation, ocular inflammation, reproductive system inflammation, and other inflammation, as exemplified below.

[0090] Musculoskeletal inflammation refers to any inflammatory condition of musculoskeletal system, particularly the condition that affects skeletal joints, including the joints of hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knee, ankle and foot, and the condition that affects the tissues that connect muscle to bone, such as tendons.The examples of musculoskeletal inflammation that can be treated with the compound of the present invention include arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, gout and pseudogout-related arthritis, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibromyalgia, epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic).

[0091] Ocular inflammation refers to inflammation of any structure of the eye, including eyelid.Examples of ocular inflammation that can be treated with the compound of the present invention include blepharitis, blepharophallus, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.

[0092] Examples of inflammation of the nervous system that may be treated with the compounds of the invention include encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, CNS vasculitis, and schizophrenia.

[0093] Examples of inflammation of the vasculature or lymphatic system which may be treated with the compounds of the invention include arthrosis, arthritis, phlebitis, vasculitis, and lymphangitis.

[0094] Examples of inflammatory conditions of the digestive system which may be treated with the compounds of the invention include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), ileitis, and proctitis.

[0095] Examples of inflammatory conditions of the reproductive system which 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.

[0096] The compounds of the present invention can be used to treat autoimmune conditions with an inflammatory component. Such conditions include acute universal alopecia, Behcet's disease, Chagas disease, STING-associated vasculitis of infancy (SAVI), Aicardi-Goutières syndrome (AGS), pernio lupus, ataxia telangiectasia (also known as Louis-Bar syndrome), retinal vasculopathy with cerebral leukodystrophy (RCVL), ANCA-associated vasculitis, chronic fatigue syndrome, autonomic neuropathy, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes, giant cell arteritis, Goodpasture's disease, and others. Syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Henoch-Schönlein purpura, Kawasaki disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia nodosa, rheumatoid arthritis, Reiter's syndrome, Sjögren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0097] The compounds of the present invention can be used to treat T cell-mediated hypersensitivity diseases with an inflammatory component. Such conditions include contact hypersensitivity, contact dermatitis (including that caused by poison ivy), urticaria, skin allergies, respiratory allergies (seasonal nasal allergy, allergic rhinitis) and gluten-sensitive enteropathy (celiac disease).

[0098] Other inflammatory conditions which may be treated with the compounds of the invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibromyalgia, gingivitis, glossitis, hepatitis, suppurative hidradenitis, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonitis, pharyngitis, pleuritis, pneumonia, prostatitis, pyelonephritis, and stomatitis, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small intestine, skin grafts, skin allografts, and heart valve xenografts, serum sickness, and graft versus host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sezary syndrome, congenital adrenal hyperplasia, nonsuppurative thyroiditis, cancer-related hypercalcemia, and rheumatoid arthritis. These include: erythema, pemphigus, bullous dermatitis herpes, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or generalized pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphoma in adults, acute leukemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ graft rejection, sepsis. Preferred treatments include the treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic pulmonary disease, and inflammation associated with infectious conditions (e.g., sepsis). In one embodiment, the compounds of the invention can be used to treat asthma. Cell proliferation

[0099] The compounds of the invention may also be useful in treating one or more diseases afflicting mammals that are characterized by cell proliferation in areas of disorders associated with angiogenesis and / or vascular permeability, including vascular proliferative disorders, including arthritis (rheumatoid arthritis) and restenosis; fibrotic disorders, including liver cirrhosis and atherosclerosis; mesangial cell proliferative disorders, including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, proliferative retinopathy, organ transplant rejection and glomerulopathies; and metabolic disorders, including psoriasis, diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases. Neurodegenerative diseases

[0100] The compounds of the present invention can be used to treat neurodegenerative diseases. Exemplary neurodegenerative diseases include, but are not limited to, multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Combination

[0101] The compounds of the present invention can be employed alone or in combination with other therapeutic agents. As modulators of immune response, the compounds of the present invention can also be used in monotherapy or in combination with other therapeutic agents in the treatment of diseases and conditions in which modulation of STING is beneficial.

[0102] Thus, the combination therapy according to the present invention comprises the administration of a compound of formula I or a pharma- ceutically acceptable salt thereof and at least one other therapeutically active agent. In one embodiment, the combination therapy according to the present invention comprises the administration of at least one compound of formula I or a pharma- ceutically acceptable salt thereof and at least one other therapeutic agent. The compound(s) of formula I and its pharma- ceutically acceptable salt thereof, and the other therapeutic agent(s) can be administered together in a single pharmaceutical composition or separately, and when administered separately, can be administered simultaneously or sequentially in any order. The amount of the compound(s) of formula I and its pharma- ceutically acceptable salt thereof, and the other therapeutic agent(s), and the relative timing of administration are selected to achieve a desired combination of therapeutic effects. Thus, in a further aspect, a combination is provided that comprises a compound of formula I or a pharma- ceutically acceptable salt thereof, together with one or more other therapeutic agents.

[0103] The compounds of formula I and their pharma- ceutically acceptable salts may be used in combination with one or more other therapeutic agents that may be useful in the prevention or treatment of allergic, inflammatory or autoimmune diseases, such as antigen immunotherapy, antihistamines, steroids, NSAIDs, bronchodilators (e.g., beta 2 agonists, adrenergic agonists, anticholinergics, theophylline), methotrexate, leukotriene modulators and similar agents; monoclonal antibody therapy, such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; receptor therapy, such as etanercept and similar agents; antigen non-specific immunotherapy (e.g., interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists and similar agents).

[0104] The compounds of formula I and their pharma- ceutically acceptable salts can be used in combination with radiation therapy and / or surgery and / or at least one other therapeutic agent that may be useful in the treatment of cancer and precancerous syndromes. Any antineoplastic agent that has activity against the susceptible tumor being treated can be utilized in this combination. Exemplary antineoplastic agents of use include, but are not limited to, (a) anti-microtubule agents, such as diterpenoids (e.g., paclitaxel, docetaxel) and vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine); (b) platinum coordination complexes (e.g., oxaliplatin, cisplatin, and carboplatin); (c) alkylating agents, such as nitrogen mustards (e.g., cyclophosphamide, melphalan, and chlorambucil), oxazaphosphorines, alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine), and triazenes (e.g., dacarbazine); (d) antibiotic agents, such as anthracyclines (e.g., daunorubicin and doxorubicin), actinomycins (e.g., dactinomycin), and bleomycin; (e) topoisomerase II inhibitors, such as epipodophyllotoxins (e.g., (f) antimetabolites, such as purine and pyrimidine analogs and antifolate compounds (e.g., fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine); (g) topoisomerase I inhibitors, such as camptothecin (e.g., irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin); (h) hormones and hormone analogs (e.g., corticosteroids, such as prednisone and prednisolone, which are useful in the treatment of malignant lymphomas and acute leukemias in children; aminoglutethimides, and other aromatase inhibitors, such as anastrozole, letrozole, vorozole, and exemestane, which are useful in the treatment of adrenocortical carcinoma and hormone-dependent breast cancers that contain estrogen receptors;Progestins, such as megestrol acetate, useful in the treatment of hormone-dependent breast and endometrial cancer; estrogens, and antiestrogens, such as fulvestrant, flutamide, nilutamide, bicalutamide, cyproterone acetate, and 5-reductase inhibitors, such as finasteride and dutasteride, useful in the treatment of prostate cancer and benign prostatic hyperplasia; antiestrogens, such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, and selective estrogen receptor modulators (SERMS), such as those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and 6,207,716, useful in the treatment of hormone-dependent breast and other susceptible cancers; and gonadotropin releasing agents, which stimulate the release of leutinizing hormone (LH) and / or follicle-stimulating hormone (FSH), for the treatment of prostate cancer. These include: endogenous hormone (GnRH) and its analogs, such as LHRH agonists and antagonists, e.g., goserelin acetate and leuprolide), (i) signal transduction pathway inhibitors, (j) non-receptor tyrosine angiogenesis inhibitors, (k) immunotherapeutics (e.g., ex-vivo and in-vivo approaches to increase the immunogenicity of tumor cells in a patient, e.g., transfection with cytokines, e.g., interleukin 2, interleukin 4, or granulocyte macrophage colony stimulating factor, approaches to reduce T cell energy, approaches using transfected immune cells, such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies), (l) pro-apoptotic agents (e.g., bcl-2 antisense oligonucleotides), (m) cell cycle signal transduction inhibitors, (n) cancer immunotherapy agents, and (o) immunostimulants. Signal transduction pathway inhibitors

[0105] Signal transduction pathway inhibitors are inhibitors that block or inhibit chemical processes that induce intracellular changes.As used herein, this change is cell proliferation or cell differentiation.Signal transduction inhibitors useful in the present invention include receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidyl inositol-3 kinase, myo-inositol signaling, and Ras oncogene inhibitors.

[0106] Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor kinases or non-receptor kinases.

[0107] Receptor tyrosine kinases are transmembrane proteins that have an extracellular ligand-binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally referred to as growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e., abnormal kinase growth factor receptor activity, for example, by overexpression or mutation, has been shown to result in uncontrolled cell growth. Thus, the abnormal activity of such kinases has been linked to malignant tissue growth. As a result, inhibitors of such kinases could provide a method of treating cancer. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony-stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptor, Trk receptor (TrkA, TrkB, and TrkC), ephrin (eph) receptor, and RET proto-oncogene. Several inhibitors of growth receptors are under development, including ligand antagonists, antibodies, tyrosine kinase inhibitors, and antisense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for example, in Kath 2000, Shawver 1997, and Lofts 1994.

[0108] Tyrosine kinase that is not a growth factor receptor kinase is called non-receptor tyrosine kinase.The non-receptor tyrosine kinase useful in the present invention, which is the target or potential target of anti-cancer drugs, includes cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Bruton's tyrosine kinase, and Bcr-Abl.The drugs that inhibit such non-receptor kinase and non-receptor tyrosine kinase function are described in Sinh 1999 and Bolen 1997.

[0109] SH2 / SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins, including the PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2 / SH3 domains as targets for anticancer drugs are discussed in Smithgall 1995.

[0110] Inhibitors of serine / threonine kinases include MAP kinase cascade blockers, including blockers of Raf kinase (rafk), mitogen or extracellular regulated kinase (MEK), and extracellular regulated kinase (ERK); and blockers of protein kinase C family members, including blockers of PKC (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, and TGF beta receptor kinase. Such serine / threonine kinases and their inhibitors are described in Yamamoto 1999, Brodt 2000, Massague 1996, Philip 1995, Lackey 2000, U.S. Pat. No. 6,268,391, and Martinez-Lacaci 2000.

[0111] Inhibitors of phosphatidylinositol-3 kinase family members, including blockers of Pekinese, ATM, DNA-PK, and Ku, are also useful in the present invention. Such kinases are discussed in Abraham 1996, Canman 1998, Jackson 1997, and Zhong 2000.

[0112] Myo-inositol signaling inhibitors, such as phospholipase C blockers and myo-inositol analogues, are also useful in the present invention. Such signaling inhibitors are described in Powis 1994.

[0113] Another group of signal transduction pathway inhibitors are inhibitors of the Ras oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranylgeranyltransferase, and CAAX protease, as well as antisense oligonucleotides, ribozymes, and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild-type mutant ras, thereby acting as antiproliferative agents. Ras oncogene inhibition is discussed in Scharovsky 2000, Ashby 1998, and Oliff 1999.

[0114] As mentioned above, antibody antagonists against receptor kinase ligand binding can also act as signal transduction inhibitors.This group of signal transduction pathway inhibitors includes the use of humanized antibodies against the extracellular ligand binding domain of receptor tyrosine kinase.For example, Imclone C225 EGFR specific antibody (see Green 2000), Herceptin® erbB2 antibody (see Stern 2000), and 2CB VEGFR2 specific antibody (see Brekken 2000). Non-receptor tyrosine angiogenesis inhibitors

[0115] Antiangiogenic therapeutic agents, including non-receptor MEK angiogenesis inhibitors, may also be useful. Antiangiogenic drugs, such as those that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab [Avastin™]), and compounds that work by other mechanisms (e.g., linomide, an inhibitor of integrin αvβ3 function, endostatin and angiostatin). Cell cycle signaling inhibitors

[0116] Cell cycle signaling inhibitors inhibit molecules involved in the control of cell cycle. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins control progression through eukaryotic cell cycle. The coordinated activation and inactivation of different cyclin / CDK complexes is necessary for normal progression through cell cycle. Several inhibitors of cell cycle signaling are under development. Examples of cyclin-dependent kinases and their inhibitors, including, for example, CDK2, CDK4, and CDK6, are described, for example, in Rosania 2000. Immune Modulators

[0117] Additional examples of other therapeutic agents (eg, anti-neoplastic agents) for use in combination or co-administered with the compounds of Formula I are immune modulators.

[0118] 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 (Opdivo / Nivolumab and Keytruda / Pembrolizumab). Other immunomodulators include, but are not limited to, ICOS antibodies, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies and GITR antibodies. Anti-PD-L1 agents

[0119] Additional examples of other therapeutic agents (anti-neoplastic agents) for use in combination with or co-administered with the compounds of the present invention are anti-PD-L1 agents. Anti-PD-L1 antibodies and methods for producing them are known in the art. Such antibodies against PD-L1 may 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. Additional exemplary antibodies to PD-L1 (also called CD274 or B7-H1) and methods for use are disclosed in U.S. Patent Nos. 7,943,743, 8,168,179, and 7,595,048, WO 2014 / 055897, WO 2016 / 007235, and U.S. Patent Application Publication Nos. 2013 / 0034559 and 2015 / 0274835. PD-L1 antibodies are under development as immune modulators for the treatment of cancer.

[0120] In one embodiment, the antibody against PD-L1 is an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the antibody against PD-L1 is an antibody disclosed in US Patent No. 8,779,108. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Patent Application Publication No. 8,779,108. In another embodiment, the antibody against PD-L1 is an antibody disclosed in US Patent Application Publication No. 2013 / 0045201. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Patent Application Publication No. 2013 / 0045201. In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105) described in WO2007 / 005874. In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446).

[0121] In another embodiment, the anti-PD-L1 antibody is MEDI4736, which is an anti-PD-L1 monoclonal antibody described in WO2011 / 066389 and US2013 / 034559. In another embodiment, the anti-PD-L1 antibody is TECENTRIQ™ (atezolizumab), which is an anti-PD-L1 cancer immunotherapy approved in the United States in May 2016 for certain types of bladder cancer. In another embodiment, the anti-PD-L1 antibody is YW243.55.S70, which is an anti-PD-L1 antibody described in WO2010 / 077634 and US Patent No. 8,217,149. Examples of anti-PD-L1 antibodies useful in the methods of the invention, and methods for making them, are described in PCT patent applications WO2010 / 077634, WO2007 / 005874, WO2011 / 066389, U.S. Patent No. 8,217,149, and US2013 / 034559. PD-1 antagonists

[0122] Additional examples of other therapeutic agents (anti-neoplastic agents) for use in combination or co-administered with the compounds of the present invention are PD-1 antagonists.

[0123] "PD-1 antagonist" means any compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include PDCDl, PDl, CD279, and SLEB2 for PD-1, PDCDlLl, PDLl, B7H1, B7-4, CD274, and B7-H for PD-L2, and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. In any of the aspects or embodiments of the invention in which a human individual is to be treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of both human PD-L1 and PD-L2 to human PD-1.

[0124] The human PD-1 amino acid sequence can be found at NCBI locus number: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI locus numbers: NP_054862 and NP_079515, respectively.

[0125] PD-1 antagonists useful in any of the aspects of the invention include monoclonal antibodies (mAbs), or antigen-binding fragments thereof, that specifically bind to PD-1 or PD-L1, preferably specifically bind to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0126] 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 useful as PD-1 antagonists in any of the aspects and embodiments of the invention include MK-3475, a humanized IgG4 mAb having a structure as described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and comprising the heavy and light chain amino acid sequences shown in FIG. 6; nivolumab, a human IgG4 mAb having a structure as described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013) and comprising the heavy and light chain amino acid sequences shown in FIG. 7; humanized antibodies h409All, h409A16 and h409A17 as described in WO2008 / 156712, and AMP-514 being developed by Mediimmune.

[0127] Other PD-1 antagonists useful in any of the aspects and embodiments of the invention include immunoadhesins that specifically bind to PD-1, preferably human PD-1, such as fusion proteins that contain the extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region, of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010 / 027827 and WO2011 / 066342. Particular fusion proteins useful as PD-1 antagonists in the treatment methods, medicaments and uses of the invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.

[0128] Other examples of mAbs that bind human PD-L1 and are useful in the treatment methods, medicaments and uses of the invention are described in WO2013 / 019906, WO2010 / 077634 and US8383796. Particular anti-human PD-L1 mAbs useful as PD-1 antagonists in the treatment methods, medicaments and uses of the invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C.

[0129] 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.

[0130] Opdivo / nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 (Programmed Death-1 or Programmed Cell Death-l / PCD-1) with immune enhancing activity. Nivolumab binds to PD-1, an Ig superfamily transmembrane protein, and blocks activation by its ligands PD-L1 and PD-L2, resulting in T cell activation and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T cell activation and effector function by suppressing activation of the PI3k / Akt pathway. Other names for nivolumab include BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence and methods of use and production for nivolumab are disclosed in U.S. Pat. No. 8,008,449. Antibodies to ICOS

[0131] An additional example of another therapeutic agent (anti-neoplastic agent) for use in combination with or co-administered with the compounds of formula I is an antibody against ICOS.

[0132] ICOS is a costimulatory T cell receptor with structural and functional relationships to the CD28 / CTLA-4-Ig superfamily (Hutloff 1999). Activation of ICOS occurs through binding by 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 both CD28 and CTLA-4 (Yao 2011). Expression of ICOS appears to be restricted to T cells. ICOS expression levels vary among different T cell subsets and depending on T cell activation status. ICOS expression has been shown on resting TH17, follicular helper T cells (TFH) and regulatory T cells (Treg), but unlike CD28, is not highly expressed on naive THI and TH2 effector T cell populations (Paulos 2010). ICOS expression is highly induced on CD4+ and CD8+ effector T cells following activation via TCR engagement (Wakamatsu 2013).

[0133] CDRs for a murine antibody against human ICOS with agonistic activity are shown in PCT / EP2012 / 055735 (WO2012 / 131004). Antibodies against ICOS are also disclosed in WO2008 / 137915, WO2010 / 056804, EP1374902, EP1374901, and EP1125585.

[0134] Agonistic antibodies or ICOS binding proteins against ICOS are disclosed in WO2012 / 131004, WO2014 / 033327, WO2016 / 120789, US20160215059, and US20160304610. In one embodiment, the agonistic antibody against ICOS includes an ICOS binding protein or an antigen-binding portion thereof comprising one or more of the CDRH1 set forth in SEQ ID NO:1, the CDRH2 set forth in SEQ ID NO:2, the CDRH3 set forth in SEQ ID NO:3, the CDRL1 set forth in SEQ ID NO:4, the CDRL2 set forth in SEQ ID NO:5, and / or the CDRL3 set forth in SEQ ID NO:6, or a direct equivalent of each CDR, wherein the direct equivalent has no more than two amino acid substitutions in said CDRs as disclosed in WO2016 / 120789, the entire contents of which are incorporated herein by reference. In one embodiment, the ICOS binding protein or antigen-binding portion thereof is an agonistic antibody against ICOS, comprising a VH domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7, and / or a VL domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:8, as described in WO2016 / 120789, wherein said ICOS binding protein specifically binds to human ICOS. In one embodiment, the ICOS binding protein is an agonistic antibody against ICOS, comprising a VH domain comprising an amino acid sequence set forth in SEQ ID NO:7, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO:8, as described in WO2016 / 120789.

[0135] Yervoy (ipilimumab) is a fully human CTLA-4 antibody sold by Bristol Myers Squibb. The protein structure and method of use of ipilimumab are described in US Patent Nos. 6,984,720 and 7,605,238.

[0136] CD134, also known as OX40, is a member of the TNFR-superfamily of receptors that, unlike CD28, is not constitutively expressed on resting naive T cells. OX40 is a secondary costimulatory molecule expressed 24-72 hours after activation, and its ligand, OX40L, is also not expressed on resting antigen-presenting cells, but is expressed after their activation. Expression of OX40 is dependent on full activation of T cells, and without CD28, OX40 expression is delayed and at 4-fold lower levels. OX-40 antibodies, OX-40 fusion proteins, and methods of their use are disclosed in U.S. Patent Nos. 7504101, 7758852, 7858765, 7550140, 7960515, WO2012 / 027328, and WO2013 / 028231.

[0137] In one embodiment, the OX40 antigen binding protein is one disclosed in WO2012 / 027328 (PCT / US2011 / 048752) with international filing date August 23, 2011. In another embodiment, the antigen binding protein comprises the CDRs of an antibody disclosed in WO2012 / 027328 (PCT / US2011 / 048752) with international filing date August 23, 2011, or CDRs that are 90% identical to the disclosed CDR sequences. In a further embodiment, the antigen binding protein comprises the VH, VL, or both of an antibody disclosed in WO2012 / 027328 (PCT / US2011 / 048752) with international filing date August 23, 2011, or a VH or VL that is 90% identical to the disclosed VH or VL sequences.

[0138] In another embodiment, the OX40 antigen binding protein is disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international application date February 9, 2012, which is incorporated herein by reference in its entirety. In another embodiment, the antigen binding protein comprises the CDRs of an antibody disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international application date February 9, 2012, or CDRs that are 90% identical to the disclosed CDR sequences. In a further embodiment, the antigen binding protein comprises the VH, VL, or both of an antibody disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international application date February 9, 2012, or a VH or VL that is 90% identical to the disclosed VH or VL sequences. In one embodiment, the OX40 antigen binding protein is an isolated agonist antibody to OX40 comprising a light chain variable region having a sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 10 described in WO2013 / 028231, and a heavy chain variable region having a sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 4 described in WO2013 / 028231. In one embodiment, the OX40 antigen binding protein is an isolated antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10 described in WO2013 / 028231, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 described in WO2013 / 028231. Immune stimulants

[0139] Additional examples of other therapeutic agents for use in combination or co-administration with a compound of Formula I, or a salt thereof, are immunostimulants.

[0140] As used herein, "immunostimulant" refers to any agent that can stimulate the immune system. As used herein, immune stimulant includes, but is not limited to, vaccine adjuvants such as Toll-like receptor agonists, T cell checkpoint blockers such as mAbs against PD-1 and CTL4, and T cell checkpoint agonists such as agonist mAbs against OX-40 and ICOS. As used herein, "immunostimulant" refers to any agent that can stimulate the immune system. As used herein, immune stimulant includes, but is not limited to, vaccine adjuvants.

[0141] The term "Toll-like receptor" (or "TLR"), as used herein, refers to a member of the Toll-like receptor family of proteins or fragments thereof that sense microbial products and / or initiate adaptive immune responses. In one embodiment, TLRs activate dendritic cells (DCs). Toll-like receptors (TLRs) are a family of pattern recognition receptors that were initially identified as sensors of the innate immune system that recognize microbial pathogens. TLRs recognize distinctive structures on microorganisms, often referred to as "PAMPs" (pathogen-associated molecular patterns). Ligand binding to TLRs triggers a cascade of intracellular signaling 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, -2, -4, -5, and -6, while TLR-3, -7 / 8, and -9 are expressed by the ER compartment. Human DC subsets can be identified based on characteristic TLR expression patterns. For example, myeloid or "conventional" DC subsets (mDCs) express TLR1-8 upon stimulation, leading to the production of activation markers (e.g., CD80, CD86, MHC class I and II, CCR7), proinflammatory cytokines, and a cascade of chemokines. The outcome of this stimulation and resulting expression is antigen-specific CD4+ and CD8+ T cell priming. These DCs acquire an enhanced ability to take up antigens and present them in an appropriate form to T cells. In contrast, the plasmacytoid subset of DCs (pDCs) express only TLR7 and TLR9 upon activation, resulting in the activation of NK and T cells. Because dying tumor cells can have a detrimental effect on DC function, it has been suggested that activation of DCs with TLR agonists may be beneficial for priming antitumor immunity in immunotherapy approaches for the treatment of cancer. It has also been suggested that TLR4 activation is required for successful treatment of breast cancer using radiation and chemotherapy.

[0142] TLR agonists known in the art and that find use in the present invention include, but are not limited to, the following: Pam3Cys, a TLR1 / 2 agonist; CFA, a TLR2 agonist; MALP2, a TLR2 agonist; Pam2Cys, a TLR2 agonist; FSL-1, a TLR-2 agonist; Hib-OMPC, a TLR-2 agonist; polyinosinic:polycytidylic acid (poly I:C), a TLR3 agonist; polyadenosinic-polyuridylic acid (poly AU), a TLR3 agonist; polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (Hiltonol), a TLR3 agonist; bacterial flagellin. These include TLR5 agonists; imiquimod, a TLR7 agonist; resiquimod, a TLR7 / 8 agonist; loxoribine, a TLR7 / 8 agonist; and unmethylated CpG dinucleotides (CpG-ODN), a TLR9 agonist.

[0143] Additional TLR agonists known in the art and found use in the present invention further include, but are not limited to, aminoalkyl glucosaminide phosphates (AGPs) that bind to TLR4 receptors, and are known to be useful as vaccine adjuvants and immunostimulants to stimulate cytokine production, activate macrophages, promote natural immune responses, and increase antibody production in immunized animals.An example of a naturally occurring TLR4 agonist is bacterial LPS.An example of a semi-synthetic TLR4 agonist is monophosphoryl lipid A (MPL).AGPs and their immunomodulatory effects via TLR4 have been disclosed in patent publications such as WO2006 / 016997, WO2001 / 090129, and / or US Pat. No. 6,113,918, and have been reported in the literature. Additional AGP derivatives are disclosed in US Patent No. 7,129,219, US Patent No. 6,525,028, and US Patent No. 6,911,434. Certain AGPs act as agonists of TLR4, while others are recognized as TLR4 antagonists.

[0144] In addition to the aforementioned immune stimulants, the compositions of the present invention may further include other therapeutic agents that, due to their adjuvant properties, may act to stimulate the immune system to respond to cancer antigens present on the inactivated tumor cell(s). Such adjuvants include, but are not limited to, lipids, liposomes, inactivated bacteria that induce innate immunity (e.g., inactivated or attenuated Listeria monocytogenes), compositions that mediate innate immune activation via NOD-like receptors (NLRs), retinoic acid-inducible gene-based (RIG)-I-like receptors (RLRs), and / or C-type lectin receptors (CLRs). Examples of PAMPs include lipoproteins, lipopolypeptides, peptidoglycans, zymosan, lipopolysaccharide, neisseria porins, flagellins, profilins, galactoceramides, and muramyl dipeptides. Peptidoglycan, lipoproteins, and lipoteichoic acid are cell wall components of Gram-positive bacteria. Lipopolysaccharide is expressed by most bacteria, MPL being one example. Flagellin refers to a structural component of the bacterial flagellum secreted by pathogenic and commensal bacteria. rt.-Galactosylceramide (rt.-GalCer) is an activator of natural killer T (NKT) cells. Muramyl dipeptide is a bioactive peptidoglycan motif common to all bacteria.

[0145] Due to their adjuvant qualities, TLR agonists are preferably used in combination with other vaccines, adjuvants and / or immune modulators, and can be combined in various combinations.Thus, in certain embodiments, the compounds of formula I described herein that bind to STING and induce inactivated tumor cells that express and secrete one or more cytokines that stimulate STING-dependent TBKI activation and DC induction, recruitment and / or maturation can be administered together with one or more TLR agonists for therapeutic purposes, as described herein.

[0146] Indoleamine 2,3-dioxygenase 1 (IDO1) is a crucial immunosuppressive enzyme that promotes regulatory T cell generation and modulates antitumor immune responses by blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to evade immune surveillance (Lemos 2016, Munn 2016). Additional active ingredients (antineoplastic agents) for use in combination with or co-administered with the compounds of formula I of the present invention are IDO inhibitors. Epacadostat, ((Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboxamidine), is a highly potent, selective, oral inhibitor of the IDO1 enzyme that reverses tumor-associated immune suppression and restores effective antitumor immune responses. Epacadostat is disclosed in US Pat. No. 8,034,953.

[0147] Additional examples of other therapeutic agents (antineoplastic agents) for use in combination with or co-administered with the compounds of Formula I are CD73 inhibitors, and A2a and A2b adenosine antagonists.

[0148] The compound of formula I and its pharmaceutically acceptable salts can be used in combination with at least one other therapeutic agent useful in preventing or treating bacterial and viral infections.Examples of such agents include, but are not limited to, polymerase inhibitors, such as those disclosed in WO2004 / 037818, and those disclosed in WO2004 / 037818 and WO2006 / 045613; JTK-003, JTK-019, NM-283, HCV-796, R-803, R1728, R1626, and WO2006 / 018725, WO2004 / 074270, WO2003 / 095441, those disclosed in US2005 / 0176701, WO2006 / 020082, WO2005 / 080388, WO2004 / 064925, WO2004 / 065367, WO2003 / 007945, WO02 / 04425, WO2005 / 014543, WO2003 / 000254, EP1065213, WO01 / 47883, WO2002 / 057287, WO2002 / 057245 and similar agents; replication inhibitors, e.g. lovir, famciclovir, ganciclovir, cidofovir, lamivudine and similar agents; protease inhibitors, such as the HIV protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, parinavir, lasinavir, and the HCV protease inhibitors BILN2061, VX-950, SCH503034; and similar agents. nucleoside and nucleotide reverse transcriptase inhibitors, such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, tenofovir disproxil fumarate, tenofovir alafenamide fumarate / hemifumarate, and similar agents;Non-nucleoside reverse transcriptase inhibitors (including agents with antioxidant activity, such as immunocal, oltipraz, etc.), such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, rilpivirine and similar 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 vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-427,85 7), TAK449, and those disclosed in WO02 / 74769, WO2004 / 054974, WO2004 / 055012, WO2004 / 055010, WO2004 / 055016, WO2004 / 055011 and WO2004 / 054581, and similar agents; pharmacokinetic enhancers, such as cobicistat; neuraminidase inhibitors, such as CS-8958, zanamivir, oseltamivir, peramivir, Mivir and similar agents; ion channel blockers such as amantadine or rimantadine and similar agents; and interfering RNA and antisense oligonucleotides and such as ISIS-14803 and similar agents; antiviral agents with undefined mechanism of action such as those disclosed in WO2005 / 105761, WO2003 / 085375, WO2006 / 122011, ribavirin and similar agents.

[0149] The compounds of formula I and pharma- ceutically acceptable salts thereof may also be used in combination with other therapeutic agents that may be useful in the treatment of Kaposi's sarcoma-associated herpesvirus infections (KSHV and KSHV-associated), including, but not limited to, chemotherapeutic agents such as bleomycin, vinblastine, vincristine, cyclophosphamide, prednisone, alitretinoin and liposomal anthracyclines such as doxorubicin, daunorubicin, immunotherapeutic agents such as rituximab, tocilizumab, siltuximab, and others such as paclitaxel and rapamycin.

[0150] In one embodiment of the invention, the at least one other therapeutic agent is an antimycobacterial agent or a bactericidal antibiotic. The compounds of formula I and pharma- ceutically acceptable salts thereof may also be used in combination with at least one other therapeutic agent that may be useful in the treatment of TB infection (Mycobacterium tuberculosis) and Tularemia (Franciseiia tularensis), including, but not limited to, first-line oral agents: isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, rifabutin; injectable agents including kanamycin, amikacin, capreomycin, streptomycin; fluoroquinolones including levofloxacin, moxifloxacin, and ofloxacin; oral bacteriostatic agents: para-aminosalicylic acid, cycloserine, terizidone, thionamide, and prothionamide; SQ-109, PNU-100480, rifapentine, linezolid, PA-824, AZD5847, and gatifloxacin. These include moxifloxacin, Sirturo (bedaquiline) delamanid (OPC-67683), and agents with an undefined mechanism of action in treating drug-resistant TB including clofazimine, linezolid, amoxicillin / clavulanate thioacetazone imipenem / cilastatin high-dose isoniazid clarithromycin, and ciprofloxacin.The compounds of formula I and pharma- ceutically acceptable salts thereof may be used in the treatment of various chronic conditions, including but not limited to, antimycobacterial agents (e.g., isoniazid (INH), ethambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)), bactericidal antibiotics (e.g., rifabutin (Mycobutin®) or rifapentine (Priftin®)), aminoglycosides (Capreomycin®), fluoroquinolones (levofloxacin, moxifloxicin, ofloxacin), thioamides (ethionamide), cyclosporine (Sandimmune®), para-aminosalicyclic acid) (Paser®), cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®), bedaquiline fumarate (Sirturo®), oxazolidinones (Sutezolid®), PNU-100480 or delamanid (OPC-67683).

[0151] The compounds of formula I and pharma- ceutically acceptable salts thereof may also be used in combination with at least one other therapeutic agent that may be useful in the treatment of chlamydia, including, but not limited to, azithromycin, doxycycline, erythromycin, levofloxacin, ofloxacin.

[0152] The compounds of the present invention may also be used in combination with at least one other therapeutic agent that may be useful in the treatment of Plasmodium infections, including, but not limited to, chloroquine, atovaquone-proguanil, artemether-lumefantrine, mefloquine, quinine, quinidine, doxocycline, cindamycin, artesunate, primaquine.

[0153] In the treatment of amyotrophic lateral sclerosis (ALS), the compound of formula I or a pharma- ceutically acceptable salt thereof may be used in combination with glutamate blockers (riluzole (Rilutek®)), quinidine (Nuedexta®), anticholinergics (amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)), sympathomimetics (pseudoephedrine), mucolytics (guaifenesin) or analgesics (tramadol (Ultram®), ketorolac (Toradol®), morphine, fentanyl patch (Duragesic®)).

[0154] In the treatment of multiple sclerosis, the compound of formula I or a pharma- ceutically acceptable salt thereof may be used in combination with corticosteroids (prednisone, methylprednisolone), interferon beta 1-A (Avonex®, Extavia®, Rebif®, Betaseron®), pegylated interferon beta-1A (Plegridy®), glatiramer acetate (Copaxone®), glatiramer acetate (Glatopa®- It can be used in combination with rivaroxaban (a generic equivalent of copaxone), dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), teriflunomide (Aubagio®), dalfampridine (Ampyra®), daclizumab (Zinbryta), alemtuzumab (Lemtrada®), natalizumab (Tysabri®), or mitoxantrone hydrochloride (Novantrone®).

[0155] The compounds of the invention can also be used as adjuvants to improve the immune response generated against any given antigen and / or to reduce reactogenicity / toxicity in patients, particularly humans, in need thereof. Thus, the compounds of the invention can be used in combination with vaccine compositions to modify, and especially enhance, the immune response, for example by increasing the level or duration of protection and / or allowing for a reduction in the antigen dose.

[0156] The compounds of formula I and their pharma- ceutically acceptable salts can be used in combination with one or more vaccines or immunogenic antigens useful in preventing or treating viral infections. Such vaccines or immunogenic antigens include, but are not limited to, pathogen-derived proteins or particles, such as attenuated viruses, virus particles, and viral proteins, that are typically used as immunogenic substances. Examples of viruses and viral antigens include, but are not limited to, poliovirus, coronaviruses and coronaviruses, rhinoviruses (all subtypes), adenoviruses (all subtypes), hepatitis A, hepatitis B, hepatitis C, hepatitis D, human papillomaviruses (including all subtypes), rabies virus, human T-cell lymphotropic viruses (all subtypes), rubella virus, mumps virus, Coxsackie virus A (all subtypes), Coxsackie virus B (all subtypes), human enteroviruses, herpes viruses including cytomegalovirus, Epstein-Barr virus, human herpes virus,ruses (all subtypes), herpes simplex virus, varicella zoster virus, human immunodeficiency virus (HIV) (all subtypes), Epstein-Barr virus, reovirus (all subtypes), filoviruses (all strains), including Marburg virus and Ebola virus, lymphocytic choriomeningitis virus, arenaviruses, including Lassa virus, Junin virus, and Machupo virus, arboviruses, including West Nile virus, dengue virus (all serotypes), Zika virus, Colorado tick fever virus, Sindh virus, Bisviruses, Togaviraidae, Flaviviridae, Bunyaviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Poxviruses including Orthopoxviruses (Variolavirus, Monkeypoxvirus, Vacciniavirus, Cowpoxvirus), Yatapoxviruses (Tanapoxvirus, Yaba Monkey Tumor Virus), Parapoxvirus, Morsipoxvirus, Yellow Fever, Hantan, Seoul, Dobrava, Sin Nombre, Nombre, Puumala, and Dobrava-like Saaremaa; human parainfluenza viruses and influenza viruses (all types); HlNl influenza and swine influenza viruses; respiratory syncytial viruses (all subgroups); rotaviruses, including human rotaviruses A-E, bovine rotavirus, rhesus rotavirus; polyomaviruses, including simian virus 40, JC virus, BK virus, cortivirus, eyach virus, calcivirus; and parvoviridae, including dependovirus, parvovirus, and erythrovirus.

[0157] Thus, the present invention provides an immunogenic composition comprising an antigen or antigenic composition and a compound of formula I, or a pharma- ceutically acceptable salt thereof. Additionally, a vaccine composition is provided comprising an antigen or antigenic composition and a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0158] The compounds of formula I and pharma- ceutically acceptable salts thereof may also be used in combination with at least one other therapeutic agent that may be useful in the prevention or treatment of viral infections, such as immunotherapeutic agents (e.g., interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists and similar agents), as well as therapeutic vaccines, antifibrotic agents, anti-inflammatory agents, such as corticosteroids or NSAIDs (nonsteroidal anti-inflammatory drugs) and similar agents.

[0159] The STING-modulating compounds, particularly the compounds of Formula I or pharma- ceutically acceptable salts thereof, can be administered in combination with other anti-inflammatory agents, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicylic acid and mesalamine preparations, hydroxycloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors; anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics, and other cytokine inhibitors or biologics against T-cell or B-cell receptors or interleukins.

[0160] For example, in the treatment of systemic lupus erythematosus and related lupus disorders, compounds that modulate STING, particularly compounds of Formula I or pharma- ceutically acceptable salts thereof, may be used in combination with corticosteroids (e.g., prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econo- pred, Flo-Pred), immunosuppressants (e.g., methotrexate (Rhuematrex®, Trexall®), dexamethasone (Decadron®, Solurex®), mycophenolate mofetil (Cellcept®), tacrolimus®, Sirolimus®), B cell therapy (belimumab (Benlysta®), B cell inhibitors (Atacice®), pt®, Apratuzumab® (anti-CD22), SBI-087 (anti-CD20), anti-BAFF antibodies (LY2127399, A623), Velcade®), azathioprine (Azasan®, Imuran®), triamcinolone (Clinacort®, Kenalog-10®), hydroxychloroquine (Plaquenil®), thalidomide (Immunoprin®, Contergan®), immunoglobulin therapy (HyQiva®, Flebogamma®, Gamunex®, Privigen®, GammaGuard®), anti-interferon-alpha therapy (Rontalizumab®, Sifalimumab®, AGS-009®, IFNKinoid), TLR7 and TLR9 blockers (IMO-3100), anti-cytokine therapy (anti-IL6 (CNTO-136), anti-interferon-gamma (AMG811), immunomodulatory therapy (Lupuzor™, Abatacept, Orencia®, AMG557, Laquinimod, Paquinimod, Leflunomide, Anti-ICOS (Medi-570), Anti-CD40 Ligand antibody (CDP7657)), and / or platelet aggregation inhibitors (aspirin).

[0161] In the treatment of vasculitis and diseases involving inflammation of small or medium-sized blood vessels, STING-modulating compounds, particularly compounds of Formula I, or pharma- ceutically acceptable salts thereof, can be administered in combination with alkylating agents (cyclophosphamide, Cytoxan®), anti-rheumatic anti-CD20 antibodies (Rituxan®, Rituximab®), and anti-TNF inhibitors (Etanrcept®).

[0162] In the treatment of psoriasis, a compound that modulates STING, particularly a compound of formula I, or a pharma- ceutically acceptable salt thereof, can be administered in combination with ixekizumab, tildrakizumab (MK-3222) or secukinumab (AIN457).

[0163] In one embodiment of the invention, the at least one other therapeutic agent is selected from an inhaled corticosteroid, a long-acting beta agonist, a combination of an inhaled corticosteroid and a long-acting beta agonist, a short-acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. For example, in the treatment of asthma, compounds that inhibit STING, in particular the compounds of formula I or a pharma- ceutically acceptable salt thereof, are used in combination with inhaled corticosteroids (ICS), such as fluticasone proprionate (Flovent®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort), triamcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone furoate (Asmanex®, Twisthaler®) or ciclesonide (Alvesco®), long-acting beta agonists (LABA), such as formoterol fumarate (Foradil®), salmeterol xinafoate (Serevent®), combinations of ICS and LABA (e.g. fluticasone furoate and vilanterol (Breo®)), Ellipta®), formoterol / budesonide inhalation (Symbicort®), beclomethasone dipropionate / formoterol (Inuvair®), and fluticasone propionate / salmeterol (Advair®), short-acting beta agonists ((SABA), such as albuterol sulfate (ProAir®, Proventil HFA®, Ventolin®,HFA®, AccuNeb® Inhalation Solution), levalbuterol tartrate (Xopenex® HFA), ipratropium bromide / albuterol (Combivent® Respimat®), ipratropium bromide (Atrovent® HFA), leukotriene modifiers (e.g., montelukast sodium (Singulair®), zafirlukast (Accolate®), or zileuton (Zyflo®), and and anti-IgE (e.g., omalizumab (Xolair®)), methylxanthine bronchodilators (e.g., theophylline (Accurbron®, Aerolate®, Aquaphyllin®, Asbron®, Bronkodyl®, Duraphyl®, Elixicon®, Elixomin®, Elixophyllin®, Labid®, Lanophyllin ( ®), Quibron-T®, Slo-Bid®, Slo-Phyllin®, Somophyllin®, Sustaire®, Synophylate®, T-Phyll®, Theo-24®, Theo-Dur®, Theobid®, Theochron®, Theoclear®, Theolair®, Theolixir®, Theophyl®, Theovent®, Uni-dur®, Unifil®), mast cell inhibitors (e.g., cromulyn sodium (Nasalcrom®) and nedocromil sodium (Tilade®)), long-acting muscarinic antagonists ((LAMA), e.g., mometasone furoate / formoterol fumarate dihydrate (Dulera®)).

[0164] Other agents that may be suitable for use in combination therapy in the treatment of asthma include protein tyrosine kinase inhibitors (masitinib), CRTH2 / D-prostanoid receptor antagonist (AMG853), indacaterol (Arcapta® Neohaler®), epinephrine inhalation aerosol (E004), fluticasone furoate / fluticasone propionate, vinanterol inhalation / fluticasone furoate powder (Relovair®), fluticasone propionate / formoterol fumarate dehydrate (eformoterol fumarate dehydrate), and fluticasone propionate / formoterol fumarate dehydrate (eformoterol fumarate dehydrate). dehydrate) (Flutiform®), reslizumab, salbutamol dry powder inhalation, tiotropium bromide (Spiriva® HandiHaler®), formoterol / budesonide (Symbicort® SMART®), fluticasone furoate (Veramyst®), VR506 from Vectura, lebrikizumab (RG3637), and a combination phosphodiesterase (PDE)-3 and (PDE)-4 inhibitor (RPL554).

[0165] In one embodiment of the invention, the at least one other therapeutic agent is selected from a long-acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, an inhaled corticosteroid combination of a long-acting beta agonist, a short-acting beta agonist, and an inhaled corticosteroid.For example, in the treatment of COPD, compounds that modulate STING, particularly compounds of formula I or pharma- ceutically acceptable salts thereof, include LABAs (e.g., salmeterol xinafoate (Serevent), umeclidinium / vilanterol (Anoro Ellipta®), umeclidinium (Incruse®), and cerebrospinal fluid (Cyclohexanol). Ellipta®), aformoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta®, Neohaler®) or fluticasone propionate / formoterol fumarate dehydrate (Flutiform®), long-acting inhaled anticholinergics (or muscarinic antagonists, such as tiotropium bromide (Spiriva®), and aclidinium bromide (Tudorza®, Pressair®), phosphodiesterase (PDE-r) inhibitors (e.g., roflumilast, Daliresp®), combination ICS / LABA (e.g., fluticasone furoate and vilanterol (Breo Ellipta®), fluticasone propionate / salmeterol (Advair®), budesonide / formoterol (Symbicort®), mometasone / formoterol (Dulera®), ipratropium bromide / albuterol sulfate (Duoneb®, Atrovent®), albuterol / ipratropium (Combivent Respimat®)), SABAs (e.g., ipratropium bromide (Atrovent®), and albuterol sulfate (ProAir®, Proventil®)), and ICS (e.g., budesonide (Pulmicort®) and fluticasone propionate (Flovent®), beclomethasone dipropionate (QVAR®).

[0166] Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (CXCR2 antagonist), glycopyrronium bromide ((NVA237) Seebri® Breezhaler®), glycopyrronium bromide and indacaterol maleate ((QVA149) Ultibro® Breezhaler®), glycopyrrolate and formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol (Striverdi® Respimat®), tiotropium (Spiriva®) / olodaterol (Striverdi® Respimat®), and aclidinium / formoterol inhalation.

[0167] In one embodiment of the invention, the at least one other therapeutic agent is selected from oral corticosteroids, antithymocyte globulin, thalidomide, chlorambucil, calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin-1 receptor inhibitors, antifibrotic agents, proton pump inhibitors or imatinib, ARG201, and tocilizumab. For example, in the treatment of systemic sclerosis, compounds that modulate STING, particularly compounds of Formula I or pharma- ceutically acceptable salts thereof, may be used in combination with oral corticosteroids (e.g., prednisolone (Delatsone®, olapred, millipred, omnipred, econopred, furo-pred), immunosuppressants (e.g., methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), antithymocyte globulin (Atgam®), mycophenolate mofetil (Cellcept®), cyclophosphamide (Cytoxan®), erythropoietin (Mycobacterium tuberculosis), and the like. trademark), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Leukeran®), azathioprine (Imuran®, Azasan®)), calcium channel blockers (e.g., nifedipine (Procardia®, Adalat®) or nicardipine (Cardene®), topical emollients (nitroglycerin ointment), ACE inhibitors (e.g., lisinopril (Zestril®, Prinivil®), diltaizem (Cardizem®, Cardizem®), SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®), serotonin reuptake inhibitors (e.g., fluoxetine (Prozac®)), endothelin-1 receptor inhibitors (e.g., bosentan (Tracleer®) or epoprostenol (Floran®, Veletri®, Prostacyclin®)).Antifibrotic agents (e.g., colchicine (Colcrys®), para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO), and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gamma (INF-g)), proton pump inhibitors (e.g., omeprazole (Prilosec®), metoclopramide (Reglan®), lansoprazole (Prevacid®), esomeprazole (Nexium®), pantoprazole (Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®), ARG201 (arGentis Pharmaceuticals), belimumab (Benlysta®), tocilizumab (Actema®)) may be administered in combination.

[0168] In the treatment of Sjogren's syndrome, compounds that modulate STING, particularly compounds of formula I or pharma- ceutically acceptable salts thereof, can be administered in combination with antirheumatic agents (hydroxychloroquine and Plaquenil®, Lidora®, Kineret®), cholinergic agonists (Salagen®, Evoxac®), JAK inhibitors (Xelijanz®), and anti-TNF treatments (Remicade®, Humira®, Enbrel®, Cimzia®, Simponi®).

[0169] In one embodiment of the present invention, at least one other therapeutic agent is ciliary neurotrophic growth factor or gene transfer agent.For example, in the treatment of retinitis pigmentosa, the compound that modulates STING, particularly the compound of formula I or its pharma- ceutically acceptable salt, can be administered in combination with ciliary neurotrophic growth factor (NT-501-CNTF) or gene transfer agent, UshStat®.

[0170] In one embodiment of the invention, the at least one other therapeutic agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a tetravalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a tetravalent live attenuated influenza vaccine, an antiviral agent, or an inactivated influenza vaccine. For example, in the treatment of influenza, a compound that modulates STING, particularly a compound of formula I or a pharma- ceutically acceptable salt thereof, can be used in the treatment of trivalent (IIV3) inactivated influenza vaccines (e.g., Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®), tetravalent (IIV4) inactivated influenza vaccines (e.g., Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), , a trivalent recombinant influenza vaccine (e.g., FluBlok®), a quadrivalent live attenuated influenza vaccine (e.g., FluMist® Quadrivalent), an antiviral agent (e.g., oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®) or amantadine (Symmetrel®)), or in combination with Fluad®, Fludase, FluNhance®, Preflucel, or VaxiGrip®.

[0171] In the treatment of staphylococcal infections, the STING-modulating compounds, particularly the compounds of Formula I or a pharma- ceutically acceptable salt thereof, can be administered in combination with an antibiotic (e.g., a β-lactam cephalosporin (Duricef®, Kefzol®, Ancef®, Biocef®, etc.), nafcillin (Unipen®), sulfonamides (sulfamethoxazole and trimethoprim (Bacrim®, Septra®), sulfasalazine (Azulfidine®), acetylsulfisoxazole (Gantrisin®), etc.), or vancomycin (Vancocin®)).

[0172] In one embodiment of the invention, the at least one other therapeutic agent is selected from a topical immune modulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, interferon gamma, an antihistamine, or an antibiotic.For example, in the treatment of atopic dermatitis, compounds that modulate STING, particularly compounds of formula I, or pharma- ceutically acceptable salts thereof, may be used in combination with topical immunomodulators or calcineurin inhibitors (e.g., pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), topical corticosteroids (e.g., hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), or other topical anti-inflammatory drugs (e.g., cyclosporine (Cordan®), ... (R), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)), oral corticosteroids (e.g., hydrocortisone (Cortef®), methylprednisolone (Medrol®) or prednisolone (Pediapred®, Prelone®), immunosuppressants (e.g., cyclosporine (Neoral®) or interferon gamma (Alferon®), N®, Infergen®, Intron A, Roferon-A®), antihistamines (for pruritus, e.g. Atarax®, Vistaril®, Benadryl®), antibiotics (e.g. penicillin derivatives flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm®, etc.)), non-steroidal immunosuppressants (e.g. azathioprine (Imuran®, Azasan®), methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®) or mycophenolate mofetil (Cellcept®)).

[0173] The compound of the present invention can also be formulated with vaccines as adjuvants to modulate its activity.Such compositions can contain one or more components with adjuvant activity, including but not limited to aluminum salts, oil and water emulsions, heat shock proteins, lipid A preparations and derivatives, glycolipids, other TLR agonists, such as CpG DNA or similar agents, cytokines, such as GM-CSF or IL-12 or similar agents, together with antigenic components, including but not limited to antibody(ies) or antibody fragment(s), or proteins, DNA, live or killed bacteria and / or viruses or virus-like particles.

[0174] In a further aspect of the invention, there is provided a vaccine adjuvant comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof. Additionally, there is provided a vaccine composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and an antigen or antigen composition. Treatment

[0175] The compounds of the present invention can be used in therapeutic methods. Also provided are methods of treatment, comprising administering a therapeutically effective amount of the compounds of the present invention to a subject in need of treatment. The term "therapeutically effective amount" refers to an amount sufficient to provide benefit to the patient. Such benefit may be at least an improvement in at least one symptom. The actual amount administered, as well as the rate and time course of administration, will vary depending on the nature and severity of what is being treated. Prescribing treatment, for example, determining dosage, is the responsibility of general medical practitioners and other physicians. Administration

[0176] The active compound or a pharmaceutical composition comprising the active compound can be administered to a subject by any convenient route of administration, whether systemically / peripherally or at a desired site of action, including, but not limited to, oral (e.g., by ingestion); topical (including, e.g., transdermal, intranasal, ophthalmic, oral buccal, and sublingual); pulmonary (e.g., using an aerosol, e.g., via the mouth or nose, e.g., by inhalation or insufflation therapy); rectal; intravaginal; parenteral, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intravitreal, and intrasternal; e.g., by implantation of a depot subcutaneously, intravitreally, or intramuscularly. The subject can be a eukaryote, animal, vertebrate, mammal, rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human.

[0177] In one embodiment for treating tumors, intratumoral injection can be used. formulation

[0178] While it is possible for the active compounds to be administered alone, they are preferably presented as a pharmaceutical composition (e.g., a formulation) comprising at least one active compound as defined above, together with one or more pharma- ceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants or other materials well known to those skilled in the art, and, if necessary, other therapeutic or prophylactic agents.

[0179] Thus, the present invention further provides a pharmaceutical composition as defined above, and a method of making a pharmaceutical composition comprising the step of mixing at least one active compound as defined above together with one or more pharma- ceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials as described herein.

[0180] The term "pharmacologically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / disadvantage ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0181] Suitable carriers, excipients, etc. can be found in standard medical texts, such as Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.

[0182] Preparation can be conveniently presented in unit dosage form and can be prepared by any method well known in the field of pharmacy.Such method includes the step of combining active compound with carrier that constitutes one or more auxiliary ingredients.Generally, preparation is prepared by uniformly and thoroughly combining active compound with liquid carrier or finely divided solid carrier or both, and then shaping product as necessary.

[0183] The formulation can be in the form of a liquid, solution, suspension, emulsion, elixir, syrup, tablet, lozenge, granule, powder, capsule, cachet, pill, ampoule, suppository, pessary, ointment, gel, paste, cream, spray, mist, foam, lotion, oil, bolus, electuary, or aerosol.

[0184] Formulations suitable for oral administration (e.g., by ingestion) may be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of the 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 or water-in-oil liquid emulsion; as a bolus, as a electuary, or as a paste.

[0185] Tablets can be prepared by conventional means, such as compression or molding, optionally with one or more auxiliary ingredients.Compressed tablets can be prepared by compressing the active compound in a free-flowing form, such as powder or granules, mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose), fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate), and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid) in a suitable machine.Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be coated or scored as required and can be formulated to provide a sustained or controlled release of the active compound therein using, for example, various percentages of hydroxypropyl methylcellulose to provide the desired release profile. Tablets can be provided with an enteric coating, if desired, for release in parts of the intestine other than the stomach.

[0186] Formulations suitable for topical administration (e.g., transdermal, intranasal, ophthalmic, buccal, and sublingual) can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. Alternatively, a formulation can comprise a patch or dressing, such as a bandage or adhesive plaster, impregnated with active compounds and optionally one or more excipients or diluents.

[0187] Formulations suitable for topical administration in the mouth include lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.

[0188] Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

[0189] Suitable formulations for nasal administration where the carrier is a solid include, for example, a coarse powder having a particle size in the range of about 20 to about 500 microns, which is administered in the manner of a sniff, i.e., by rapid inhalation through the nostrils from a container of the powder held close to the nose. Suitable formulations where the carrier is a liquid, for example for administration as a nasal spray, nasal drops, or by aerosol administration by nebulizer, include aqueous or oily solutions of the active compound.

[0190] Formulations suitable for administration by inhalation include those presented as an aerosol spray from pressurized packs using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gas.

[0191] Suitable formulations for topical administration through the skin include ointments, creams, and emulsions. When formulated into an ointment, the active compound can be employed with either a paraffinic or water-miscible ointment base as needed. Alternatively, the active compound can be formulated into a cream using an oil-in-water cream base. If desired, the aqueous phase of the cream base can contain, for example, at least about 30 w / w% of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations can desirably contain a compound that enhances the absorption or penetration of the active compound through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0192] When formulated as a topical emulsion, the oil phase may optionally comprise simply an emulsifier (otherwise known as an emulgent), or may comprise a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. Overall, the emulsifier(s), with or without the stabilizer(s), constitute the so-called emulsifying wax, which, together with the oil and / or fat, constitutes the so-called emulsifying ointment base, which forms the oil-dispersed phase of the cream formulation.

[0193] Suitable emulsifiers and emulsion stabilizers include Tween® 60, Span® 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low, so the selection of the appropriate oil or fat for the formulation is based on the achievement of the desired cosmetic properties. Thus, the cream should preferably be a non-greasy, non-staining, washable product with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters can be used, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched esters known as Crodamol CAP, the last three being the preferred esters. These may be used alone or in combination depending on the properties required.

[0194] Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0195] Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0196] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active compound, such carriers as are known in the art to be appropriate.

[0197] Suitable formulations for parenteral administration (e.g., by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal) include aqueous and non-aqueous isotonic, pyrogen-free sterile injection solutions that may contain antioxidants, buffers, preservatives, stabilizers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents, and liposomes or exosomes or other microparticulate systems that are designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of the active compound in the solution is about 1 ng / mL to about 10 μg / mL, for example about 10 ng / ml to about 1 μg / mL. The formulations can be presented in single-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use.Injection solutions and suspensions to be used without preparation can be prepared from sterile powders, granules, and tablets.The formulations can also be in the form of liposomes or exosomes or other microparticulate systems designed to target the active compound to blood components or one or more organs. Dosage

[0198] Those skilled in the art will recognize that the appropriate dosage of the compound and the composition containing the compound may vary from patient to patient. Determining the optimal dosage generally involves balancing the therapeutic benefit level against any risk or harmful side effects. The selected dosage level will depend on a variety of factors, including, but not limited to, the activity of the particular compound, the route of administration, the timing of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds and / or materials used in combination, the severity of the condition, and the patient's species, sex, age, weight, condition, overall health, and past medical history. The amount of the compound and the route of administration are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dosage is selected to achieve a local concentration at the site of action that achieves the desired effect without causing significant harm or harmful side effects.

[0199] Administration can be in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosages of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the therapeutic purpose, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level or pattern being selected by the treating physician, veterinarian, or clinician.

[0200] In general, a suitable dose of an active compound is within the range of about 100 ng to about 25 mg (more typically about 1 μg to about 10 mg) per kilogram of subject body weight per day. Where the active compound is a salt, ester, amide, prodrug, or the like, the amount administered is calculated based on the parent compound, and therefore the actual weight to be used will be increased proportionately.

[0201] In one embodiment, the active compound is administered to a human patient according to a dosage regimen of about 100 mg three times daily.

[0202] In one embodiment, the active compound is administered to a human patient according to a dosage regimen of about 150 mg twice daily.

[0203] In one embodiment, the active compound is administered to a human patient according to a dosage regimen of about 200 mg twice daily.

[0204] However, in one embodiment, the active compound is administered to a human patient according to a dosage regimen of about 50 mg or about 75 mg three or four times daily.

[0205] In one embodiment, the active compound is administered to a human patient according to a dosing regimen of about 100 mg or about 125 mg twice daily. treatment

[0206] The term "treatment" in the context of treating a condition, as used herein, generally relates to treatments and therapies, whether in humans or animals (e.g., veterinary applications), in which some desired therapeutic effect is achieved, such as inhibition of progression of the condition, including reducing the rate of progression, halting the rate of progression, regressing the condition, ameliorating the condition, and curing the condition. Treatment as a preventative measure (i.e., prophylaxis, prevention) is also included.

[0207] The term "therapeutically effective amount," as used herein, relates to an amount of an active compound, or a material, composition, or dosage form containing an active compound, effective, commensurate with a reasonable benefit / loss ratio, to provide some desired therapeutic effect when administered in accordance with a desired treatment regimen.

[0208] Similarly, the term "prophylactically effective amount," as used herein, relates to an amount of an active compound, or a material, composition or dosage form containing an active compound, effective, commensurate with a reasonable benefit / loss ratio, to provide some desired prophylactic effect when administered in accordance with a desired treatment regimen. Subjects / Patients

[0209] The subject / patient may be an animal, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), monotreme (e.g., platypus), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human.

[0210] Furthermore, the subject / patient may be any of its forms of development, such as a fetus, hi a preferred embodiment, the subject / patient is a human. General synthesis method

[0211] The compounds of the present invention can be prepared by employing the following general methods and using the procedures detailed in the Examples. The reaction conditions mentioned are exemplary and non-limiting, for example, a person skilled in the art can use various synthetic methods to synthesize the desired compounds, for example, but not limited to, methods described in the literature (for example, but not limited to, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition or Larock's Comprehensive Organic Transformations: Comprehensive Organic Transformations: A Guide to Functional Group Preparations).

[0212] The compounds of formula I above can be prepared by the synthetic strategies outlined below, where the above definitions apply. General synthesis 1 [ka]

[0213] Scheme 1a illustrates the synthesis of compounds having structure G8. The first step involves reacting an appropriately substituted ketone G1 with ethyl 2-mercaptoacetate G2 in the presence of a suitable base, such as but not limited to K2CO3. Bromination of product G3 to form alkyl bromide G4 can be carried out 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 reaction of G4 can be carried out using a suitable oxidizing agent, such as but not limited to N-methylmorpholine N-oxide, to give compounds of type G5. Compounds of formula G7 can be made by condensing an appropriately substituted benzothiophene, thienopyridine or thienopyrimidine G5 with an appropriately substituted di-aniline G6 in the presence of either (a) a suitable acid, such as but not limited to acetic acid, or (b) sodium bisulfite, or (c) sodium metabisulfite. Carboxylic acid G8 can be formed by hydrolysis of ester G7 with a base such as an alkali metal hydroxide or an acid such as aqueous hydrochloric acid. [ka]

[0214] R C2 or R C3 Compounds of formula G11, where either R is C(=O)NH2, can be converted to appropriately substituted di-anilines G9, where R is C(=O)NH2, in the presence of either (a) a suitable acid, such as, but not limited to, acetic acid, or (b) sodium bisulfite, or (c) sodium metabisulfite. C2 or R C3where R is C(=O)NH2) with an appropriately substituted benzothiophene, thienopyridine or thienopyrimidine G5 to give compounds of type G10 (Scheme 1b). Carboxylic acids G11 can be formed by hydrolysis of ester G10 with a base such as an alkali metal hydroxide or an acid such as aqueous hydrochloric acid. Compounds of formula G10 can be prepared by reaction of G7 (where R N1 ═H) with an alkyl halide, such as, but not limited to, iodomethane, in the presence of a base, such as, but not limited to, KCO, to give a mixture of regioisomers (isomer 1:R C2 =C(=O)NH2, R C3 =H and isomer 2: R C3 =C(=O)NH2, R C2 =H), and the isomers can be separated by chromatographic methods known to those skilled in the art. [ka] General synthesis 2 [ka]

[0215] Compounds of structure G1 can be obtained by reacting an appropriately substituted aldehyde G12 with a Grignard reagent, such as methylmagnesium bromide, to give alcohol G13. Methods for oxidizing alcohol G13 to give ketone G1 will be apparent to those skilled in the art, but include, for example, the use of reagents such as chromium trioxide and sulfuric acid. General synthesis 3 [ka]

[0216] Compounds of structure G12 can be made by treating an appropriately substituted arene or heteroarene GX with either an alkyllithium, such as but not limited to, n-butyllithium, or a lithium amide base, such as but not limited to, lithium diisopropylamide, followed by quenching the resulting lithiated species with N,N-dimethylformamide. Alternatively, the lithiated species formed by treating GX with an alkyllithium or lithium amide can be quenched with acetaldehyde to directly provide compound G13. General synthesis 4 [ka]

[0217] Conditions for converting acid G8 to ester or amide G15 will be apparent to one skilled in the art, but include excess of the appropriate nucleophile G14 and a catalyst, such as concentrated sulfuric acid (for the formation of esters), as shown in Scheme 4a. Alternatively, G8 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, and then reacted with nucleophile G14 in the presence of a catalyst, such as but not limited to 4-dimethylaminopyridine (for the formation of esters or amides), or in the presence of a base, such as but not limited to N,N-diisopropylethylamine (for the formation of amides).

[0218] Esters G17 can be obtained by reacting acids G8 with appropriate alkyl halides G16 in the presence of a suitable base, such as, but not limited to, cesium carbonate, as shown in Scheme 4b. [ka] General synthesis 5 [ka]

[0219] Compounds of type G7 can also be formed by condensing an appropriately substituted benzothiophene, thienopyridine or thienopyrimidine G5 with an appropriately substituted di-aniline benzoic acid G18 in the presence of either (a) a suitable acid, such as, but not limited to, acetic acid, or (b) sodium bisulfite, or (c) sodium metabisulfite. Formation of G7 from acid G19 can then proceed using a coupling reagent, such as, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide, followed by reaction with an ammonia source, such as, but not limited to, ammonium chloride, in the presence of a base, such as, for example, N,N-diisopropylethylamine. Further embodiments R N1

[0220] R N1 When R is H, the amide-benzimidazole moiety exhibits tautomerism. For example, C1 and R C4 If is H, then R C2 =C(=O)NH2 and R C3 =H and R C3 =C(=O)NH2 and R C2 The compounds with =H are tautomers.

[0221] In contrast, R N1 When R is Me, the amide-benzimidazole moiety does not exhibit tautomerism. C1 and R C4 If is H, then R C2=C(=O)NH2 and R C3 =H and R C3 =C(=O)NH2 and R C2 The compounds with =H are positional isomers.

[0222] In some embodiments, R N1 is H. In some embodiments, R N1 is Me. R 1

[0223] In some embodiments, R C2 is C(=O)NH2, W is O, and R 1 is H. In these embodiments, the compound has formula Ia1: [ka] wherein A 1 ~A 4 , R N1 , R C1 , R C3 and R C4 is as defined above. In some embodiments, R C3 is C(=O)NH2, W is O, and R 1 is H. In these embodiments, the compound has formula Ia2: [ka] wherein A 1 ~A 4 , R N1 , R C1 , R C2 and R C4 is as defined above.

[0224] In other embodiments, R C2 is C(=O)NH2, W is NH, and R 1 is H. In these embodiments, the compound has formula Ic1: [ka] wherein A 1 ~A 4 , R N1 , R C1 , R C3 and R C4 is as defined above.

[0225] In other embodiments, R C3 is C(=O)NH2, W is NH, and R 1 is H. In these embodiments, the compound has formula Ic2: [ka] wherein A 1 ~A 4 , R N1 , R C1 , R C2 and R C4 is as defined above.

[0226] In other embodiments, R C2 is C(=O)NH2, W is O or NH, R 1 is R 1B R 1B is C 3~6 Cycloalkyl, optionally substituted C 3~7 Heterocyclyl and optionally substituted straight or branched C 1~4 In these embodiments, the compound has formula Ib1: [ka] wherein A 1 ~A 4 , R N1 , R C1 , R C3 and R C4 is as defined above, and R 1B is C 3~6 Cycloalkyl, optionally substituted C 3~7 Heterocyclyl and optionally substituted straight or branched C1~4 is selected from alkyl.

[0227] In other embodiments, R C3 is C(=O)NH2, W is O or NH, R 1 is R 1B R 1B is C 3~6 Cycloalkyl, optionally substituted C 3~7 Heterocyclyl and optionally substituted straight or branched C 1~4 In these embodiments, the compound has formula Ib2: [ka] wherein A 1 ~A 4 , R N1 , R C1 , R C2 and R C4 is as defined above, and R 1B is C 3~6 Cycloalkyl, optionally substituted C 3~7 Heterocyclyl and optionally substituted straight or branched C 1~4 is selected from alkyl.

[0228] In some embodiments, R 1 / R 1B is an optionally substituted linear or branched C 1~4 In some embodiments, R 1 / R 1B is unsubstituted C 1~4 In some embodiments, R 1 / R 1B is a substitution C 1~4 It is an alkyl.

[0229] R 1 / R 1B C 1~4 In some of these embodiments, when R is alkyl, 1 / R 1Bis methyl. In other of these embodiments, R 1 / R 1B In other of these embodiments, R 1 / R 1B is propyl (e.g., iso-propyl, n-propyl). In other of these embodiments, R 1 / R 1B is butyl (e.g., iso-butyl, sec-butyl, tert-butyl, n-butyl).

[0230] In some embodiments, R 1 / R 1B is C 3~6 In some of these embodiments, R 1 / R 1B In other of these embodiments, R 1 / R 1B In other of these embodiments, R 1 / R 1B is cyclopentyl. In other of these embodiments, R 1 / R 1B is cyclohexyl.

[0231] In some embodiments, R 1 / R 1B is C 3~7 In some of these embodiments, C is heterocyclyl. 3~7 Heterocyclyl has a single nitrogen ring atom. In some of these embodiments, R 1 / R 1B is azetidinyl, pyrrolidinyl, or piperidinyl. In some of these embodiments, R 1 / R 1B is azetidinyl. In some of these embodiments, R 1 / R 1B is piperidinyl. R 1 Substituents on

[0232] In some embodiments, R 1 / R 1B is C3~7 When R is heterocyclyl, it is substituted with a group selected from methyl and ester. 1 / R 1B is C 3~7 When R is heterocyclyl, it is substituted with methyl. 1 / R 1B is C 3~7 When it is heterocyclyl, it is substituted with an ester.

[0233] In some embodiments, R 1 / R 1B is linear or branched C 1~4 When it is alkyl, it is optionally substituted with a group selected from alkoxy, amino, amido, acylamido, acyloxy, alkylcarboxyl ester, alkylcarbamoyl, alkylcarbamoyl ester, phenyl, phosphonate ester, methyl and oxo. 3~7 Substituted with a group selected from heterocyclyl and naturally occurring amino acids, optionally N-substituted with a group selected from methyl, acetyl and boc.

[0234] In some embodiments, R 1 / R 1B is linear or branched C 1~4 When R is alkyl, it is substituted with a group selected from acyloxy and phenyl. 1 / R 1B is a straight or branched C substituted with acyloxy. 1~4 When it is alkyl, it has the formula: [ka] The group is pivaloyloxymethyl.

[0235] In some embodiments, R 1 / R 1B is a straight or branched C substituted with acyloxy. 1~4 When it is alkyl, it has the formula: [ka] The group is propanoyloxyisobutyl.

[0236] In some embodiments, R 1 / R 1B is a straight or branched C substituted with phenyl 1~4 When it is alkyl, it is benzyl.

[0237] In some embodiments, R 1 / R 1B is linear or branched C 1~4 If it is alkyl, it is substituted with a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl, and boc. 1 / R 1B is substituted with a naturally occurring amino acid, 1~4 When it is alkyl, the naturally occurring amino acid is valine. 1 / R 1B is substituted with a naturally occurring amino acid, 1~4 When it is alkyl, the naturally occurring amino acid is N-methylvaline. 1 / R 1B is substituted with a naturally occurring amino acid, 1~4 When it is alkyl, the naturally occurring amino acid is N-acetylvaline. 1 / R 1B is substituted with a naturally occurring amino acid, 1~4 When it is alkyl, the naturally occurring amino acid is N-boc valine.

[0238] In some embodiments, R 1 / R 1B is linear or branched C 1~4 When R is alkyl, it is substituted with amino. 1 / R 1B is linear or branched C1~4 When R is alkyl, it is substituted with an amide. 1 / R 1B is linear or branched C 1~4 When R is alkyl, it is substituted with acylamido. 1 / R 1B is linear or branched C 1~4 When R is alkyl, it is substituted with acyloxy. 1 / R 1B is linear or branched C 1~4 When it is alkyl, it is substituted with an alkyl carboxyl ester. 1 / R 1B is linear or branched C 1~4 When R is alkyl, it is substituted with alkylcarbamoyl. 1 / R 1B is linear or branched C 1~4 When it is alkyl, it is substituted with an alkyl carbamoyl ester. 1 / R 1B is linear or branched C 1~4 When R is alkyl, it is substituted with phenyl. 1 / R 1B is linear or branched C 1~4 If it is alkyl, it is substituted with a phosphonate ester.

[0239] In some embodiments, R 1 / R 1B is linear or branched C 1~4 If alkyl, optionally substituted with a group selected from methyl and oxo. 3~7 In some embodiments, R is substituted with heterocyclyl. 1 / R 1B But, C 3~7 Straight or branched C substituted with heterocyclyl 1~4 If it is alkyl, C 3~7 Heterocyclyl is dioxole optionally substituted with a group selected from methyl and oxo.

[0240] The compounds of formulae (Ib1), (Ib2), (Ic1) and (Ic2) are prodrugs of the acids of formulae (Ia1) and (Ia2). A 1 ~A 4

[0241] In some embodiments, A 1 CR A It is.

[0242] In another embodiment, A 1 is N.

[0243] In some embodiments, A 2 CR B It is.

[0244] In another embodiment, A 2 is N.

[0245] In some embodiments, A 3 CR C It is.

[0246] In another embodiment, A 3 is N.

[0247] In some embodiments, A 4 CR D It is.

[0248] In another embodiment, A 4 is N.

[0249] In some embodiments, A 1 , A 2 , A 3 and A 4 Two of them are N.

[0250] In another embodiment, A 1 , A 2 , A 3 and A 4 One of them is N.

[0251] In another embodiment, A 1 , A 2 , A 3 and A 4 None of the above is N, i.e. A 1 , A 2 , A 3 and A 4 are CR A , C.R. B , C.R. C , and C.R. D It is.

[0252] In some embodiments, the compound of formula I has the formula (IIIa1)-(IIIe1): [ka] [ka] The compound is selected from the group consisting of

[0253] In some embodiments, the compound of formula I has the formula (IIIa2)-(IIIe2): [ka] [ka] The compound is selected from the group consisting of R A , R B , R C and R D (if present)

[0254] In some embodiments, R A , R B , R C and R D (when present) is selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CHOMe, and OH.

[0255] In some embodiments, RA , R B , R C and R D One of (if present) is selected from F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH. The rest (if present) are H.

[0256] In other embodiments, R A , R B , R C and R D Two of (if present) are selected from F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, OEt, CHOH, CHOMe and OH. The remaining (if present) is H.

[0257] In some embodiments, R A , R B , R C and R D One or two of (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, and OMe. The remaining (if present) are H. In some of these embodiments, R A , R B , R C and R D One or two of (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, and OMe. The remaining (if present) are H. In some of these embodiments, R A , R B , R C and R D One or two of (if present) are selected from H, F, Cl, Br, Me, CF3, and OMe. The remaining (if present) are H. In some of these embodiments, R A , R B , R C and R D One or two of (if present) are selected from H, F, Cl, Br and OMe. The remaining (if present) are H.

[0258] In some embodiments, R A and R D is selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano and OMe; R B and R C is H. In some embodiments, R A and R D is selected from H, F, Cl, Br and OMe, R B and R C is H.

[0259] In some embodiments, R A is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, OEt, and CHOMe. A is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, and OMe. A is selected from Cl, Br, and OMe. A is selected from Cl, Br, Me, and CF. In some embodiments, R A is Cl. In some embodiments, R A is Br. In some embodiments, R A is OMe.

[0260] In some embodiments, R D is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, OMe, CHOH, and CHOMe. D is selected from H, F, Cl, Br, Me, CF, cyclopropyl, cyano, and OMe. D is selected from H, F, Br, Me, and OMe. D is selected from H and F. In some embodiments, R D is H. In some embodiments, R D is F. In some embodiments, R D is Br. In some embodiments, RD is Me. In some embodiments, R D is OMe.

[0261] In some embodiments, A 1 , A 2 , A 3 and A 4 is combination 1 to 9 in the table below. [Table 1] is selected from.

[0262] In some embodiments, combinations 1, 5, 7 and 8 are preferred. R C1 , R C2 , R C3 and R C4

[0263] In some embodiments, R C1 and R C4 , and R C2 and R C3 is independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, and CH2OH. C1 and R C4 , and R C2 and R C3 is independently selected from H, Cl, F, CF3, OMe, and CH2OH. In further of these embodiments, R C1 and R C4 , and R C2 and R C3 is independently selected from H, Cl, F and OMe.

[0264] In some embodiments, R C1 and R C4 , and R C2 and R C3 One of them is all H.

[0265] In other embodiments, R C1 , R C3and R C4 or R C1 , R C2 and R C4 Two of R are H and the others are selected from the groups defined (excluding H). In some of these embodiments, R C4 is F. In some of these embodiments, R C1 In some of these embodiments, R C1 is Cl.

[0266] In other embodiments, R C1 , R C3 and R C4 or R C1 , R C2 and R C4 One of R is H and the other two are independently selected from the groups defined (excluding H). In some of these embodiments, R C1 is OMe, R C4 is F.

[0267] Other embodiments In some embodiments, the present invention provides a compound of formula IV: [ka] Regarding the compound [In the formula, W is O or NH; R 1 teeth, (i) H, (ii) C 3~6 Cycloalkyl, (iii) methyl, and ester C optionally substituted with a group selected from 3~7 Heterocyclyl, and (iv) alkoxy, amino, Amides, Acylamide, Acyloxy, Alkyl carboxyl esters, Alkylcarbamoyl, Alkyl carbamoyl esters, Phenyl, phosphonate esters, C optionally substituted with a group selected from methyl and oxo 3~7 Heterocyclyl, and Naturally occurring amino acids, optionally N-substituted with a group selected from methyl, acetyl and boc. Linear or branched C optionally substituted with a group selected from 1~4 Alkyl is selected from A 1 CR A or N, A 2 CR B or N, A 3 CR C or N, A 4 CR D or N, Here, A 1 , A 2 , A 3 , and A 4 may be N, R A , R B , R C and R D one or two of (when present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CHOMe and OH; R A , R B , R C and R D the remainder, if any, are H; R N1 is H, R C1 , R C3 and R C4 are independently H, Cl, F, Br, Me, OMe, cyano, CF3, CH2OH, CHOMe, C 2~4alkenyl and C5 heterocyclyl. EXAMPLES

[0268] The following examples are provided merely to illustrate the present invention and are not intended to limit the scope of the invention described herein. acronym

[0269] 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).

[0270] For convenience, many compounds may be used, including but not limited to methanol (MeOH), deuterated methanol (MeOD-d4 or CD3OD), ethanol (EtOH), isopropanol (i-PrOH), ether or diethyl ether (Et2O), ethyl acetate (EtOAc), acetic acid (AcOH), acetonitrile (MeCN or ACN), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), deuterated chloroform (CDCl3), diethylamine (DEA), deuterium oxide (DEA), and tetrahydrofuran (THF). dimethyl sulfoxide (DMSO-d6), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl), meta-chloroperoxybenzoic acid (mCPBA), 1,1'-bis(diphenylphosphino)ferrocene (dppf), tert-butyloxycarbonyl (Boc, BOC), 2-(trimethylsilyl)ethoxymethyl (SEM), triethylamine (Et3N or TEA), 2-(1H-7-azabenzoxazole), triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA or DIEA), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (PdCl2(dppf)), trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2), tris(di benzylideneacetone)dipalladium(0) (Pd2(dba)3), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), propylphosphonic anhydride (T3P), hexamethylphosphoramide (HMPA), 1,2-dichloroethane (DCE), chromium(VI) oxide (CrO3), n-bromosuccinimide (NBS), potassium hydroxide (KOH), benzoyl peroxide (BPO), carbon tetrachloride (CCl4), petroleum ether (Pet.These compounds are represented using well-known abbreviations, including ethyl ether (Et2CO3), potassium carbonate (K2CO3), sodium sulfate (Na2SO4), lithium diisopropylamine (LDA), azobisisobutyronitrile (AIBN), N-methylmorpholine N-oxide (NMO), benzoyl peroxide (BPO), and 1-hydroxybenzotriazole (HOBt).

[0271] Other abbreviations: thin layer chromatography (TLC), retention time (rt). General Experimental Details

[0272] Unless otherwise stated, the following generalizations apply: 1 H NMR spectra were recorded on a Bruker Ultrashield Plus (400 MHz) or a Bruker AVANCE III (400 MHz). Signal multiplicities are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; td, triplet of doublets; ddd, doublet of doublets of doublets; br, broad; m, multiplet. All observed coupling constants, J, are reported in Hertz. Exchangeable protons are not always observed.

[0273] LCMS data was generated using the following conditions: Chlorine isotopes: 35 Bromine isotopes reported as Cl are 79 Br or 81 Either Br or 79 Br / 81 Br.

[0274] LC-MS method A (LCMS-A): Device information LC model: Agilent 1200 (Pump type: binary pump, detector type: DAD) MS model: Agilent G6110A Quadrupole LCMS parameters LC: Column: Xbridge-C18, 2.5 μm, 2.1 × 30 mm Column temperature: 30℃ Wavelength acquisition: 214nm, 254nm Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH MS: Ion source: ES+ (or ES-) MS range: 50-900 m / z Fragmenter: 60 Drying gas flow: 10L / min Nebulizer pressure: 35psi Drying gas temperature: 350℃ Vcap: 3.5kV Gradient table: [Table 2]

[0275] Sample preparation Samples were dissolved in methanol at a concentration of approximately 0.11-1 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1-10 μL).

[0276] LC-MS method B (LCMS-B): Device information LC model: Agilent 1200 (Pump type: binary pump, detector type: DAD) MS model: Agilent G6110A Quadrupole LCMS parameters LC: Column: Xbridge-C18, 2.5 μm, 2.1 × 30 mm Column temperature: 30℃ Wavelength acquisition: 214nm, 254nm Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH MS: Ion source: ES+ (or ES-) MS range: 50-900 m / z Fragmenter: 60 Drying gas flow: 10L / min Nebulizer pressure: 35psi Drying gas temperature: 350℃ Vcap: 3.5kV Gradient table: [Table 3]

[0277] Sample preparation Samples were dissolved in methanol at a concentration of approximately 0.11-1 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1-10 μL).

[0278] LC-MS method C (LCMS-C): Device information LC model: Waters 2695 alliance (pump type: quaternary pump, detector: 2996 photodiode array detector) MS model: Micromass ZQ LCMS parameters LC: Column: Xbridge-C18, 3.5 μm, 2.1 × 50 mm Column temperature: 30℃ Wavelength acquisition: 214nm, 254nm Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH MS: Ion source: ES+ (or ES-) MS range: 50-900 m / z Capillary: 3kV Cone: 3V Extractor: 3V Drying gas flow: 600L / hr Cone: 50L / hr Desolvation temperature: 300℃ Source temperature: 100℃ Gradient table: [Table 4]

[0279] Sample preparation Samples were dissolved in methanol at a concentration of approximately 0.11-1 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1-10 μL).

[0280] LC-MS method D (LCMS-D): Device information LC model: Waters 2695 alliance (Pump: Quaternary pump, Detector: 2996 photodiode array detector) MS model: Micromass ZQ LCMS parameters LC: Column: Xbridge-C18, 2.5 μm, 2.1 × 30 mm Column temperature: 30℃ Wavelength acquisition: 214nm, 254nm Mobile phase: A: 0.05% HCOOH aqueous solution, B: MeOH Duration: 5 minutes MS: Ion source: ES+ (or ES-) MS range: 50-900 m / z Capillary: 3.5kV Cone: 35V Extractor: 3V Drying gas flow: 350L / hr Cone: 50L / hr Desolvation temperature: 300℃ Source temperature: 120℃ Duration: 5 minutes Gradient table: [Table 5]

[0281] Sample preparation Samples were dissolved in methanol at a concentration of approximately 0.11-1 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1-10 μL).

[0282] Preparative RP-HPLC: Instrument Type: Varian 940-LC Series; Pump type:Quaternary pump; Detector type: Diode array detector

[0283] HPLC conditions: Waters Sunfire prep C18 OBD, 5 μm 19×100 mm column, eluted with a gradient of MeOH in water containing 0.07% TFA at a flow rate of 15 mL / min. Acquisition wavelengths 214 nm, 254 nm.

[0284] Analytical thin layer chromatography was performed on Merck silica gel 60 F254 aluminum-backed plates, which were visualized using fluorescence quenching under UV light or using drops of basic KMnO4 or ninhydrin.

[0285] Preparative thin layer chromatography (preparative TLC) was performed using Tklst (China), top grade: (HPTLC): 8±2 μm>80%; (TLC): 10-40 μm, type: GF254. Compounds were visualized by UV (254 nm).

[0286] Flash chromatography was performed using a Biotage Isolera purification system using either Grace or RediSep® silica cartridges.

[0287] Column chromatography was performed using Tklst (China), top grade, 100-200 mesh silica gel.

[0288] Microwave irradiation was accomplished using a CEM Explorer SP microwave reactor.

[0289] Where necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods. Solutions of inorganic acids or bases were made up as aqueous solutions unless otherwise stated.

[0290] The additional cartridges used were as follows: Phase separator: Manufacturer: Biotage Product: ISOLUTE® Phase Separator (3 mL unless otherwise stated)

[0291] SCX and SCX-2 cartridges: Manufacturer: Biotage Product: ISOLUTE® SCX 1g (6mL SPE column unless otherwise stated) Manufacturer: Biotage Product: ISOLUTE® SCX-2 1g (6mL column) Manufacturer: Silicycle Product: SCX-2 500mg or 5g Manufacturer:Agilent Product: Bond Elut(R) SCX 10g

[0292] Sampling Cartridge: Manufacturer: Waters Product: Oasis® HLB 35cc (6g) LP Extraction Cartridge

[0293] Solutions of hydrogen chloride, sodium hydroxide, potassium carbonate and sodium bicarbonate are aqueous solutions unless otherwise stated.

[0294] Preparation of intermediates (i) 3,4-Diaminobenzamide (I1) [ka] A solution of 3,4-diaminobenzonitrile (1.0 g, 7.51 mmol) in concentrated sulfuric acid (20 mL) was stirred at room temperature overnight. Water (100 mL) was added and the resulting mixture was adjusted to pH 10 with 4 M aqueous NaOH and extracted with EtOAc (100 mL x 3). The combined organic extracts were concentrated under reduced pressure to give the title compound I1 (800 mg, 70%) as a pale yellow solid. LCMS-A (ES-API): rt 0.31 min, m / z 152.0 [M+H] + . (ii) 3,4-Diamino-5-fluorobenzamide (I4) [ka] (a) 4-Amino-3-fluoro-5-nitrobenzonitrile (I2)

[0295] To a solution of 4-bromo-2-fluoro-6-nitroaniline (9.23 g, 39.3 mmol) in DMF (150 mL) was added CuCN (7.04 g, 78.6 mmol) and the mixture was heated at 165° C. overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether / EtOAc=10:1) to give the title compound I2 (5.0 g, 70%) as a yellow solid. LCMS-B (ES-API): rt 0.30 min, m / z 182.0 [M+H] + . (b) 4-amino-3-fluoro-5-nitrobenzamide (I3)

[0296] A solution of 4-amino-3-fluoro-5-nitrobenzonitrile (I2) (1.5 g, 8.28 mmol) in concentrated H2SO4 (15 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM / MeOH=50:1) to give the title compound I3 (1.63 g, 99%) as a yellow solid. LCMS-B (ES-API): rt 0.30 min, m / z 200.0 [M+H] + . (c) 3,4-diamino-5-fluorobenzamide (I4)

[0297] To a solution of 4-amino-3-fluoro-5-nitrobenzamide (I3) (1.63 g, 8.19 mmol) in MeOH (50 mL) and THF (50 mL) was added 10% Pd / C (87 mg) and the mixture was stirred at room temperature under H2 atmosphere overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM / MeOH=10:1) to give the title compound I4 (1.2 g, 87%) as a green solid. LCMS-B (ES-API): rt 0.29 min, m / z 170.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 2H), 7.56 - 7.47 (m, 2H), 7.45 (s, 2H), 7.26 - 7.12 (m, 2H). (iii) 3,4-Diamino-2-methoxybenzoic acid (I5) [ka]

[0298] To a solution of methyl 3,4-diamino-2-methoxybenzoate (200 mg, 1.02 mmol) in THF (10 mL) and water (5 mL) was added NaOH (122 mg, 3.06 mmol) and the mixture was heated at 50° C. overnight. Most of the THF was removed under reduced pressure and the aqueous residue was adjusted to pH 5 with 1 M aqueous HCl and then concentrated under reduced pressure. The residue was suspended in MeOH, filtered and the filtrate was concentrated under reduced pressure to give the title compound I5 (183 mg, 98%) as a black solid. LCMS-B (ES-API): rt 0.29 min, m / z 205.0 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.76 (d, J = 8.0 Hz, 1H), 6.19 (d, J = 8.1 Hz, 1H), 4.52 (s, 2H), 4.02 (s, 2H), 3.69 (s, 3H). (iv) Ethyl 4-chloro-3-formylbenzo[b]thiophene-2-carboxylate (I8) [ka] (a) Ethyl 4-chloro-3-methylbenzo[b]thiophene-2-carboxylate (I6)

[0299] A solution of 1-(2-chloro-6-fluorophenyl)ethanone (25.0 g, 145 mmol), ethyl 2-mercaptoacetate (17.4 g, 145 mmol) and K2CO3 (30.0 g, 217 mmol) in DMF (200 mL) was heated at 100 °C overnight. The mixture was allowed to cool to room temperature and then poured into water (1.0 L) and EtOAc (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by recrystallization from Pet. ether / EtOAc to give the title compound I6 (28.0 g, 76%) as a yellow solid. LCMS-A: rt 2.82 min; m / z 255.0 [M+H] + . (b) Ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate (I7)

[0300] A suspension of ethyl 4-chloro-3-methylbenzo[b]thiophene-2-carboxylate (I6) (28.0 g, 0.11 mol), NBS (19.6 g, 0.11 mol) and BPO (2.67 g, 0.011 mol) in CCl4 (200 mL) was heated at 115° C. for 1.5 h. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure and the residue was purified by recrystallization from DCM / Pet. ether to afford the title compound I7 (26.0 g, 71%) as a purple solid. 1 H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 8.0, 1.2 Hz, 1H), 7.46 (dd, J = 7.6, 0.8 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 5.61 (s, 2H), 4.44 (q, J = 7.1 Hz 2H), 1.44 (t, J = 7.1 Hz, 3H). (c) Ethyl 4-chloro-3-formylbenzo[b]thiophene-2-carboxylate (I8)

[0301] A mixture of ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate (I7) (10.00 g, 29.97 mmol) and NMO (14.00 g, 119.88 mmol) in THF (250 mL) was heated to reflux for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether / EtOAc=100:1 to 50:1) to give the title compound I8 (2.70 g, 34%) as a white solid. LCMS-B (ES-API): rt 4.16 min, m / z 269.0 [M+H] + , 290.9[M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.17 (dd, J = 7.6, 1.5 Hz, 1H), 7.66 - 7.58 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). (v) Ethyl 4-chloro-7-fluoro-3-formylbenzo[b]thiophene-2-carboxylate (I13) [ka] (a) 1-(6-chloro-2,3-difluorophenyl)ethan-1-ol (I9)

[0302] To a solution of diisopropylamine (4.4 g, 43.9 mmol) in dry THF (100 mL) was added dropwise at −78° C. under nitrogen, followed by dropwise addition of n-BuLi (2.5 M solution in n-hexane, 17.6 mL, 43.9 mmol), followed by dropwise addition of 4-chloro-1,2-difluorobenzene (5.0 g, 33.8 mmol) and the mixture was stirred for 1 h. Acetaldehyde (4.4 g, 101.4 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched by addition of saturated aqueous NH4Cl solution and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether / EtOAc=1:0 to 20:1) to give the title compound (3.0 g, 46%) as a yellow oil. LCMS-B:rt 3.39min;m / z 175.0[M-OH] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.33 (m, 1H), 7.31 - 7.25 (m, 1H), 5.54 (d, J = 4.4 Hz, 1H), 5.25 - 5.16 (m, 1H), 1.45 (d, J = 6.7 Hz, 3H). (b) 1-(6-chloro-2,3-difluorophenyl)ethan-1-one (I10)

[0303] To a solution of 1-(6-chloro-2,3-difluorophenyl)ethan-1-ol (I9) (3.0 g, 15.6 mmol) in dry DCM (50 mL) was added Dess-Martin periodinane (19.8 g, 46.7 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was diluted with water and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether) to give the title compound (2.3 g, 79%) as a yellow oil, which was used directly in the next step. (c) Ethyl 4-chloro-7-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I11)

[0304] To a mixture of 1-(6-chloro-2,3-difluorophenyl)ethan-1-one (I10) (1.8 g, 9.3 mmol) and K2CO3 (3.9 g, 28.0 mmol) in DMF (20 mL) under nitrogen was added ethyl 2-mercaptoacetate (1.3 g, 11.2 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc=1:0) to give the title compound (1.5 g, 60%) as a brown solid. LCMS-A: rt 3.54 min; m / z 273.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.50 (m, 1H), 7.40 (t, J = 8.7 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.97 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). (d) Ethyl 3-(bromomethyl)-4-chloro-7-fluorobenzo[b]thiophene-2-carboxylate (I12)

[0305] To a solution of ethyl 4-chloro-7-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I11) (1.5 g, 5.5 mmol) in CCl4 (50 mL) was added NBS (978 mg, 5.5 mol) and AIBN (451 mg, 2.75 mmol) and the mixture was heated at 80° C. under N2 overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with water, brine and concentrated under reduced pressure to give the title compound (1.3 g, 80%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.67 - 7.61 (m, 1H), 7.50 (t, J = 8.7 Hz, 1H), 5.47 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). (e) Ethyl 4-chloro-7-fluoro-3-formylbenzo[b]thiophene-2-carboxylate (I13)

[0306] To a solution of ethyl 3-(bromomethyl)-4-chloro-7-fluorobenzo[b]thiophene-2-carboxylate (I12) (1.0 g, 2.8 mmol) in THF (20 mL) was added NMO (1.33 g, 11.4 mmol) under N2 and the mixture was heated to reflux for 16 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1:0 to 100:1) to give the title compound (250 mg, 31%) as a white solid. LCMS-B: rt 4.39 min; m / z 286.9 [M+H] + , 308.9[M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.73 - 7.66 (m, 1H), 7.57 (t, J = 8.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). (vi) Ethyl 4-bromo-7-fluoro-3-formylbenzo[b]thiophene-2-carboxylate (I15) [ka] I14 is compound I52 of WO2019 / 219820. Ethyl 4-bromo-7-fluoro-3-formylbenzo[b]thiophene-2-carboxylate (I15)

[0307] A solution of ethyl 4-bromo-3-(bromomethyl)-7-fluorobenzo[b]thiophene-2-carboxylate (I14) (676 mg, 1.71 mmol) and NMO (800 mg, 6.84 mmol) in THF (5 mL) was heated to reflux under N2 for 16 h. The mixture was partitioned between water (30 mL) and EtOAc (30 mL), the layers were separated, and the aqueous layer was further extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1 to 30:1) to give the title compound (243 mg, 43%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 7.85 (dd, J = 8.4, 4.4 Hz, 1H), 7.52 (t, J = 9.2 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). (vii) Ethyl 7-bromo-3-formyl-4-methoxythieno[3,2-c]pyridine-2-carboxylate (I18) [ka] I16 is compound I29 of WO2019 / 219820. (a) Ethyl 7-bromo-3-(bromomethyl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate (I17)

[0308] To a solution of ethyl 4-methoxy-3-methylthieno[3,2-c]pyridine-2-carboxylate (I16) (2.0 g, 7.96 mmol) and NBS (2.2 g, 11.9 mmol) in ACN (50 mL) was added AIBN (654 mg, 3.98 mmol) and the mixture was heated at 80° C. for 3 h. The mixture was partitioned between water and EtOAc, the layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product (3.2 g) as a yellow solid. NMR analysis indicated the presence of a 1:2 mixture of the title compound and ethyl 7-bromo-4-methoxy-3-methylthieno[3,2-c]pyridine-2-carboxylate. This mixture was used in the next step without further purification.

[0309] Regarding the title compound (minor component) 1 H NMR: 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 5.29 (s, 2H), 4.41 (q, J = 7.2 Hz, 2H), 4.08 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H).

[0310] About Ethyl 7-bromo-4-methoxy-3-methylthieno[3,2-c]pyridine-2-carboxylate (Main Component) 1 H NMR: 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 2.85 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). (b) Ethyl 7-bromo-3-formyl-4-methoxythieno[3,2-c]pyridine-2-carboxylate (I18)

[0311] To a solution of a 1:2 mixture of ethyl 7-bromo-3-(bromomethyl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate / ethyl 7-bromo-4-methoxy-3-methylthieno[3,2-c]pyridine-2-carboxylate (I17) (2.5 g, estimated 2.3 mmol of ethyl 7-bromo-3-(bromomethyl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate) in THF (50 mL) was added NMO (5.4 g, 30.3 mmol) and the mixture was heated to reflux overnight. The mixture was partitioned between water and EtOAc, the layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1 / 0 to 5 / 1) to give the title compound as a yellow solid (350 mg, 13% yield over two steps from ethyl 4-methoxy-3-methylthieno[3,2-c]pyridine-2-carboxylate I16). 1 H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H), 8.37 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.99 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). (viii) 3,4-Diamino-2-methoxybenzamide (I23) [ka] (a) Methyl 4-acetamido-5-chloro-2-methoxy-3-nitrobenzoate (I19)

[0312] The title compound was prepared from commercially available methyl 4-acetamido-5-chloro-2-methoxybenzoate according to the procedure described in WO2008 / 65508. 1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 8.15 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 2.03 (s, 3H). (b) 4-Acetamido-5-chloro-2-methoxy-3-nitrobenzoic acid (I20)

[0313] To a solution of methyl 4-acetamido-5-chloro-2-methoxy-3-nitrobenzoate (I19) (4.0 g, 0.013 mol) in EtOH / water (10:1, 30 mL) was added NaOH (5.2 g, 0.13 mol) and the mixture was stirred at room temperature overnight. Most of the EtOH was removed under reduced pressure and the aqueous residue was acidified to pH 7 with 2 M aqueous HCl. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (2.3 g, 61%) as a white solid. LCMS-B (ES-API): rt 1.70 min, m / z 310.9, 312.9 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 8.10 (s, 1H), 3.87 (s, 3H), 2.03 (s, 3H). (c) 4-Amino-5-chloro-2-methoxy-3-nitrobenzoic acid (I21)

[0314] A mixture of 4-acetamido-5-chloro-2-methoxy-3-nitrobenzoic acid (I20) (2.3 g, 0.008 mol) and NaOH (3.2 g, 0.08 mol) in MeOH (20 mL) was heated at 70° C. for 16 h. The mixture was diluted with water and most of the MeOH was removed under reduced pressure. The aqueous residue was acidified to pH 6 with 2 M aqueous HCl and extracted with EtOAc (40 mL×3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc=20:1 to 8:1) to give the title compound (1.36 g, 69%) as a white solid. LCMS-B (ES-API): rt 2.90 min, m / z 247.0, 249.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.0 (s, 1H), 7.83 (s, 1H), 6.74 (s, 2H), 3.81 (s, 3H). (d) 4-Amino-5-chloro-2-methoxy-3-nitrobenzamide (I22)

[0315] A mixture of 4-amino-5-chloro-2-methoxy-3-nitrobenzoic acid (I21) (1.36 g, 5.5 mmol), NH4Cl (0.44 g, 8.3 mmol), HOBt (1.12 g, 8.3 mmol), EDCI.HCl (1.27 g, 6.6 mmol) and DIPEA (1.08 g, 8.3 mmol) in DMF (20 mL) was stirred at room temperature under N2 overnight. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether / EtOAc = 20:1 to 3:1) to give the title compound (1.2 g, 89%) as a yellow solid. LCMS-B (ES-API): rt 2.70 min, m / z 246.0, 247.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.53 (br s, 2H), 6.50 (s, 2H), 3.79 (s, 3H). (e) 3,4-Diamino-2-methoxybenzamide (I23)

[0316] A solution of 4-amino-5-chloro-2-methoxy-3-nitrobenzamide (I22) (1.2 g, 5.9 mmol) in MeOH (30 mL) was degassed by bubbling with N2 for 10 min. 10% Pd / C (1.5 g) was added followed by Et3N (30 mL) and the resulting mixture was stirred under H2 (5 atm) for 6 h. The mixture was filtered through a Celite pad, rinsed with MeOH and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH=100:1 to 90:1) to give the title compound (534 mg, 50%) as a white solid. LCMS-B (ES-API): rt 0.8 min, m / z 182.0 [M+H] + . 1H NMR (400 MHz, DMSO-d-6) δ 7.38 (s, 1H), 7.05 (s, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 4.35 (s, 2H), 3.65 (s, 3H). Working Example Ethyl 3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (1) [ka]

[0317] To a solution of 3,4-diaminobenzamide (I1) (50 mg, 0.33 mmol) and ethyl 4-chloro-3-formylbenzo[b]thiophene-2-carboxylate (I8) (89 mg, 0.33 mmol) in EtOH (5 mL) was added AcOH (2 drops) and the mixture was stirred at room temperature for 48 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM / MeOH=15:1) to give the title compound 1 (40 mg, 30%) as a white solid. LCMS-A (ES-API): rt 0.72 min, m / z 399.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.0 - 12.9 (m, 1H), 8.26 - 8.11 (m, 2H), 8.00 - 7.99 (m, 1H), 7.85 - 7.78 (m, 1H), 7.70 - 7.56 (m, 3H), 7.28 - 7.25 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H). 3-(5-Carbamoyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (2) [ka]

[0318] To a solution of ethyl 3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (1) (50 mg, 0.13 mmol) in methanol (6 mL) and water (2 mL) was added KOH (35 mg, 0.63 mmol) and the mixture was heated at 60° C. for 1 h. Most of the methanol 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, washed with water (10 mL) and dried under reduced pressure to give the title compound 2 (20 mg, 42%) as a white solid. LCMS-A (ES-API): rt 0.39 min, m / z 371.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.19 (m, 2H), 8.03 (br s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.30 (br s, 1H). Ethyl 3-(5-carbamoyl-7-fluoro-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (3) [ka]

[0319] To a solution of 3,4-diamino-5-fluorobenzamide (I4) (300 mg, 1.77 mmol), ethyl 4-chloro-3-formylbenzo[b]thiophene-2-carboxylate (I8) (477 mg, 1.77 mmol) in EtOH (20 mL) was added AcOH (0.3 mL) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (DCM / MeOH=50:1) to give the title compound 3 (80 mg, 10%) as a white solid. LCMS-D (ES-API): rt 1.20 min, m / z 417.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.6 - 13.3 (m, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.20 - 7.96 (m, 2H), 7.70 - 7.54 (m, 3H), 7.45 - 7.38 (m, 1H), 4.12 (q, J = 7.0 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H). Ethyl 3-(6-carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (4) [ka] (a) 2-(4-chloro-2-(ethoxycarbonyl)benzo[b]thiophen-3-yl)-7-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (A1)

[0320] To a solution of 3,4-diamino-2-methoxybenzoic acid (I5) (90 mg, 0.49 mmol) in DMF (10 mL) was added ethyl 4-chloro-3-formylbenzo[b]thiophene-2-carboxylate (I8) (133 mg, 0.49 mmol) and NaHSO3 (103 mg, 0.99 mmol) and the mixture was heated at 80 °C under N2 overnight. Water was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water (50 mL x 3), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 15:1) to give the title compound A1 (66 mg, 31%) as a white solid. LCMS-B(ES-API):rt 3.41min;m / z 431.0[M+H] + . (b) Ethyl 3-(6-carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (4)

[0321] A mixture of 2-(4-chloro-2-(ethoxycarbonyl)benzo[b]thiophen-3-yl)-7-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (A1) (77 mg, 0.18 mmol), NH4Cl (19 mg, 0.36 mmol), HATU (82 mg, 0.21 mmol) and DIPEA (69 mg, 0.54 mmol) in DMF (5 mL) was stirred at room temperature under N2 overnight. The mixture was poured into water (50 mL), extracted with EtOAc (50 mL x 3) and the combined organic extracts were washed with water (50 mL x 3), brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=15:1) to give the title compound 4 (60 mg, 78%) as a white solid. LCMS-B(ES-API): rt 3.28 min; m / z 430.0[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.2 - 13.1 (m, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.84 - 7.68 (m, 2H), 7.68 - 7.51 (m, 2H), 7.41 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 4.36 (s, 3H), 4.11 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H). Ethyl 3-(5-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate and Ethyl 3-(6-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (5.1 and 5.2) [ka]

[0322] A suspension of ethyl 3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (1) (0.050 g, 0.13 mmol), MeI (0.054 mg, 0.38 mmol) and K2CO3 (0.052 g, 0.38 mmol) in DMF (5 mL) was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with water (50 mL x 2), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Agilent ProStar, YMC-C18, 150×20 mm column, eluting with a gradient of MeOH in water containing 0.07% TFA at a flow rate of 20 mL / min) to give 5.1 as the first-eluting regioisomer ("Peak 1") and 5.2 as the second-eluting regioisomer ("Peak 2"). The structures shown for 5.1 and 5.2 are merely illustrative, as the structures were not assigned. Peak 1-5.1 (HPLC: rt 6.36 min): as a white solid (15 mg, 29%). LCMS-A (ES-API): rt 0.25 min; m / z 413.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.22 (m, 2H), 8.07 (br s, 1H), 7.95 - 7.84 (m, 1H), 7.82 - 7.56 (m, 3H), 7.41 (br s, 1H), 4.11 (br s, 2H), 3.65 (s, 3H), 0.87 (br s, 3H). Peak 2-5.2 (HPLC: rt 6.75 min): as a white solid (5 mg, 9%). LCMS-A (ES-API): rt 0.28 min; m / z 413.9 [M+H] + . 1H NMR (400 MHz, DMSO- d6) δ 8.30 - 8.24 (m, 2H), 8.08 (br s, 1H), 7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.69 - 7.58 (m, 2H), 7.34 (br s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.65 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H). 3-(5-Carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylic acid and 3-(6-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (6.1 and 6.2) [ka]

[0323] (a) Ethyl 3-(5-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate and Ethyl 3-(6-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (A2)

[0324] A suspension of ethyl 3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (1) (0.200 g, 0.501 mmol), MeI (0.214 g, 1.50 mmol) and K2CO3 (0.208 g, 1.50 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with water (100 mL x 3), brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20:1) to give a mixture of the two title compounds (30 mg, 14%) as a white solid.

[0325] (b) 3-(5-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylic acid and 3-(6-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 6.1 and 6.2

[0326] To a solution of a mixture of ethyl 3-(5-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate and ethyl 3-(6-carbamoyl-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (A2) (0.030 g, 0.07 mmol) in methanol (10 mL) and water (3 mL) was added KOH (0.21 g, 0.36 mmol) and the mixture was heated at 60° C. for 1 h. Most of the methanol was removed under reduced pressure and the aqueous residue was adjusted to pH 5 with 1 M aqueous HCl (5 mL) solution. The resulting precipitate was collected by filtration, washed with water (10 mL), EtO (10 mL), and dried under reduced pressure to give a mixture of the two title compounds (0.023 g, 85%) as a yellow solid in which the ratio of the unassigned regioisomers was: 1 The ratio was about 2:1 as determined by H NMR. The structures shown for 6.1 and 6.2 are merely illustrative as the structures were not assigned. LCMS-A (ES-API): rt 0.39 min, m / z 386.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.36 (s, 0.5H), 8.33 - 8.28 (m, 1.5H), 8.22 (br s, 1.5H), 8.08 - 8.03 (m, 1.5H), 7.95 (d, J = 8.4 Hz, 0.5H), 7.88 (d, J = 8.4 Hz, 1H), 7.68 - 7.61 (m, 3H), 7.52 (br s, 1H), 7.45 (br s, 0.5H), 3.77 (s, 3H), 3.74 (s, 1.5H). Ethyl 4-bromo-3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (7) and 4-bromo-3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylic acid (8). [ka] (a) Ethyl 4-bromo-3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (7)

[0327] A solution of ethyl 4-bromo-7-fluoro-3-formylbenzo[b]thiophene-2-carboxylate (I15) (0.218 g, 0.66 mmol), 3,4-diaminobenzamide (I1) (0.200 g, 0.66 mmol) and NaHSO3 (0.069 g, 0.66 mmol) in DMF (10 mL) was heated at 80 °C overnight under N2. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (280 mg, 92%) as a white solid. LCMS-B (ES-API): rt 3.27 min, m / z 462.0, 464.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.19 (m, 1H), 8.15 - 8.00 (m, 1H), 7.99 - 7.66 (m, 3H), 7.65 - 7.25 (m, 1H), 7.42 - 7.25 (m, 1H), 4.13 - 4.01 (m, 2H), 1.02 - 0.82 (m, 3H). (b) 4-Bromo-3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylic acid (8)

[0328] A mixture of ethyl 4-bromo-3-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (7) (0.120 g, 0.26 mmol) and LiOH.H2O (0.0326 g, 0.78 mmol) in water (1 mL) and THF (9 mL) was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and washed with EtOAc (50 mL x 3). The aqueous phase was acidified with aqueous HCl and extracted with DCM (50 mL x 4). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (65 mg, 57%) as a white solid. LCMS-B (ES-API): rt 2.62 min, m / z 433.9, 435.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.99 (br s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.23 (br s, 1H). 3-(6-Carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (9) [ka]

[0329] A mixture of ethyl 3-(6-carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (4) (0.060 g, 0.14 mmol) and LiOH.H2O (0.018 g, 0.42 mmol) in THF (4 mL) and water (2 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was diluted with water (2 mL) and adjusted to pH 4-5 with 2 M aqueous HCl. The resulting precipitate was collected by filtration and dried under vacuum at 55 °C for 1 h to give the title compound (20 mg, 35%) as a white solid. LCMS-B (ES-API): rt 2.76 min, m / z 402.0, 404.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (dd, J = 7.6, 1.6 Hz, 1H), 7.81 (br s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.59 (br s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 4.19 (s, 3H). Ethyl 4-bromo-3-(6-carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (10) and 4-bromo-3-(6-carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylic acid (11). [ka] (a) 2-(4-bromo-2-(ethoxycarbonyl)-7-fluorobenzo[b]thiophen-3-yl)-7-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (A3)

[0330] To a solution of 3,4-diamino-2-methoxybenzoic acid (I5) (408 mg, 2.24 mmol) in DMF (23 mL) was added ethyl 4-bromo-7-fluoro-3-formylbenzo[b]thiophene-2-carboxylate (I15) (742 mg, 2.24 mmol) and NaHSO3 (233 mg, 2.24 mmol) and the mixture was heated at 80 °C under N2 overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 100:1 to 90:1) to give the title compound (238 mg, 22%) as a brown solid. LCMS-C (ES-API): rt 4.05 min, m / z 493.0, 495.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.1 (br s, 1H), 7.82 (dd, J = 8.5, 4.7 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.26 (d, J = 8.5 Hz, 1H), 4.26 (s, 3H), 4.14 (q, J = 7.1 Hz, 2H), 0.93 (t, J = 7.1 Hz, 3H). (b) Ethyl 4-bromo-3-(6-carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (10)

[0331] To a solution of 2-(4-bromo-2-(ethoxycarbonyl)-7-fluorobenzo[b]thiophen-3-yl)-7-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (A3) (228 mg, 0.462 mmol) in DMF (9 mL) was added EDCI.HCl (133 mg, 0.693 mmol), HOBt (94 mg, 0.69 mmol), DIPEA (299 mg, 2.31 mmol) and concentrated aqueous NH4OH (65 mg, 1.85 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=20:1) to give the title compound (65 mg, 29%) as a white solid. LCMS-C (ES-API): rt 3.85 min, m / z 491.9, 493.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.1 (br s, 1H), 7.84 - 7.78 (m, 2H), 7.72 (br s, 1H), 7.56 - 7.51 (m, 1H), 7.41 (br s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 4.37 (s, 3H), 4.14 (q, J = 7.1 Hz, 2H), 0.93 (t, J = 7.1 Hz, 3H). (c) 4-Bromo-3-(6-carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylic acid (11)

[0332] To a solution of ethyl 4-bromo-3-(6-carbamoyl-7-methoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (10) (0.060 g, 0.12 mmol) in EtOH / water (6 mL / 3 mL) was added NaOH (15 mg, 0.37 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was diluted with water and adjusted to pH 4-5 with 2 M aqueous HCl, and the resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (48 mg, 84%) as a white solid. LCMS-C (ES-API): rt 2.85 min, m / z 464.0, 466.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 7.81 - 7.74 (m, 2H), 7.70 (br s, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.42 (br s, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.32 (s, 3H). Ethyl 3-(5-carbamoyl-4-chloro-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (12) [ka] (a) 4-Bromo-3-chloro-2-nitroaniline (A4)

[0333] A solution of 3-chloro-2-nitroaniline (25.0 g 0.145 mol) and NBS (25.8 g 0.145 mol) in acetic acid (1 L) was heated to reflux overnight under N2. Water (1 L) was added and the insoluble material was collected by filtration to give the title compound (22.3 g, 62%) as a grey solid. LCMS-C (ES-API): rt 3.84 min; m / z 250.9, 252.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.41 (s, 2H). (b) Methyl 3,4-diamino-2-chlorobenzoate (A5)

[0334] A mixture of 4-bromo-3-chloro-2-nitroaniline (A4) (18.9 g 75.5 mmol), Pd(dppf)Cl2 (8.27 g, 11.3 mmol) and Et3N (22.9 g, 226.5 mmol) in MeOH (250 mL) was heated to reflux under carbon monoxide atmosphere for 48 h. The mixture was poured into water (500 mL) and extracted with EtOAc (250 mL x 3). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether / EtOAc = 5:1 to 2:1) to give the title compound (1.0 g, 6%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.08 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.58 (s, 2H), 4.89 (s, 2H), 3.72 (s, 3H). (c) 3,4-Diamino-2-chlorobenzoic acid (A6)

[0335] A mixture of methyl 3,4-diamino-2-chlorobenzoate (A5) (0.200 g, 1.0 mmol) and NaOH (400 mg, 10 mmol) in EtOH / H2O (8 mL / 2 mL) was heated at 80 °C for 5 h. The pH of the mixture was adjusted to about 4-5 with 2 M aqueous HCl, diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (160 mg, 86%) as a red solid. LCMS-C (ES-API): rt 0.48 min; m / z 187.0, 189.0 [M+H] + . (d) 4-chloro-2-(4-chloro-2-(ethoxycarbonyl)benzo[b]thiophen-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (A7)

[0336] A solution of 3,4-diamino-2-chlorobenzoic acid (A6) (150 mg, 0.8 mmol), ethyl 4-chloro-3-formylbenzo[b]thiophene-2-carboxylate (I8) (215 mg, 0.8 mmol) and NaHSO3 (167 mg, 1.6 mmol) in DMF (15 mL) was heated at 120 °C under N2 overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc) to give the title compound (250 mg, 72%) as a black solid. LCMS-C (ES-API): rt 3.70 min; m / z 434.9, 436.9 [M+H] + . (e) Ethyl 3-(5-carbamoyl-4-chloro-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (12)

[0337] A solution of 4-chloro-2-(4-chloro-2-(ethoxycarbonyl)benzo[b]thiophen-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (A7) (0.200 g, 0.46 mmol), EDCI.HCl (0.132 g, 0.69 mmol), DIPEA (0.297 g, 2.3 mmol) and HOBt (0.093 g, 0.69 mmol) in DMF (10 mL) was stirred at room temperature for 15 min. Then, NH4Cl (0.123 g, 2.3 mmol) was added and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether / EtOAc=1:1 to 1:4) to give the title compound (110 mg, 55%) as a white solid. LCMS-C (ES-API): rt 3.28 min; m / z 433.96, 435.98 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.2 (s, 1H), 8.26 - 8.22 (m, 1H), 7.96 - 7.83 (m, 1H), 7.68 - 7.53 (m, 4H), 7.35 - 7.33 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). 3-(5-Carbamoyl-4-chloro-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (13) [ka]

[0338] A solution of ethyl 3-(5-carbamoyl-4-chloro-1H-benzo[d]imidazol-2-yl)-4-chlorobenzo[b]thiophene-2-carboxylate (12) (50 mg, 0.1 mmol) and NaOH (40 mg, 10 mmol) in EtOH / water (4 mL / 1 mL) was heated at 80° C. for 6 h. The solvent was removed under reduced pressure and the residue was diluted with water (2 mL) and acidified to pH 4-5 with 2 M aqueous HCl. The resulting precipitate was collected by filtration to give the title compound (30 mg, 75%) as a white solid. LCMS-C (ES-API): rt 2.42 min; m / z 405.9, 407.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J = 8.0, 0.8 Hz 1H), 7.86 (s, 1H), 7.61 - 7.53 (m, 4H), 7.32 (d, J = 8.2 Hz 1H). Ethyl 4-bromo-3-(6-carbamoyl-7-ethoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (14) [ka] (a) Methyl 4-fluoro-2-hydroxybenzoate (A8)

[0339] A mixture of 4-fluoro-2-hydroxybenzoic acid (50.0 g, 320.3 mmol) and concentrated H2SO4 (40 mL, 672.7 mmol) in MeOH (600 mL) was heated to reflux under N2 for 16 h. 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), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 100:1 to 20:1) to give the title compound (50.0 g, 91%) as a white solid. LCMS-A (ES-API): rt 1.80 min, m / z 171.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 7.83 (dd, J = 8.9, 6.8 Hz, 1H), 6.90 - 6.70 (m, 2H), 3.88 (s, 3H). (b) Methyl 4-fluoro-2-hydroxy-3-nitrobenzoate (A9)

[0340] To a solution of methyl 4-fluoro-2-hydroxybenzoate (A8) (20.0 g, 117 mmol) in concentrated H2SO4 (40 mL) was added concentrated HNO3 (8 mL) dropwise at 0 °C under N2, and the mixture was stirred at 0 °C overnight. The mixture was diluted with water and extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1:0 to 100:1) to give the title compound (1.7 g, 6%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J = 9.1, 6.4 Hz, 1H), 7.17 (t, J = 9.3 Hz, 1H), 3.93 (s, 3H). (c) Methyl 2-ethoxy-4-fluoro-3-nitrobenzoate (A10)

[0341] To a solution of methyl 4-fluoro-2-hydroxy-3-nitrobenzoate (A9) (900 mg, 4.2 mmol) in DMF (20 mL) was added iodoethane (980 mg, 6.3 mmol) and K2CO3 (1.74 g, 12.6 mmol), and the mixture was stirred at room temperature under N2 overnight. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1:0 to 100:1) to give the title compound (600 mg, 58%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (dd, J = 9.1, 6.5 Hz, 1H), 7.48 (t, J = 9.0 Hz, 1H), 4.13 (d, J =7.0 Hz, 2H), 3.89 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). (d) Methyl 4-amino-2-ethoxy-3-nitrobenzoate (A11)

[0342] A mixture of methyl 2-ethoxy-4-fluoro-3-nitrobenzoate (A10) (0.900 g, 4.2 mmol) and a solution of 0.5 M NH3 in 1,4-dioxane (200 mL) was heated at 100 °C overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 1:0 to 100:1) to give the title compound (600 mg, 67%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 9.0 Hz, 1H), 6.68 (s, 2H), 6.64 (d, J = 9.0 Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.77 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H). (e) 4-Amino-2-ethoxy-3-nitrobenzoic acid (A12)

[0343] To a solution of methyl 4-amino-2-ethoxy-3-nitrobenzoate (A11) (0.900 g, 3.75 mmol) in EtOH (10 mL) was added a solution of NaOH (1.5 g, 37.5 mmol) in water (10 mL) and the resulting 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 1 M aqueous HCl. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (570 mg, 67%) as a yellow solid. LCMS-B (ES-API): rt 2.85 min, m / z 226.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 7.67 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.0 Hz, 1H), 6.56 (s, 2H), 4.03 (q, J = 7.0 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H). (f) 3,4-Diamino-2-ethoxybenzoic acid (A13)

[0344] To a solution of 4-amino-2-ethoxy-3-nitrobenzoic acid (A12) (0.470 g, 2.08 mmol) in EtOH (22 mL) was added Zn dust (0.816 g, 12.5 mmol) and saturated aqueous NH4Cl (11 mL) and the mixture was stirred at room temperature overnight. Most of the EtOH was removed under reduced pressure and the aqueous residue was lyophilized. The residue was rinsed with 10:1 DCM / MeOH (50 mL) and the filtrate was concentrated under reduced pressure to give the title compound (400 mg, 98%) as a black solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.98 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 8.4 Hz, 1H), 5.24 (s, 2H), 4.25 (s, 2H), 3.85 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). (g) 2-(4-bromo-2-(ethoxycarbonyl)-7-fluorobenzo[b]thiophen-3-yl)-7-ethoxy-1H-benzo[d]imidazole-6-carboxylic acid (A14)

[0345] To a solution of 3,4-diamino-2-ethoxybenzoic acid (A13) (110 mg, 0.56 mmol) in DMF (6 mL) was added NaHSO3 (59 mg, 0.56 mmol) and ethyl 4-bromo-7-fluoro-3-formylbenzo[b]thiophene-2-carboxylate (I15) (185 mg, 0.56 mmol) and the mixture was heated at 80 °C under N2 overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 15:1) to give the title compound (80 mg, 28%) as a yellow solid. LCMS-B (ES-API): rt 3.81 min, m / z 507.0, 509.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.1 (br s, 1H), 12.3 (br s, 1H), 7.82 (dd, J = 8.8, 4.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 8.9 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 4.70 (q, J = 7.0 Hz, 2H), 4.14 (q, J = 6.8 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H). (h) Ethyl-4-bromo-3-(6-carbamoyl-7-ethoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (14)

[0346] To a solution of 2-(4-bromo-2-(ethoxycarbonyl)-7-fluorobenzo[b]thiophen-3-yl)-7-ethoxy-1H-benzo[d]imidazole-6-carboxylic acid (A14) (0.080 g, 0.16 mmol) in DMF (4 mL) was added EDCI.HCl (0.045 g, 0.24 mmol), HOBt (0.032 g, 0.24 mmol), DIPEA (0.102 g, 0.79 mmol) and concentrated aqueous NH4OH (0.022 g, 0.62 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=15:1) to give the title compound (7.0 mg, 9%) as a white solid. LCMS-B (ES-API): rt 3.62 min, m / z 506.1, 508.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.0 (br s, 1H), 7.85 - 7.76 (m, 3H), 7.53 (t, J = 8.7 Hz, 1H), 7.42 (br s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.70 (q, J = 6.7 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H). 4-Bromo-3-(6-carbamoyl-7-ethoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylic acid (15) [ka]

[0347] To a solution of ethyl-4-bromo-3-(6-carbamoyl-7-ethoxy-1H-benzo[d]imidazol-2-yl)-7-fluorobenzo[b]thiophene-2-carboxylate (14) (0.050 g, 0.099 mmol) in EtOH (2 mL) was added a solution of NaOH (0.040 g, 0.99 mmol) in water (2 mL) 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 1 M aqueous HCl. The resulting precipitate was collected by filtration and purified by preparative HPLC (Varian-940-LC, BOSTON, 250×2.12 mm, 10 μm column, eluted with a gradient of ACN in water containing 0.1% formic acid at a flow rate of 20.0 mL / min) to give the title compound (5 mg, 10%) as a white solid. LCMS-B (ES-API): rt 2.88 min, m / z 478.0, 480.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.9 (br s, 1H), 7.78 - 7.75 (m, 2H), 7.68, (br s, 1H), 7.39 - 7.35 (m, 2H), 7.27 - 7.19 (m, 1H), 4.88 - 4.75 (m, 2H), 1.34 (t, J = 6.0 Hz, 3H).

[0348] Ethyl 7-bromo-3-(5-carbamoyl-4-methoxy-1H-benzo[d]imidazol-2-yl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate (16) and 7-bromo-3-(5-carbamoyl-4-methoxy-1H-benzo[d]imidazol-2-yl)-4-methoxythieno[3,2-c]pyridine-2-carboxylic acid (17). [ka] (a) Ethyl 7-bromo-3-(5-carbamoyl-4-methoxy-1H-benzo[d]imidazol-2-yl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate (16)

[0349] A mixture of ethyl 7-bromo-3-formyl-4-methoxythieno[3,2-c]pyridine-2-carboxylate (I18) (100 mg, 0.3 mmol), 3,4-diamino-2-methoxybenzamide (I23) (52.6 mg, 0.3 mmol) and NaHSO3 (15.6 mg, 0.15 mmol) in DMF (5 mL) was heated at 80 °C under N2 overnight. Water (5 mL) was added and the mixture was extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (126 mg, 83%) as a yellow solid. LCMS-B (ES-API): rt 3.44 min, m / z 505.0, 507.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 8.41 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.73 (s, 1H), 7.42 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 4.39 (s, 3H), 4.15 (q, J = 6.9 Hz, 2H), 3.70 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). (b) 7-Bromo-3-(5-carbamoyl-4-methoxy-1H-benzo[d]imidazol-2-yl)-4-methoxythieno[3,2-c]pyridine-2-carboxylic acid (17)

[0350] A mixture of ethyl 7-bromo-3-(5-carbamoyl-4-methoxy-1H-benzo[d]imidazol-2-yl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate (16) (118 mg, 0.23 mmol) and NaOH (93.4 mg, 2.3 mmol) in 10:1 EtOH / H2O (5 mL) was stirred at room temperature overnight. Most of the EtOH was removed under reduced pressure and the aqueous residue was adjusted to pH 6 with 2 M aqueous HCl. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (92 mg, 84%) as a yellow solid. LCMS-B (ES-API): rt 2.85 min, m / z 477.0, 479.0 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.73 (s, 1H), 7.43 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 4.34 (s, 3H), 3.68 (s, 3H). Ethyl 3-(5-carbamoyl-7-chloro-4-methoxy-1H-benzo[d]imidazol-2-yl)-4-chloro-7-fluorobenzo[b]thiophene-2-carboxylate (18) [ka]

[0351] A mixture of ethyl 4-chloro-7-fluoro-3-formylbenzo[b]thiophene-2-carboxylate (I13) (0.100 g, 0.35 mmol), 4-amino-5-chloro-2-methoxy-3-nitrobenzamide (I22) (0.086 g, 0.35 mmol), NaHSO3 (18.2 mg, 0.175 mmol) and Na2S2O4 (183 mg, 1.05 mmol) in DMF (5 mL) was heated at 80 °C under N2 overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 100:1) to give the title compound (69 mg, 41%) as a white solid. LCMS-B (ES-API): rt 3.56 min, m / z 482.0, 484.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.5 (s, 1H), 7.76 (s, 1H), 7.69 - 7.56 (m, 4H), 4.37 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H). Further Examples

[0352] The following examples were prepared by analogous methods. [Table 6] [Table 7]

[0353] Assay Protein purification and purification Biophysical experiments were performed with three different recombinant human STING protein variants, designated according to the allelic nomenclature of Yi et al. (2013). Codon-optimized DNA sequences (for expression in Escherichia coli) encoding amino acid residues 149–345 (Swiss Prot Q86WV6) of human STING (WT), human STING (HAQ) and human STING (R232H) were synthesized by GenScript USA Inc (Piscataway, New Jersey, USA). These were ligated into a modified pET43a E. coli expression vector designed to encode an N-terminal His tag followed by a tobacco etch virus protease (TEV) cleavage site and the STING gene sequence. The protein sequences obtained for the three allelic variants are listed below. [ka]

[0354] To produce recombinant human STING protein, expression plasmids encoding the aforementioned constructs were transformed into E. coli BL21 DE3 strain and cultured at an OD of 0.8 in 2 x 1 L volumes of Terrific Broth (TB) supplemented with 100 μg / ml ampicillin. 600The cells were grown at 37°C with shaking until a total expression of 0.5 mM was reached. The cultures were 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 cultures were shaken for an additional 16 h overnight. After expression, the cell cultures were centrifuged at 5000 × g for 20 min, and the cell pellets were stored frozen at -70°C.

[0355] Protein purification was initiated by thawing the cell pellet in lysis buffer (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 2 mM MgCl2, 10 mM imidazole, 0.5 mg / ml lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, EDTA-free complete protease inhibitor tablets [Roche]) using a ratio of 7 ml buffer per gram of cells. Cells were further lysed by three passes through an ice-cold Avestin C5 cell crusher, followed by centrifugation at 48,000×g at 4° C. The supernatant (cell lysate) was filtered through a 5 μm filter and loaded onto a 5 mL HiTrap IMAC Sepharose FF column (GE Healthcare) pre-equilibrated with IMAC Wash Buffer 1 (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 10 mM imidazole) using a Profinia affinity chromatography purification system (Bio-Rad). The IMAC column was then washed sequentially with IMAC Wash Buffer 1 and IMAC Wash Buffer 2 (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 20 mM imidazole) and the bound His-TEV-hSTING protein was eluted with IMAC Elution Buffer (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 250 mM imidazole). The IMAC eluted protein was further purified by passing it through a HiLoad 26 / 60 Superdex 75 column pre-equilibrated with storage buffer (25 mM Tris-HCl, pH 8.0, 150 mM NaCl, 5 mM DTT 0.02% [w / v] sodium azide). Finally, the hSTING protein was concentrated to ≥ 2 mg / ml using Amicon Ultra centrifugal filter units (Utra-15 MWCO 10 kDa), flash frozen in liquid nitrogen, and stored in a -70°C freezer. Differential Scanning Fluorescence (DSF)

[0356] Differential scanning fluorimetry (DSF) is a rapid screening method to identify low molecular weight ligands that bind to purified proteins and thereby stabilize (or sometimes destabilize) them (Niesen 2007). DSF monitors the thermal unfolding of proteins in the presence of fluorescent dyes and is typically performed using a real-time PCR instrument. The temperature at which the protein unfolds is measured by the increase in fluorescence of a dye that has affinity for hydrophobic parts of the protein that are gradually exposed during unfolding. The fluorescence of the dye is quenched in an aqueous environment, but increases when the dye associates with a hydrophobic site on the unfolded protein. The fluorescence intensity is plotted as a function of temperature, producing an S-shaped curve that can be described by a two-state transition. The inflection point (Tm) of the transition curve is calculated using simple formulas, such as the Boltzmann formula.

[0357] Thermostability of STING protein (liganded and unliganded) was measured using previously described methodology (Seabrook & Newman, 2013) with samples tested in triplicate using 96-well PCR microplates (AB Gene, ABGAB-0600 / W). 2 μM protein in 1× HBS buffer (50 mM HEPES, pH 7.4, 150 mM NaCl) was mixed with SYPRO Orange dye (Sigma-Aldrich S5692, final reaction mix dilution 1:1200) and compounds (final concentration 100 μM) in a final volume of 20 μL. Sealed plates were then read using a Bio-Rad CFX96 / C1000 thermocycler and FRET scanning mode (lambda excitation 490 nm, λ emission Melting curves were recorded by reading each increment from 20°C to 100°C in 0.5°C increments every 30 seconds. Data were analyzed using the "Meltdown analysis" protocol described by Rosa (2015). The melting temperatures (T m) to the T obtained for the protein incubated with the ligand. m ΔT listed in the table below. m DSF data were generated for each compound for three different STING protein variants - human STING (WT), human STING (HAQ) and human STING (R232H). [Table 8]

[0358] Surface Plasmon Resonance (SPR) The binding interaction of the ligand with STING protein was quantified using surface plasmon resonance (SPR) by immobilizing minimally biotinylated STING protein on a streptavidin chip surface. This method yielded a highly active STING protein surface that was not compromised by the low pH required for the amine coupling method. Minimal biotinylation of purified huSTING protein was performed using a methodology previously described (Chhabra 2012). Briefly, approximately 20 nmol of recombinant STING protein was mixed with EZ-Link™ Sulfo-NHS-LC-LC-Biotin (Thermofisher Scientific, Cat. No. 21338) at a molar ratio of 1 to 0.6 in 1×TBS buffer (25 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM DTT) and incubated on ice for 2 hours. To remove any unreacted biotin reagent, the protein / biotin mixture was passed through a Superdex 75 (10 / 300GL) column equilibrated with 10 mM HEPES, pH 7.4, 150 mM NaCl, 5 mM DTT, 5% [v / v] glycerol. The protein peak containing the biotinylated huSTING protein was collected and stored in aliquots at -80°C.

[0359] Streptavidin was simultaneously immobilized onto all four channels of a CM5 sensor chip docked to a Biacore instrument (either Biacore S200 or Biacore T200, GE Healthcare) as previously described (Zender 2013). Minimally biotinylated STING protein was incubated at 8 °C in SPR binding buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 2% [v / v] DMSO) on the streptavidin-coated chip surface until the desired capture level, typically 3000–7000 RU (1 RU = 1 pg / mm ). 2 ) was captured by gradually injecting a constant flow rate of 2 μL / min into a single channel.

[0360] All binding experiments were carried out at 8°C in SPR binding buffer. To determine binding affinity, compound interactions with immobilized STING protein were analyzed using dose-response experiments. Fresh 10 mM DMSO solutions of compounds were directly diluted in SPR binding buffer to a concentration of typically 50 μM, then further diluted 2- or 3-fold to target either a 5- or 7-point concentration series range. Concentration series of each ligand were injected at a constant flow rate of 60 μL / min with an association time of 90 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 for the compound to fully dissociate before subsequent injections. Where appropriate, more tightly bound compounds (approximately K D <1 uM) were tested using a single cycle kinetic format (Karlsson 2006) with long association and dissociation times (typically 450 and 1800 seconds, respectively).

[0361] Scrubber 2 (biologic.com.au) was used for data processing and signals were referenced to a blank surface (streptavidin + D-biotin) and further corrected for the refractive index change of DMSO and then "double referenced" using a buffer-blank injection (Papalia 2006). Binding affinities (alternative K for the occurrence of two binding events) were calculated from dose-response experiments. D Equilibrium binding responses were fitted to the Hill equation to determine the 50% occupancy as a function of time (Hill coefficient was allowed to vary (≦2)). For single cycle kinetic experiments, sensorgrams were fitted to a two-step kinetic model with sequential binding of two analyte molecules (Biacore T200 or S200 evaluation software). [Table 9]

[0362] THP-1 reporter cell line assay THP-1 STING Lucia ISG cells (InvivoGen number thpI-isg) were cultured in RPMI-1640 containing 2 mM L-glutamine, 25 mM HEPES, 100 μg / mL Normocin (InvivoGen) and 10% heat-inactivated FBS. Cells were cultured at 7 × 10 5 Cells were seeded at a density of 100 cells / mL, maintained at 37°C / 5% CO2, and passaged every 3-4 days. Selection pressure was maintained by adding 100 μg / mL Zeocin every 2 passages.

[0363] Assay conditions: Cells were harvested and resuspended in fresh growth medium at 5 × 10 5 From this cell preparation, 20 μL per well was dispensed into a 384-well cell culture plate (Greiner, no. 781098X) and incubated for 2 hours at 37° C. / 5% CO2.

[0364] Concentration response curves (typically 11 doses) were prepared by 2.5-fold serial dilutions starting from 10 mM compound stock solutions in DMSO. Compound dilutions were transferred to cell culture plates using a pintool (0.1 μL transfer), and control wells were matched for DMSO. Positive control wells received ML RR-S2 CDA (Med Chem Express HY12885B) in 5 μL medium to a final concentration of 40 μM. All other wells received an additional 5 μL medium simply to equalize the volume. Plates were incubated at 37° C. / 5% CO2 for 24 hours.

[0365] For the detection step, QUANTI-Luc (InvivoGen no. rep-qlc1) was prepared according to the manufacturer's instructions and 10 μL was added per well to the culture plate. The plate was shaken for 10 seconds on an orbital shaker and left for 2 minutes at room temperature in the dark before reading the luminescence on a Perkin Elmer Envision plate reader.

[0366] Data analysis: Luminescence raw data was normalized % activity relative to the signal from positive control wells and negative control wells not treated with compound. The following formula was used to calculate normalized % activity from the raw signal: Activity %=(Sample-Negative) / (Positive-Negative)

[0367] ECs from THP-1 STING Lucia ISG cells 50 provides an assessment of activity of the human HAQ isoform of STING. An equivalent method was performed to assess activity of compounds against the WT human STING isoform, where the cells used were THP-1-Dual KI-hSTING-R232 (InvivoGen no. thpd-r232). [Table 10-1] [Table 10-2]

[0368] Description of the invention 1. Formula I: [ka] Compound [In the formula, W is O or NH; R 1 teeth, (i) H, (ii) C 3~6 Cycloalkyl, (iii) methyl, and ester C optionally substituted with a group selected from 3~7 Heterocyclyl, and (iv) alkoxy, amino, Amides, Acylamide, Acyloxy, Alkyl carboxyl esters, Alkylcarbamoyl, Alkyl carbamoyl esters, Phenyl, phosphonate esters, C optionally substituted with a group selected from methyl and oxo 3~7 Heterocyclyl, and Naturally occurring amino acids, optionally N-substituted with a group selected from methyl, acetyl and boc. Linear or branched C optionally substituted with a group selected from 1~4 Alkyl is selected from A 1 CR A or N, A 2 CR B or N, A 3 CR C or N, A 4 CR D or N, Here, A 1 , A 2 , A 3 , and A 4 may be N, R A , R B , R C and R D one or two of (when present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CHOMe and OH; R A , R B , R C and R D the remainder, if any, are H; R N1 is H or Me, R C2 and R C3 One of them is C(=O)NH2, and the other is H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl; R C1 and R C4 are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CHOMe, C 2~4 alkenyl and C5 heterocyclyl.

[0369] 2. The compound according to statement 1, wherein W is O.

[0370] 3. The compound according to statement 1, wherein W is NH.

[0371] 4.R 1 A compound according to any one of statements 1-3, wherein

[0372] 5.R 1 But, C 3~6 Cycloalkyl, optionally substituted C 3~7 Heterocyclyl and optionally substituted straight or branched C1~4 A compound according to statement 1, wherein said compound is selected from alkyl.

[0373] 6.R 1 But, C 3~6 A compound according to any one of statements 1 to 3 and statement 5, which is cycloalkyl.

[0374] 7.R 1 A compound according to description 6, wherein is cyclopropyl.

[0375] 8.R 1 A compound according to description 6, wherein is cyclobutyl.

[0376] 9.R 1 A compound according to description 6, wherein is cyclopentyl.

[0377] 10.R 1 A compound according to statement 6, wherein is cyclohexyl.

[0378] 11.R 1 C, with substitutions as necessary 3~7 A compound according to any one of statements 1 to 3 and statement 5 which is heterocyclyl.

[0379] 12.R 1 optionally substituted C containing a single nitrogen ring atom 3~7 A compound according to description 11 which is a heterocyclyl.

[0380] 13.R 1 A compound according to statement 12, wherein is optionally substituted azetidinyl.

[0381] 14.R 1 A compound according to statement 12, wherein is optionally substituted pyrrolidinyl.

[0382] 15.R 1 A compound according to statement 12, wherein is optionally substituted piperidinyl.

[0383] 16.R 1 A compound according to any one of statements 11 to 15, wherein is substituted with methyl.

[0384] 17.R 1 A compound according to any one of statements 11 to 15, wherein is substituted with an ester.

[0385] 18.R 1 Optionally substituted linear or branched C 1~4 A compound according to any one of statements 1 to 3 and statement 5, wherein:

[0386] 19.R 1 A compound according to statement 18, wherein is optionally substituted methyl.

[0387] 20.R 1 A compound according to description 18, wherein is optionally substituted ethyl.

[0388] 21.R 1 A compound according to statement 18, wherein is optionally substituted propyl.

[0389] 22.R 1 A compound according to statement 18, wherein is optionally substituted butyl.

[0390] 23.R 1 A compound according to description 18, wherein is optionally substituted iso-propyl.

[0391] 24.R 1 A compound according to description 18, wherein is optionally substituted sec-butyl.

[0392] 25.R 1 A compound according to description 18, wherein is optionally substituted iso-butyl.

[0393] 26.R 1A compound according to description 18, wherein is optionally substituted tert-butyl.

[0394] 27.R 1 27. The compound according to any one of statements 18-26, wherein:

[0395] 28.R 1 27. The compound according to any one of statements 18 to 26, wherein is substituted with amino.

[0396] 29.R 1 A compound according to any one of statements 18 to 26, wherein is substituted with an amide.

[0397] 30.R 1 A compound according to any one of statements 18 to 26, wherein is substituted with an acylamido.

[0398] 31.R 1 A compound according to any one of statements 18 to 26, wherein is substituted with acyloxy.

[0399] 32.R 1 A compound according to description 31, wherein is pivaloyloxymethyl.

[0400] 33.R 1 A compound according to description 31, wherein is propanoyloxyisobutyl.

[0401] 34.R 1 27. The compound according to any one of statements 18 to 26, wherein is substituted with an alkyl carboxyl ester.

[0402] 35.R 1 27. The compound according to any one of statements 18 to 26, wherein is substituted with alkylcarbamoyl.

[0403] 36.R 1 27. The compound according to any one of statements 18 to 26, wherein is substituted with an alkyl carbamoyl ester.

[0404] 37.R 1 A compound according to any one of statements 18 to 26, wherein is substituted with phenyl.

[0405] 38.R 1 The compound according to description 37, wherein is benzyl.

[0406] 39.R 1 27. The compound according to any one of statements 18 to 26, wherein is substituted with a phosphonate ester.

[0407] 40.R 1 But, C 3~7 A compound according to any one of descriptions 18 to 26, which is substituted with heterocyclyl.

[0408] 41.R 1 is substituted with methyl 3~7 A compound according to any one of descriptions 18 to 26, which is substituted with heterocyclyl.

[0409] 42.R 1 is substituted with oxo 3~7 A compound according to any one of descriptions 18 to 26, which is substituted with heterocyclyl.

[0410] 43.R 1 27. The compound according to any one of statements 18 to 26, wherein is substituted with a naturally occurring amino acid.

[0411] 44.R 1 27. The compound according to any one of statements 18 to 26, wherein N-substituted with methyl is substituted with a naturally occurring amino acid.

[0412] 45.R 1 27. The compound according to any one of statements 18 to 26, wherein is N-substituted with acetyl, and is substituted with a naturally occurring amino acid.

[0413] 46.R 127. The compound according to any one of statements 18 to 26, wherein is N-substituted with boc and is substituted with a naturally occurring amino acid.

[0414] 47. The compound according to any one of statements 43-46, wherein the naturally occurring amino acid is valine.

[0415] 48.A 1 But, CR A 48. The compound according to any one of statements 1 to 47,

[0416] 49.A 1 The compound according to any one of statements 1 to 47, wherein

[0417] 50.A 2 But, CR B 50. The compound according to any one of statements 1 to 49,

[0418] 51.A 2 The compound according to any one of statements 1 to 49, wherein is N.

[0419] 52.A 3 But, CR C 36. The compound according to any one of statements 1 to 51,

[0420] 53.A 3 The compound according to any one of statements 1 to 51, wherein

[0421] 54.A 4 But, CR D 54. The compound according to any one of statements 1 to 53,

[0422] 55.A 4 The compound according to any one of statements 1 to 53, wherein

[0423] 56.A 1 But, CR A And A 2 But, CR B And A 3 But, CR CAnd A 4 But, CR D 48. The compound according to any one of statements 1 to 47,

[0424] 57.A 1 , A 2 , A 3 and A 4 The compound according to any one of statements 1 to 47, wherein one of is N.

[0425] 58.A 1 , A 2 , A 3 and A 4 The compound according to any one of statements 1 to 47, wherein two of are N.

[0426] 59. The compound has the formula IIIb1 or IIIb2: [ka] 48. The compound according to any one of statements 1 to 47,

[0427] 60. The compound has the formula IIIc1 or IIIc2: [ka] 48. The compound according to any one of statements 1 to 47,

[0428] 61. The compound has the formula IIId1 or IIId2: [ka] 48. The compound according to any one of statements 1 to 47,

[0429] 62. The compound has the formula IIIe1 or IIIe2: [ka] 48. The compound according to any one of statements 1 to 47,

[0430] 63.R A , R B , R C and R D A compound according to any one of statements 1-62, wherein one or two of (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano and OMe, and the remaining (if present) are H.

[0431] 64.R A , R B , R C and R D A compound according to any one of statements 1-62, wherein one or two of (if present) are selected from H, F, Cl, Br, Me, CF3 and OMe, and the remaining (if present) are H.

[0432] 65.R A , R B , R C and R D A compound according to any one of statements 1-62, wherein one or two of (if present) are selected from H, F, Cl, Br and OMe, and the remaining (if present) are H.

[0433] 66.R A (when present) is selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, and CHOMe; R B (if present) is H; R C (if present) is H; R D (when present) is selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, CH2OH and CHOMe; A compound according to any one of descriptions 1 to 62.

[0434] 67.R A (when present) is selected from Cl, Br and OMe; R B (if present) is H; R C (if present) is H; R D (when present) is selected from H, Me, F, Br, OMe; A compound according to any one of descriptions 1 to 62.

[0435] 68.R A is Cl, R B But H, R C But H, R D But H. Compound according to description 56.

[0436] 69.R A is Cl, R B But H, R C But H, R D But, Me, Compound according to description 56.

[0437] 70.R A is Cl, R B But H, R C But H, R D But Br, Compound according to description 56.

[0438] 71.R A But Br, R B But H, R C But H, R D But H. Compound according to description 56.

[0439] 72.R A is Cl, R B But H, R C But H, R D But F. Compound according to description 56.

[0440] 73.R A is Cl, R B But H, R C But H, R D But OMe, Compound according to description 56.

[0441] 74.R A But Br, R B But H, R C But H, R D But F. Compound according to description 56.

[0442] 75.R A But OMe, R B But H, R C But H, R D But H. Compound according to description 56.

[0443] 76.R C1 and R C4 , and R C2 and R C3 and are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, and CH2OH.

[0444] 77.R C1 and R C4 , and R C2 and R C3and are independently selected from H, Cl, F, CF3, OMe, and CH2OH.

[0445] 78.R C1 and R C4 , and R C2 and R C3 and are independently selected from H, Cl, F and OMe.

[0446] 79.R C1 , R C3 and R C4 or R C1 , R C2 and R C4 A compound according to any one of statements 1 to 78, wherein two of are H and the others are selected from the groups defined except H.

[0447] 80.R C1 , R C3 and R C4 or R C1 , R C2 and R C4 A compound according to any one of statements 1-78, wherein one of is H and the other two are independently selected from the groups defined except H.

[0448] 81.R C1 and R C4 , and R C2 and R C3 and is H.

[0449] 82.R C1 But H, R C2 or R C3 But H, R C4 But F. A compound according to any one of descriptions 1 to 75.

[0450] 83.RC1 But OMe, R C2 or R C3 But H, R C4 But H. A compound according to any one of descriptions 1 to 75.

[0451] 84.R C1 But OMe, R C2 or R C3 But H, R C4 But F. A compound according to any one of descriptions 1 to 75.

[0452] 85.R C1 is Cl, R C2 or R C3 But H, R C4 But H. A compound according to any one of descriptions 1 to 75.

[0453] 86.R N1 A compound according to any one of statements 1 to 85, wherein

[0454] 87.R N1 A compound according to any one of statements 1 to 85, wherein is Me.

[0455] 88. A compound as defined in any one of statements 1 to 87 for use in a method of treatment.

[0456] 89. A pharmaceutical composition comprising a compound as defined in any one of statements 1 to 87, and a pharma- ceutically acceptable excipient.

[0457] 90. A method for 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 87 or a pharmaceutical composition according to statement 89.

[0458] 91. Use of a compound as defined in any one of statements 1 to 87 in the manufacture of a medicament for treating or preventing a disease ameliorated by modulation of STING.

[0459] 92. A compound as defined in any one of statements 1 to 87, or a pharmaceutical composition thereof, for use in the treatment or prevention of a disease that is ameliorated by modulation of STING. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10]

Claims

1. Formula I: 【Chemistry 57】 Compound [In the formula, W is O or NH; R １ teeth, (i) H, (ii) C ３～６ Cycloalkyl, (iii) methyl, and ester and 3- to 7-membered heterocyclyl optionally substituted with a group selected from (iv) alkoxy, amino, Amides, Acylamide, Acyloxy, Alkyl carboxyl esters, Alkylcarbamoyl, Alkyl carbamoyl esters, Phenyl, phosphonate esters, 3- to 7-membered heterocyclyl optionally substituted with a group selected from methyl and oxo, and Naturally occurring amino acids, optionally N-substituted with a group selected from methyl, acetyl and boc. Linear or branched C optionally substituted with a group selected from １～４ Alkyl is selected from A １ is CR Ａ or N, A ２ is CR Ｂ or N, A ３ is CR Ｃ or N, A ４ is CR Ｄ or N, Here, A １ , A ２ , A ３ , and A ４ may be N, R Ａ , R Ｂ , R Ｃ and R Ｄ One or two of (if present) are H, F, Cl, Br, Me, CF ３ , cyclopropyl, cyano, OMe, OEt, CH ２ OH, CH ２ is selected from OMe and OH; R Ａ , R Ｂ , R Ｃ and R Ｄ the remainder (if any) are H; R Ｎ１ is H or Me, R Ｃ２ and R Ｃ３ One of the groups is C(=O)NH ２ and the other is H, Cl, F, Br, Me, OMe, OEt, cyano, CF ３ , C.H. ２ OH, CH ２ OMe, C ２～４ alkenyl and 5-membered heterocyclyl; R Ｃ１ and R Ｃ４ are independently H, Cl, F, Br, Me, OMe, OEt, cyano, CF ３ , C.H. ２ OH, CH ２ OMe, C ２～４ alkenyl and 5-membered heterocyclyl; wherein each 3- to 7-membered heterocyclyl is a monocyclic heterocyclic group having 3 to 7 ring atoms of which 1 to 2 ring atoms are heteroatoms, and the ring heteroatoms of said 3- to 7-membered heterocyclyl are selected from oxygen and nitrogen; Each 5-membered heterocyclyl is a monocyclic heterocyclic group having 5 ring atoms, of which 1 to 2 ring atoms are heteroatoms, and the ring heteroatoms of said 5-membered heterocyclyl are selected from oxygen and nitrogen.

2. The compound of claim 1 , wherein W is O.

3. R １ The compound according to claim 1 or 2, wherein is H.

4. R １ But, C ３～６ Cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, and optionally substituted straight or branched C １～４ 3. The compound according to claim 1 or 2, wherein the aryl group is selected from alkyl.

5. R １ is an optionally substituted linear or branched C １～４ 5. The compound of claim 1, 2 or 4, which is alkyl.

6. R １ The compound of claim 5 , wherein is optionally substituted ethyl.

7. A １ But, CR Ａ And A ２ But, CR Ｂ And A ３ But, CR Ｃ And A ４ But, CR Ｄ The compound according to any one of claims 1 to 6,

8. The compounds have the formula IIIb1, IIIc1, IIId1 and IIIe1: 【Chemistry 58】 The compound according to any one of claims 1 to 6, which is selected from the compounds of

9. The compounds have the formula IIIb2, IIIc2, IIId2 and IIIe2: 【Chemistry 59】 【Chemistry 60】 The compound according to any one of claims 1 to 6, which is selected from the compounds of

10. R Ａ (if present) is selected from Cl, Br and OMe; R Ｂ (if present) is H; R Ｃ (if present) is H; R Ｄ (if present) is selected from H, Me, F, Br, OMe; A compound according to any one of claims 1 to 9.

11. A １ , A ２ , A ３ and A ４ However, combinations 1 to 9 【Chemistry 61】 The compound according to any one of claims 1 to 6, selected from:

12. R Ｃ１ , R Ｃ２ Or R Ｃ３ , and R Ｃ４ However, combinations 1 to 5 【Chemistry 62】 【Chemistry 63】 The compound according to any one of claims 1 to 11, selected from:

13. R Ｎ１ The compound according to any one of claims 1 to 12, wherein is H.

14. 【Chemical 64】 2. The compound of claim 1 , selected from:

15. 【Chemical 65】 【Chemistry 66】 2. The compound of claim 1 , selected from:

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