Heterocyclic compounds capable of activating STING

Abstract

The present invention relates to heterocyclic compounds of formula (I) that are capable of activating STING (stimulator of interferon genes). JPEG2025536352000085.jpg77150

Description

[Technical Field]

[0001] The present invention relates to small molecules and salts thereof that can activate STING (stimulator of interferon genes). Specifically, the present invention relates to heterocyclic compounds that can activate STING. Furthermore, the present invention relates to pharmaceutical compositions and formulations containing these compounds and their use in methods for treating diseases associated with or modulated by STING. In particular, the pharmaceutical compositions of the present invention are suitable for the treatment of inflammation, allergies and autoimmune diseases, infectious diseases, and cancer, and as vaccine adjuvants. [Background technology]

[0002] STING is a pattern recognition receptor (PRRP) that plays a central role in the innate immune system by identifying pathogens and host cells by detecting extracellular and intracellular danger signals, including damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). These recognition processes constitute the first line of defense against viral and bacterial infections and malignant cells. However, pathogens and cancer cells have evolved ways to evade recognition by the immune system. Therefore, the goal of immunotherapy is to elicit antigen-specific immune responses or reactivate existing responses in certain cell types of the immune system against pathogenic invaders or cancerous cells.

[0003] Among PRRPs, STING (also known as TMEM173, MPYS, MITA, and ERIS) belongs to a family of nucleic acid sensors and is an adaptor for cytosolic DNA signaling. In mammalian cells, DNA is compartmentalized in the nucleus under healthy conditions. In pathogenic situations, such as invasion by DNA-containing pathogens, or in malignant cells, DNA is present in the cytoplasm. In this case, STING is important for detecting the above cytosolic DNA and inducing an immune response to pathogenic events. STING exists as a dimer in the basal state, with its N-terminal domain anchored in the ER and its C-terminal domain residing in the cytosol. Cyclic dinucleotides (CDNs) produced by the protein cyclic GMP-AMP synthase (cGAS) are natural ligands of STING (Ablasser et al., Nature 498, 380-384, 2013). Binding of CDNs to STING induces a conformational change, allowing binding and activation of TANK-binding kinase (TBK1) and interferon regulatory factor 3 (IRF3), followed by relocalization from the ER to perinuclear endosomes (Liu et al., Science 347, Issue 6227, 2630-1-2630-14, 2015). Phosphorylation of the transcription factors IRF3 and NF-κB by TBK1 leads to the expression of multiple cytokines, including type I interferons (IFNs).

[0004] Type I IFN production by antigen-presenting cells and other cell types is thought to be a critical event in T cell activation and the subsequent differentiation of antigen-specific effector CD4 and CD8 T cells. The absence of type I IFN has been shown to reduce T cell-dependent immune responses to viral infections or tumor cells (Zitvogel et al., Nature Reviews Immunology 15, 405–414, 2015). Meanwhile, the presence of a type I IFN signature during cancer therapy is associated with increased numbers of tumor-infiltrating T cells and potentially favorable clinical outcomes (Sistigu et al., Nature Medicine 20, 1301–1309, 2014). Efficient secretion of type I IFNs in the tumor microenvironment and induction of T cell-dependent immune responses against cancer cells depend on the presence of STING, as shown in recent studies in mice (Woo et al., Immunity 41, 5, 830-842, 2014; Corrales et al., Cell Reports 11, 1018-1030, 2015; Deng et al., Immunity 41, 5, 843-852, 2014). STING deficiency reduced type I IFN levels in the tumor microenvironment and reduced antitumor efficacy in several mouse tumor models, thereby emphasizing the importance of type I IFN. On the other hand, specific activation of STING improved antigen-specific T cell immune responses against cancer cells.

[0005] Type I interferons can significantly enhance antitumor immune responses by inducing the activation of both adaptive and innate immune cells. Given the importance of type I IFNs in several malignancies, including viral infections, and in cancer therapy, strategies that enable specific activation of STING are therapeutically important. STING activation can be synergistic with various approved chemotherapeutic agents or other anticancer therapies, such as radiation therapy (Wu et al., Med Res Rev 2020 May;40(3):1117-1141), or infectious disease treatments.

[0006] In the prior art, small molecule regulators of STING have been described, for example in WO2020075790. Summary of the Invention

[0007] The compounds according to the present invention are novel activators of STING as demonstrated in an in vitro reporter system using the THP1-Blue reporter cell line.

[0008] In one aspect, the present invention relates to a compound of formula (I) or a salt thereof: [ka] (In the formula, B is 5- to 7-membered monocyclic heterocyclyl containing 1 or 2 N atoms, 6-membered bicyclic heterocyclyl containing one N atom, and 6-membered monocyclic heterocyclyl containing one N atom and one heteroatom selected from the group consisting of O and S is a group selected from the group consisting of R 1 is -H or -C 1-6 -alkyl, R 2 is -H or -halogen, R 3 is -H or -halogen, However, R 2 and / or R 3 is a halogen; R 4 -H, -S(O2)-C 1-6 -Alkyl, =O, -C(O)H, -C(O)OH, -C(O)OC 1-6 -Alkyl, -C 1-6 -alkylene-C(O)OH, and -C(O)NH; R 5 is absent or selected from the group consisting of -H and =O The compounds of formula (I) or salts thereof as defined herein are particularly suitable for the treatment of pathophysiological processes associated with or modulated by STING, in particular for the treatment of inflammation, allergic or autoimmune diseases, infectious diseases, or cancer, or for use as vaccine adjuvants. In another aspect, the present invention relates to methods of treatment involving compounds of formula (I) or salts thereof. In another aspect, the present invention relates to the use of compounds of general formula (I) as medicaments. In another aspect, the present invention relates to pharmaceutical compositions comprising at least one compound of general formula (I). In another aspect, the present invention relates to the use of compounds of general formula (I) in pharmaceutical formulations containing another active substance. In another embodiment, the present invention provides a general synthetic scheme for compounds of general formula (I), including examples and methods. DETAILED DESCRIPTION OF THE INVENTION

[0009] The compounds of the present invention exhibit several advantageous properties, including favorable binding affinity to human STING, favorable cellular activity as measured by cellular EC50, i.e., in cells harboring different human STING alleles, and favorable permeability in cellular assays, as described below. Thus, in a first aspect, the present invention provides new compounds of formula (I), including their salts, which activate STING and thus induce cytokine production in a STING-dependent manner in vitro and / or in vivo, and which have suitable pharmacological and pharmacokinetic properties for use in therapy, i.e., for use as pharmaceuticals. Compounds according to the invention typically exhibit a cellular EC50 against the STING "HAQ" version of less than 7 μM, preferably less than 4 μM, more preferably less than 2 μM, and most preferably less than 1 μM.

[0010] Furthermore, the compounds according to the present invention also exhibit a cellular EC50 of less than 3 μM, preferably less than 2 μM, more preferably less than 1 μM, and most preferably less than 0.7 μM against the human STING variant "H232R" (sometimes also designated as wildtype, Yi et al., 2013; PLOS ONE 8(10)). Furthermore, the compounds according to the present invention also exhibit a cellular EC50 against the human STING variant "R232H" of less than 3 μM, preferably less than 2 μM, more preferably less than 1 μM, and most preferably less than 0.7 μM. Furthermore, the compounds according to the present invention also exhibit a cellular EC50 against the human STING variant "R293Q" of less than 10 μM, preferably less than 5 μM, more preferably less than 3 μM, even more preferably less than 2 μM, and most preferably less than 1 μM. Furthermore, the compounds according to the present invention also exhibit a cellular EC50 against human STING variant "AQ" of less than 7 μM, preferably less than 3 μM, more preferably less than 2 μM, and most preferably less than 1 μM.

[0011] "H232R," "R232H," and "R293Q" are single amino acid substitutions at the given position. "AQ" is a variant consisting of two substitutions, G230A and R293Q, and "HAQ" is a STING variant consisting of three substitutions, R71H, G230A, and R293Q (Yi et al., 2013; PLOS ONE 8(10)). Activity against various human STING variants is advantageous because it maximizes the chance of inducing the desired pharmacological response in patients with single nucleotide polymorphisms. Compounds having a cellular EC50 of less than 1 μM against human STING variants "AQ," "HAQ," and "R293Q," and a cellular EC50 of less than 0.7 μM against human STING variants "R232H" and "H232R" are preferred.

[0012] Furthermore, the compounds of the present invention exhibit favorable binding to the human STING protein. Favorable binding affinity to human STING, coupled with favorable cellular activity and / or favorable pharmacokinetic properties, can allow for dose reduction for pharmacological efficacy. Dose reduction has the advantages of reducing the "drug burden" or "drug burden" (parent drug and its metabolites) for patients, potentially reducing side effects, and reducing production costs for the formulation.

[0013] The binding of a compound to a protein can be determined by known methods such as surface plasmon resonance, scintillation proximity assay, isothermal titration calorimetry, or differential scanning fluorimetry. In the latter test, the melting temperature T m The temperature at which a protein unfolds, also called the T, is measured by the change in fluorescence of a dye that binds to the hydrophobic portion of the protein. m The shift correlates with the binding affinity of the small molecule. A high binding affinity for a STING agonist is a T of >10K, preferably >13K, and more preferably >15K. m is reflected by a shift in

[0014] In another aspect of the present invention, the compounds of the present invention exhibit good cell permeability as measured in Caco-2 cell line, promote target binding of intracellular STING protein, and inhibit P app,AB is measured from the apical to the basolateral side of the cell monolayer (Caco-2 A→B) and is 5 × 10E -6 cm / s, preferably greater than 8×10E -6 cm / s, more preferably 10×10E -6 Furthermore, the compounds of the present invention exhibit low efflux ratios from Caco cells (calculated as shown below) of <8, preferably <5, more preferably <3.5, indicating good residence times inside the cells, thereby promoting long-lasting target binding.

[0015] In another aspect of the invention, compounds of the invention exhibit a cellular EC50 of less than 1 μM for human STING variant "HAQ" and an efflux ratio from Caco cells of <3.5. In another aspect of the invention, compounds of the invention exhibit a cellular EC50 of less than 0.7 μM for human STING variant "H232R" and an efflux ratio from Caco cells of <3.5. Compounds having a cellular EC50 of less than 0.7 μM for human STING variant "H232R," a cellular EC50 of less than 1 μM for human STING variant "HAQ," and an efflux ratio from Caco cells of <3.5 are preferred.

[0016] The compounds of the invention according to general formula (I) as defined herein or salts thereof are particularly suitable for the treatment of pathophysiological processes associated with or modulated by STING, in particular for the treatment of inflammation, allergic or autoimmune diseases, infectious diseases, or cancer, or for use as vaccine adjuvants. [ka] (In the formula, B is 5- to 7-membered monocyclic heterocyclyl containing 1 or 2 N atoms, 6-membered bicyclic heterocyclyl containing one N atom, and 6-membered monocyclic heterocyclyl containing one N atom and one heteroatom selected from the group consisting of O and S is a group selected from the group consisting of R 1 is -H or -C 1-6 -alkyl, R 2 is -H or -halogen, R 3 is -H or -halogen, However, R 2 and / or R 3 is a halogen; R 4 -H, -S(O2)-C 1-6 -Alkyl, =O, -C(O)H, -C(O)OH, -C(O)OC 1-6 -Alkyl, -C 1-6 -alkylene-C(O)OH, and -C(O)NH; R 5 is absent or selected from the group consisting of -H and =O Thus, in another aspect, the present invention also relates to a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. Other aspects of the present invention will be apparent to those skilled in the art directly from the description and examples set forth above and below.

[0017] Terms and definitions used Terms not specifically defined herein should be given the meaning that one of ordinary skill in the art would give them in light of the disclosure and context. However, as used herein, unless otherwise specified, the following terms have the indicated meanings and the following conventions are followed:

[0018] For groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, e.g., C 1-6 -Alkyl means an alkyl group or radical having 1 to 6 carbon atoms. Generally, for groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., one skilled in the art will recognize the point of attachment of the radical to the molecule from the free valence of the group itself. In combined groups containing two or more subgroups, the last-mentioned subgroup is the point of radical attachment, e.g., "aryl-C 1-3 The "-alkylene" substituent means that the aryl group is C 1-3 - means attached to an alkyl group, which in turn is attached to a core or group to which the substituent is attached.

[0019] When compounds of the invention are depicted in chemical name form and in formula form, in the event of any discrepancy, the formula shall prevail. In subformulas, wavy lines may be used to indicate bonds that are connected to the defined core molecule.

[0020] For example, the term "3-carboxypropyl group" represents the following substituent: [ka] (wherein the carboxy group is attached to the third carbon atom of the propyl group) The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" refer to the following groups: [ka] In subformulas, wavy lines can be used to indicate bonds that are connected to the core molecule being defined.

[0021] 1.1.1.1 The term "substituted" As used herein, the term "substituted" means that one or more hydrogens on the named atom have been replaced with a group selected from the defined group of substituents, provided that the normal valence of the named atom is not exceeded and that the substitution results in a stable compound. Similarly, the term "substituted" can be used in conjunction with a chemical moiety rather than a single atom (e.g., "substituted alkyl," "substituted aryl," etc.).

[0022] 1.1.1.2 Stereochemistry - Solvates - Hydrates Unless otherwise indicated, throughout the specification and the appended claims, a given chemical formula or name is intended to encompass its tautomers and all stereoisomers, optical isomers, geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates, as well as mixtures of different proportions of separate enantiomers, mixtures of diastereomers, or mixtures of any of the above forms in which such isomers and enantiomers exist, as well as solvates thereof, such as hydrates. Unless specifically indicated, "pharmaceutically acceptable salts," as defined in more detail below, are also intended to encompass solvates thereof, such as hydrates.

[0023] 1.1.1.3 Stereoisomers In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of corresponding mixtures, by the use of stereochemically pure starting materials, and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms by resolution of racemates or, for example, by synthesis starting from optically active starting materials and / or by the use of chiral reagents. Enantiomerically pure compounds or intermediates of the present invention may be prepared via asymmetric synthesis, for example by the preparation and subsequent separation of suitable diastereomeric compounds or intermediates which may be separated by known methods (e.g., chromatographic separation or crystallization) and / or by the use of chiral reagents, such as chiral starting materials, chiral catalysts, or chiral auxiliaries. Furthermore, methods are known to those skilled in the art for preparing enantiomerically pure compounds from the corresponding racemic mixture, for example by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase; or by resolution of the racemic mixture using a suitable resolving agent, for example by formation of diastereomeric salts of the racemate with an optically active acid or base, followed by resolution of the salts and liberation of the desired compound from the salt; or by derivatization of the corresponding racemate with an optically active chiral auxiliary reagent, followed by diastereomeric separation and removal of the chiral auxiliary; or by kinetic resolution (for example by enzymatic resolution) of the racemate; by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0024] 1.1.1.4 Salt The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without undue toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include those derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Other pharmaceutically acceptable salts can be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. For example, salts of acids other than those mentioned above (eg, trifluoroacetates), which are useful for purifying or isolating the compounds of this invention, also form part of this invention.

[0025] 1.1.1.5 Halogens The term halogen refers to fluorine, chlorine, bromine and iodine.

[0026] 1.1.1.6 Heteroatoms Heteroatoms can be present in all possible oxidation states, for example, sulfur can be present as sulfoxide (RS(O)-R') and sulfone (-RS(O)2-R').

[0027] 1.1.1.7 Alkyl "C 1-nThe term "-alkyl" (where n is an integer selected from 2, 3, 4, 5, or 6, preferably 4, 5, or 6), alone or in combination with another radical, denotes an acyclic, saturated, branched or straight-chain hydrocarbon radical having 1 to n C atoms. For example, C 1-5 The term -alkyl encompasses the radicals H3C, H3CCH2, H3CCH2CH2, H3CCH(CH3), H3CCH2CH2CH2, H3CCH2CH(CH3), H3CCH(CH3)CH2, H3CC(CH3)2, H3CCH2CH2CH2CH2, H3CCH2CH2CH(CH3), H3CCH2CH(CH3)CH2, H3CCH(CH3)CH2CH2, H3CCH2C(CH3)2, H3CC(CH3)2CH2, H3CCH(CH3)CH(CH3), and H3CCH2CH(CH2CH3).

[0028] 1.1.1.8 Alkylene "C 1-n The term "-alkylene" (where n is an integer selected from 2, 3, 4, 5, or 6, preferably 4, 5, or 6), alone or in combination with another radical, denotes an acyclic, saturated, branched or straight-chain divalent alkyl radical containing 1 to n carbon atoms. For example, C 1-4 The term -alkylene includes -CH-, -CH-CH-, -CH(CH)-, -CH-CH-CH-, -C(CH)-, -CH(CHCH)-, -CH(CH)-CH-, -CH-CH(CH)-, -CH-CH-CH-CH-, -CH-CH-CH(CH)-, -CH(CH)-CH-CH-, -CH-CH(CH)-CH-, -CH-C(CH)-, -C(CH)-CH-, -CH(CH)CH-(CH)-, -CH-CH(CHCH)-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCHCH)-, -CH(CHCHCH)-CH-, -CH(CHCHCH)-, -CH(CHCHCH)-, and -C(CH)(CHCH)-.

[0029] 1.1.1.9 Alkenyl "C 2-m The term -alkenyl refers to "C2-m -alkyl" group (where m is an integer selected from 3, 4, 5, or 6, preferably 4, 5, or 6) is used where at least two carbon atoms of the group are joined to each other by a double bond. 1.1.1.10 Alkenylene "C 2-m The term -alkenylene refers to "C 2-m -alkylene" group, where m is an integer selected from 3, 4, 5, or 6, preferably 4, 5, or 6, is used where at least two carbon atoms are joined to each other by a double bond. 1.1.1.11 Alkynyl "C 2-m The term -alkynyl refers to "C 2-m -alkyl" group (where m is an integer selected from 3, 4, 5, or 6, preferably 4, 5, or 6) is used where at least two carbon atoms of the group are joined to each other by a triple bond. 1.1.1.12 Alkynylene "C 2-m The term -alkynylene refers to "C 2-m -alkylene" group, where m is an integer selected from 3, 4, 5, or 6, preferably 4, 5, or 6, is used where at least two of the carbon atoms are joined to each other by a triple bond.

[0030] 1.1.1.13 Cycloalkyl "C 3-k The term "-cycloalkyl" (where k is an integer selected from 3, 4, 5, 6, 7, or 8, preferably 4, 5, or 6), alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical having 3 to k C atoms. For example, C 3-7 The term -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 1.1.1.14 Cycloalkenyl "C 3-kThe term "cycloalkenyl" (where k is an integer selected from 3, 4, 5, 6, 7, or 8, preferably 4, 5, or 6), alone or in combination with another radical, denotes a cyclic, unsaturated but non-aromatic, unbranched hydrocarbon radical having 3 to k C atoms, at least two of which are connected to each other by a double bond. For example, C 3-7 The term -cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and cycloheptatrienyl. 1.1.1.15 Halo-(alkyl, alkylene, or cycloalkyl) The term "halo" appended to "alkyl," "alkylene," or "cycloalkyl" (saturated or unsaturated) groups defines an alkyl, alkylene, or cycloalkyl group in which one or more hydrogen atoms have been replaced by a halogen atom selected from fluorine, chlorine, or bromine, preferably fluorine and chlorine, and particularly preferably fluorine. Examples include HFC-, HFC-, and FC-.

[0031] 1.1.1.16 Carbocyclyl The term "carbocyclyl," alone or in combination with another radical, means a monocyclic, bicyclic, or tricyclic ring structure of 3 to 14 carbon atoms. The term "carbocyclyl" refers to fully saturated, partially saturated, and aromatic ring systems. The term "carbocyclyl" includes fused, bridged, and spiro ring systems. [ka]

[0032] 1.1.1.17 Aryl The term "aryl," as used herein, alone or in combination with another radical, refers to a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered aromatic, saturated, or unsaturated carbocyclic group. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, and dihydronaphthyl.

[0033] 1.1.1.18 Heterocyclyl The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic ring system, which may contain an aromatic ring and which contains one or more heteroatoms selected from N, O, S, SO, SO2, and which consists of 3 to 14 ring atoms, none of which is part of an aromatic ring. The term "heterocyclyl" is intended to include all possible isomers.

[0034] Thus, the term "heterocyclyl" encompasses the following exemplary structures (not shown as radicals because each form may be attached through a covalent bond to any atom as long as appropriate valences are maintained): [ka] [ka] [ka]

[0035] 1.1.1.19 Heteroaryl The term "heteroaryl" refers to a monocyclic or polycyclic ring system containing at least one aromatic ring and containing one or more heteroatoms selected from N, O, S, SO, or SO, and consisting of 5 to 14 ring atoms, wherein at least one of the heteroatoms is part of an aromatic ring, provided that the resulting ring system is chemically stable. The term "heteroaryl" is intended to include all possible isomers.

[0036] Thus, the term "heteroaryl" encompasses the following exemplary structures (not shown as radicals because each form may be attached through a covalent bond to any atom as long as appropriate valences are maintained): [ka]

[0037] Many of the terms described above can be used repeatedly in the definitions of formulae or groups and can in each case, independently of one another, have one of the meanings described above.

[0038] The term "bicyclic ring system" means a group consisting of two linked cyclic moieties, including spirocyclic, fused, and bridged ring systems.

[0039] Preferred Embodiments One particular embodiment of the present invention relates to compounds of formula (I) or salts thereof: [ka] (In the formula, R 1 Ha-C 1-3 -alkyl)

[0040] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 1 is —CH3, or a salt thereof. Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 2 is selected from the group consisting of -H, -F, and -Cl, or a salt thereof. Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 3 is selected from the group consisting of -H, -F, and -Cl, or a salt thereof. Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 2is selected from the group consisting of -H, -F, and -Cl; R 3 is selected from the group consisting of -H, -F, and -Cl, with the proviso that R 2 and / or R 3 relates to a compound or a salt thereof, provided that it is -F or -Cl.

[0041] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 4 But -H, -S(O2)-C 1-6 -Alkyl, =O, -C(O)H, -C(O)OH, -C(O)OC 1-6 -alkyl, or a salt thereof. Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 4 But -H, -S(O2)-C 1-6 -alkyl, ═O, —C(O)H, —C(O)OH, or a salt thereof.

[0042] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 4 But -S(O2)-C 1-6 -alkyl, ═O, —C(O)H, —C(O)OH, or a salt thereof. Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 4 is —C(O)OH, or a salt thereof.

[0043] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein B is 5- to 7-membered monocyclic heterocyclyl containing 1 or 2 N atoms, 6-membered bicyclic heterocyclyl containing one N atom, and 6-membered monocyclic heterocyclyl containing one N atom and one heteroatom selected from the group consisting of O and S The present invention relates to a compound or a salt thereof, wherein the compound is a group selected from the group consisting of:

[0044] Another particular embodiment of the present invention relates to compounds of formula (I) or salts thereof, wherein B is selected from the group consisting of: [ka]

[0045] Another particular embodiment of the present invention relates to compounds of formula (I) or salts thereof, wherein B is selected from the group consisting of: [ka]

[0046] Another particular embodiment of the present invention relates to compounds of formula (I) or salts thereof, wherein B is selected from the group consisting of: [ka]

[0047] Another particular embodiment of the present invention relates to compounds of formula (I) or salts thereof, wherein B is selected from the group consisting of: [ka]

[0048] Another particular embodiment of the present invention relates to compounds of formula (I) or salts thereof, wherein B is selected from the group consisting of: [ka] (In the formula, R 4 -H, -S(O2)-C 1-6 -alkyl, ═O, —C(O)H, —C(O)OH; R 5is absent or selected from the group consisting of -H and =O

[0049] Another particular embodiment of the present invention relates to compounds of formula (I) or salts thereof, wherein B is selected from the group consisting of: [ka] (In the formula, R 1 is -CH3 and R 2 is selected from the group consisting of -H, -F, and -Cl; R 3 is selected from the group consisting of -H, -F, and -Cl, with the proviso that R 2 and / or R 3 is -F or -Cl, R 4 is -S(O2)-C 1-6 -alkyl, ═O, —C(O)H, —C(O)OH; R 5 is absent or selected from the group consisting of -H and =O

[0050] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka] [ka]

[0051] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka] [ka]

[0052] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka]

[0053] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka]

[0054] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka]

[0055] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka]

[0056] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka]

[0057] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka]

[0058] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka]

[0059] Another particular embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: [ka]

[0060] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0061] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0062] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0063] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0064] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0065] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0066] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0067] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0068] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0069] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0070] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0071] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0072] Another particular embodiment of the present invention relates to the following: or a pharmaceutically acceptable salt thereof: [ka]

[0073] B, R 1 , R 2 , R 3 , R 4 , R 5 Any and each of the definitions may be combined with each other.

[0074] In one aspect, the present invention relates to compounds of formula (I) in free form.

[0075] In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical. In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease selected from the group consisting of inflammation, allergy or autoimmune diseases, infectious diseases, and cancer, or for use as a vaccine adjuvant. In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, and, as another active substance, a substance selected from the group consisting of a cytostatic substance, a cytotoxic substance, a cell growth inhibitory substance, an antiangiogenic substance, a steroid, a virus, an immunogenic cell death inducer, a cancer targeting agent, an immunomodulatory agent, an antibody, and a nanobody.

[0076] Treatment method In another aspect of the present invention, it is found that compounds of general formula (I) or their salts may be useful in the prevention and / or treatment of diseases and / or conditions in which modulation of STING is therapeutically beneficial. Furthermore, due to their activity, the compounds of the present invention are suitable as vaccine adjuvants. Diseases and conditions associated with or modulated by STING include, but are not limited to, inflammatory, allergic or autoimmune diseases such as allergic rhinitis or asthma, infectious diseases, or cancer. Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), dermatomyositis, and Sjogren's syndrome (SS).

[0077] The compounds of the present invention can be used to treat inflammation in any tissue or organ of the body, including, but not limited to, musculoskeletal inflammation, vascular inflammation, neuroinflammation, gastrointestinal inflammation, ocular inflammation, reproductive system inflammation, and other inflammation. 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, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibromyalgia, epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cysticus).Examples of ocular inflammation that can be treated with the compound of the present invention include blepharitis, cutis laxa, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis. Examples of inflammation of the nervous system that can be treated with the compounds of the present invention include encephalitis, Guillain-Barré syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, and schizophrenia. Examples of inflammation of the vasculature or lymphatic system that can be treated with the compounds of the present invention include arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis. Examples of inflammatory conditions of the digestive system that can be treated with the compounds of the present invention include cholangitis, cholecystitis, enteritis, enteritis, gastritis, gastroenteritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), ileitis, and proctitis. Examples of inflammatory conditions of the reproductive system that can be treated with the compounds of the present invention include cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[0078] Compound can be used to treat autoimmune conditions that have inflammatory factors.Such conditions include acute disseminated alopecia universalis, Behcet's disease, Chagas' disease, 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 syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schönlein purpura, Kawasaki disease, lupus erythematosus, microscopic colitis. , microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, moles, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0079] The compounds can be used to treat T cell-mediated hypersensitivity disorders with inflammatory factors, including contact hypersensitivity, contact dermatitis (including that caused by poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0080] Other inflammatory conditions that can be treated with the compounds include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, pneumonitis, 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 allografts, skin homografts, and heart valve xenografts, serum sickness, and graft-versus-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, César's syndrome, congenital adrenal hyperplasia, and inflammatory conditions such as erythritis, rheumatoid arthr ... hyperplasis), non-dense thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis, and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphoma in adults, acute childhood leukemia, regional enterocolitis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, and sepsis. Preferred treatments include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic lung disease, and inflammation associated with infectious conditions (e.g., sepsis).

[0081] In one embodiment, the disease or condition treated using the compounds of the present invention is cancer. Examples of cancer diseases and conditions for which the compounds of formula (I) or their salts or solvates can potentially have beneficial anti-tumor effects include cancer of the lung, bone, pancreas, skin, brain, head, neck, uterus, ovary, stomach, colon, colorectum, breast, esophagus, small intestine, intestine, endocrine system, thyroid, parathyroid, adrenal gland, urethra, prostate, penis, testicle, ureter, bladder, kidney or liver, bile duct; urothelial cancer; rectal cancer; anal cancer; fallopian tube, endometrium, cervix, vagina, These include, but are not limited to, vulvar, renal pelvic, and renal cell carcinoma; sarcoma; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangiomas; hepatocarcinoma; 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; chondromatous hamartoma; mesothelioma; Hodgkin's disease, or a combination of one or more of the above cancers.

[0082] Preferred cancers that can be treated with the compounds according to the invention are skin, lung, e.g. small cell lung cancer, non-small cell lung cancer, liver, pancreas, colon, colorectal, brain, breast, ovarian, prostate, kidney, bladder, bile duct, endometrial, thyroid, cervix, stomach, head, neck, sarcoma, soft tissue sarcoma, esophagus, head and neck cancer, rectal and urothelial cancer, and lymphoma. The new compounds can also be used in any combination with surgery, radiotherapy, or other "modern" compounds, such as cytostatic or cytotoxic agents, cell growth inhibitors, anti-angiogenic agents, steroids, antibodies, nanobodies, cancer-targeting agents, viruses, including but not limited to oncolytic viruses, or immunogenic cell death inducers, for the prevention, palliative, curative or semi-curative, short-term or long-term treatment of the above-mentioned diseases.

[0083] The new compounds can also be used in any combination with surgery, radiation therapy, or other "modern" compounds, such as cytostatic or cytotoxic substances, cell growth inhibitors, antiangiogenic substances, steroids, antibodies, nanobodies, cancer-targeting agents, viruses, including but not limited to oncolytic viruses, or immunogenic cell death inducers, by combining various routes of administration of the compounds, such as intravenous, intratumoral, subcutaneous, inhalation, or oral administration, for the prophylactic, palliative, curative, or semi-curative, short-term, or long-term treatment of the above-mentioned diseases. As just one example of surgery, partial or complete tumor resection can be combined with the compounds of the present invention. As just one example of radiation therapy, external beam radiation therapy can be combined with the compounds of the present invention. In their role as adjuvants, the present compounds and compositions can, in some embodiments, be used as adjuvants in therapeutic or preventive strategies that use vaccines. Thus, the compounds of the present invention or their salts can be used with one or more vaccines selected to stimulate an immune response to one or more predetermined antigens. The compounds of the present invention or their salts can be provided together with or in addition to such vaccines.

[0084] Such vaccines may include inactivated or attenuated bacteria or viruses containing the antigen of interest, purified antigen, live viral or bacterial delivery vectors engineered to express and / or secrete the antigen, antigen-presenting cell (APC) vectors comprising cells loaded with the antigen or transfected with a composition comprising a nucleic acid encoding the antigen, liposomal antigen delivery vehicles, or naked nucleic acid vectors encoding the antigen. This list is not limiting. By way of example, such vaccines may also include inactivated tumor cells or oncolytic viruses that express and secrete one or more of the following cytokines: GM-CSF, CCL20, CCL3, IL-12p70, FLT-3 ligand.

[0085] Thus, the present invention relates to compounds of general formula (I) for use as a medicament or vaccine adjuvant. In another aspect, the present invention provides novel compounds of formula (I), including salts thereof, for use in methods of treating diseases or conditions associated with or modulated by STING. In another aspect, the present invention provides new compounds of formula (I) or salts thereof for treating inflammatory, allergic or autoimmune diseases, such as allergic rhinitis or asthma, for treating infectious diseases or cancer, or for use as vaccine adjuvants.

[0086] Furthermore, the present invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of diseases and / or conditions associated with or modulated by STING. Diseases and conditions associated with or modulated by STING include, but are not limited to, inflammatory, allergic, or autoimmune diseases, such as allergic rhinitis or asthma, infectious diseases, or cancer, including but not limited to the specific diseases mentioned above. Furthermore, due to their activity, the compounds of the present invention are suitable as vaccine adjuvants, including but not limited to the specific applications mentioned above. Thus, the present invention relates to compounds of general formula (I) for use as a medicament or vaccine adjuvant.

[0087] Furthermore, the present invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of the above-mentioned diseases and conditions. In another aspect, the present invention relates to compounds of general formula (I) for use in the treatment and / or prevention of the above mentioned diseases and conditions. In another aspect, the present invention relates to compounds of general formula (I) for use in the treatment and / or prevention of the above mentioned cancers, before or after tumor resection and / or radiotherapy. In another aspect, the present invention relates to the use of compounds of general formula (I) for preparing a medicament for the treatment and / or prevention of the above mentioned diseases and conditions. In another aspect, the present invention relates to a method for the treatment or prevention of the above-mentioned diseases and conditions, comprising the step of administering to a human an effective amount of a compound of general formula (I). The daily dosage range of the compound of general formula (I) applicable is usually 0.00001 to 100 mg per kg of patient body weight, for example 0.00001 to 10 mg per kg of body weight. Each dosage unit may conveniently contain 0.001 to 1000 mg, for example 0.001 to 100 mg.

[0088] The actual therapeutically effective amount or therapeutic dose will, of course, depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease, etc. In any event, the compound or composition will be administered in a variety of dosages and in a form that will deliver a therapeutically effective amount based on the patient's unique condition. In a related aspect, the invention relates to methods of inducing, stimulating, or adjuvanting an immune response in an individual, the methods comprising administering to the individual a compound of the invention. In another aspect, the present invention provides the use of a compound of general formula (I) for the preparation of an immunogenic composition comprising an antigen or antigenic composition for the treatment or prevention of a disease.

[0089] In another aspect, the present invention provides a method of treating or preventing a disease, the method comprising administering to a human subject suffering from or susceptible to the disease an immunogenic composition comprising an antigen or antigenic composition and a compound of general formula (I). In another aspect, the present invention provides a vaccine composition comprising an antigen or antigen composition and a compound of general formula (I) for use in the treatment or prevention of disease. In another aspect, the present invention provides the use of a compound of general formula (I) for the manufacture of a vaccine composition comprising an antigen or antigen composition for the treatment or prevention of a disease. In another aspect, the present invention provides a method for treating or preventing a disease, the method comprising administering to a human subject suffering from or susceptible to the disease a vaccine composition comprising an antigen or antigen composition and a compound of general formula (I).

[0090] Pharmaceutical Composition In another aspect of the present invention, it is understood that pharmaceutical compositions of the compounds can be formulated suitable for administering a therapeutically effective amount of the compounds. Suitable preparations for administering the compounds of formula (I) will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, oral solutions, syrups, elixirs, sachets, injection solutions (subcutaneous, intravenous, intramuscular, intraperitoneal, intratumoral, and peritumoral), inhalants, infusions, elixirs, emulsions, and powders. Furthermore, the compounds according to the present invention can be administered via targeted delivery platforms, for example, such targeted delivery platforms can be antibody-drug conjugates, nanobody-drug conjugates, peptide-drug conjugates, virus-like particles, or nanoparticle formulations. Suitable tablets can be obtained, for example, by mixing one or more compounds according to formula I with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants.

[0091] In the present disclosure, the pharmaceutical compositions can be administered by various means, including oral, parenteral, inhalation spray, topical, nasal, oral, or rectal administration, as formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles. The pharmaceutical compositions of the present disclosure can be administered in the form of sterile injectable preparations, such as sterile aqueous or oily injectable suspensions. According to another embodiment, there is provided a vaccine comprising one or more compounds of general formula (I). In another aspect, the present invention provides a vaccine adjuvant comprising a compound of general formula (I). In another aspect, the present invention provides an immunogenic composition comprising an antigen or antigen composition and a compound of general formula (I). In another aspect, the present invention provides an immunogenic composition comprising an antigen or antigenic composition and a compound of general formula (I) for use in the treatment or prevention of disease.

[0092] Combination Therapy The compounds of the present invention may be used alone or in combination with a pharmaceutically acceptable excipient in an amount sufficient to induce, modify, or stimulate an appropriate immune response, which may include, but is not limited to, a specific immune response, a non-specific immune response, both specific and non-specific responses, an innate response, a primary immune response, adaptive immunity, a secondary immune response, a memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression. In some embodiments, the compounds described herein and compositions thereof are administered in conjunction with one or more additional compositions, including vaccines intended to stimulate an immune response to one or more predetermined antigens; adjuvants; CTLA-4 and PD-1 pathway antagonists, lipids, liposomes, chemotherapeutic agents, immunomodulatory cell lines, cancer-targeting agents, immunogenic cell death inducers, immunomodulatory agents, which can be understood generally as activation-modulatory agents, and agents that modulate and / or increase the frequency of certain immune cell subtypes. The compounds described herein and compositions thereof can be administered before, after, and / or simultaneously with additional therapeutic or prophylactic compositions or modalities.

[0093] The compounds, compositions according to the present invention, including any combination with one or more additional therapeutic agents, can be administered via mucosal (e.g., oral, sublingual, intravaginal, nasal, cervical, etc.), intratumoral, intraperitoneal, peritumoral, transdermal, inhalation, or parenteral (e.g., subcutaneous, intravenous, intramuscular, intraarterial, intradermal, intrathecal, and epidural administration) routes. Furthermore, the compounds, compositions according to the present invention, including any combination with one or more additional therapeutic agents, can be administered via a targeted delivery platform, for example, such a targeted delivery platform can be an antibody-drug conjugate, a nanobody-drug conjugate, a peptide-drug conjugate, a virus-like particle, or a nanoparticle.

[0094] Among the possible administration methods, intraperitoneal, intratumoral, peritumoral, subcutaneous, inhalation, or intravenous administration is preferred. The compounds and compositions of the present invention can also be administered before, after, and / or simultaneously by a combination of various administration methods, including any combination with one or more additional therapeutic agents. By way of example only, inhalation or intravenous administration can be followed by intratumoral or peritumoral administration, or intratumoral or peritumoral administration can be followed by inhalation or intravenous administration. Additionally, such administration of the compounds via various routes can occur before or after an additional therapeutic step, such as tumor resection or radiation therapy. By way of example only, the compounds of the present invention can be administered after radiation therapy. Furthermore, the compounds of the present invention can be administered by intravenous administration after radiation therapy. Furthermore, the compounds of the present invention can be administered by intravenous administration after tumor resection. Furthermore, the compounds of the present invention can be administered by intratumoral administration after radiation therapy. Furthermore, the compounds of the present invention can be administered by peritumoral administration after radiation therapy. Furthermore, the compounds of the present invention can be administered by inhalation administration after tumor resection. Furthermore, the compounds of the present invention can be administered by intravenous administration followed by intratumoral administration, both of which occur after radiation therapy. Additionally, the compounds of the present invention can be administered by intratumoral administration followed by intravenous administration, both of which occur after radiation therapy. Additionally, the compounds of the present invention can be administered by intravenous administration followed by peritumoral administration, both of which occur after radiation therapy. Additionally, the compounds of the present invention can be administered by peritumoral administration followed by intravenous administration, both of which occur after radiation therapy.

[0095] Methods for co-administration with additional therapeutic agents are well known in the art. Because of the adjuvant properties of the compounds of the present invention, their use may also be combined with other therapeutic modalities, including other vaccines, adjuvants, antigens, antibodies, and immunomodulators. In addition to the compounds of the invention and compositions thereof described herein, the compositions or methods of the invention may further comprise one or more additional substances that, by their nature, can act to stimulate or otherwise harness the immune system to respond to cancer antigens present on target tumor cells.

[0096] The compounds of the present invention can be used in combination with an immune checkpoint inhibitor, such as an immune checkpoint inhibitor selected from the group consisting of a CTLA-4 pathway antagonist, a PD-1 pathway antagonist, a Tim-3 pathway antagonist, a Vista pathway antagonist, a BTLA pathway antagonist, a LAG-3 pathway antagonist, or a TIGIT pathway antagonist.

[0097] The compounds of the invention can be used in combination with immuno-oncological agonists, in combination with T cell receptor agonists, or in combination with TNF receptor superfamily agonists or antagonists. The compounds of the invention can be used in combination with therapeutic antibodies or therapeutic nanobodies. In some embodiments, the mechanism of action of therapeutic antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC).

[0098] In additional embodiments of the methods described herein, the compounds of the present invention are used in combination with chemotherapeutic agents known to those skilled in the art (e.g., small molecule pharmaceutical compounds). Accordingly, the methods further include administering to the subject an effective amount of one or more chemotherapeutic agents as an additional or combined treatment. Additional pharmacologically active substances that may also be used together / in combination with the compounds of formula (I) or pharmaceutically acceptable salts thereof (including any individual embodiment or general subset of compound (I)), or in the medical uses, methods of use, treatment and / or prevention disclosed herein (above and below), include hormones, hormone analogs, and antihormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, phenytoin ... gesterone, octreotide); aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane); LHRH agonists and antagonists (e.g., goserelin acetate, luprolide); inhibitors of growth factors and / or their corresponding receptors (growth factors are, for example, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4)) and / or their corresponding receptors;Inhibitors include, for example, (anti) growth factor antibodies, (anti) growth factor receptor antibodies, and tyrosine kinase inhibitors, such as afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, olmutinib, osimertinib, almonertinib, nazartinib, lazertinib, pelitinib, erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340, necitumumab, panitumumab, cetuximab, amivantanab, pertuzumab, trastuzumab, trastuzumab emtansine, or inhibitors of mutated EGFR, inhibitors of HER2 with exon 20 mutations, and hepatocyte growth factor (HGF, c-MET, e.g., emibetuzumab, amivantanab, savolitinib, cabozantinib, foretinib); antimetabolites (e.g., methotrexate, raltitrexed, 5-fluorouracil (5-FU), capecitabine, floxuridine, gemcitabine, mercaptopurine, thioguanine, cladribine, pentostatin, cytarabine (arabine) C), fludarabine, a combination of trifluridine and tipiracil (=TAS102)); antitumor antibiotics (e.g., doxorubicin, Doxil (pegylated liposomal doxorubicin hydrochloride), Myoset (non-pegylated liposomal doxorubicin), anthracyclines such as daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkyl anti-mitotic agents (e.g., estramustine, meclorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); anti-mitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine, vinorelbine, and vincristine; and taxanes such as paclitaxel, docetaxel, nab-paclitaxel (Abraxane));Angiogenesis inhibitors (e.g., tasquinimod, bevacizumab), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone); serine / threonine kinase inhibitors (e.g., PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, torin1, dactosilib, GDC-0349, vs-5584; bistusertib; AZD8055), mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors (e.g., alpelisib, selavelisib, GDC-0077, HH-CYH33, AMG 511, buparlisib, dactosilib, pictilisib, taselisib), dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600), Aurora kinase inhibitors; tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors); protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimetics, MCL-1 (e.g., AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477), MDM2, MDM2 / MDMX); MEK inhibitors (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib); SOS1 inhibitors (i.e. compounds which regulate / inhibit the GEF functionality of SOS1, for example by binding to SOS1 and interfering with the protein-protein interaction between SOS1 and (mutated) Ras proteins, for example KRAS; e.g. BAY-293), inhibitors of GDP- or GTP-loaded RAS and / or any mutants thereof (i.e. compounds which regulate / inhibit the functionality of (mutated) RAS proteins, for example by binding to GDP- or GTP-loaded (mutated) RAS proteins, for example KRAS, NRAS and / or HRAS, preferably KRAS);Irreversible inhibitors of KRAS G12C (AMG-510, MRTX849, ARS-324, GDC-6036); reversible or irreversible binders of GDP-loaded (mutant) KRAS; reversible or irreversible binders of GTP-loaded (mutant) KRAS; ALK inhibitors (e.g., crizotinib, alectinib, entrectinib, brigatinib, ceritinib); ERK inhibitors; FLT3 inhibitors; BRD4 inhibitors; IGF-1R inhibitors; TRAILR2 agonists; Bcl-xL inhibitors; Bcl-2 inhibitors (e.g., venetoclax, obatoclax, navitoclax, oblimersen); Bcl-2 / Bcl-xL inhibitors; ErbB Receptor inhibitors; BCR-ABL inhibitors; ABL inhibitors; Src inhibitors (e.g., dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU 6656, WH-4-023; rapamycin analogues (e.g., everolimus, temsirolimus, ridaforolimus, sirolimus); androgen synthesis inhibitors; androgen receptor inhibitors; DNMT inhibitors; HDAC inhibitors; ANG1 / 2 inhibitors; histone deacetylase inhibitors; inhibitors of IL6; inhibitors of JAK and / or any mutants thereof; inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutants thereof (encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (= WO 2014 / 15161 No. 6, Example 131), LXH254, sorafenib, LY-3009120 (= Example 1 of WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265); inhibitors of receptor tyrosine kinases (RTKs) and / or any of their mutants; inhibitors of SHP2 and / or any of its mutants (e.g., SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909); CYP17 inhibitors; radiopharmaceuticals; proteasome inhibitors (e.g., carfilzomib);Immunotherapeutic agents such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, SIRPα antibodies, and TIM3-binding molecules / immunoglobulins (ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab) ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies); T cell engagers, such as PSMA×CD3, B7H6 / CD3 (e.g., as disclosed in WO 2021 / 064137), DLL3 / CD3 (e.g., as disclosed in WO 2021 / 064137), Examples of suitable anti-cancer agents include, but are not limited to, bispecific T cell engagers (BiTE®), such as CD3×BCMA, CD3×CD33, and CD3×CD19 (disclosed in International Publication No. 2019 / 234220), cancer vaccines, MDM2 inhibitors, oncolytic viruses, and various chemotherapeutic agents, such as amifostine, anagrelide, clodronate, filgrastim, interferon, interferon α, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer. The compounds of the present invention can be used in combination with OX40 agonists, ICOS-ligands, CD27 agonists, GITR agonists, and Toll-like receptor agonists.

[0099] In a preferred embodiment, additional pharmacologically active substances that may also be used together / in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments or general subsets of compound (I)), or in the medical uses, methods of use, treatment and / or prevention disclosed herein (above and below), include checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab, sintilimab, camrilizumab, cefotaxime ... These include izumab, toripalimab, tislelizumab), taxanes (paclitaxel, docetaxel, nab-paclitaxel (Abraxane)), T cell engagers, such as PSMAxCD3, B7H6 / CD3 (disclosed, for example, in WO 2021 / 604137), DLL3 / CD3 (disclosed, for example, in WO 2019 / 234220), bispecific T cell engagers (BiTE®), such as CD3xBCMA, CD3xCD33, CD3xCD19, cancer vaccines, MDM2 inhibitors, and oncolytic viruses.

[0100] In additional embodiments of the methods described herein, the compounds of the present invention are used in combination with chemotherapeutic agents and / or additional agents, such as cancer-targeting therapeutic agents, to treat the indications described in the methods herein. Accordingly, the methods further comprise administering to the subject an effective amount of one or more cancer-targeting agents as an additional or combined treatment.

[0101] In additional embodiments of the methods described herein, the compounds of the invention are used in combination with chemotherapeutic agents and / or additional agents, and / or additional therapies such as radiation therapy and / or tumor resection to treat the indications described in the methods herein. In yet another aspect, the present invention relates to a method of treating a disease or condition associated with or modulated by STING in a patient, comprising administering to a human patient in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described above. The use of the compounds according to the invention in combination with an additional therapeutic agent may be simultaneous or staggered.

[0102] The compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, or may be present separately in two identical or different formulations, for example as a so-called kit of parts. Therefore, in another aspect, the present invention provides a combination comprising a compound of general formula (I) and at least one further therapeutic agent. Another aspect of the present invention is to provide pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more of at least one additional therapeutic agent and a pharmaceutically acceptable excipient. In another aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent for use in therapy.

[0103] In another aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent for use in the treatment of a disease or condition in which modulation of STING is beneficial. In another aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent for use in the treatment of inflammation, allergic and autoimmune diseases, infectious diseases, and cancer. In another aspect, the present invention provides a method of treating a disease or condition in a patient where modulation of STING is beneficial, comprising the step of administering a therapeutically effective amount of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent. In another aspect, the present invention provides a method of treating inflammation, an allergic or autoimmune disease, an infectious disease, or cancer in a patient, comprising the step of administering a therapeutically effective amount of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent.

[0104] The actual pharmaceutically effective amount or therapeutic dose will, of course, depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease, etc. In all cases, the combinations will be administered in various dosages and in a form that will deliver a pharmaceutically effective amount based on the patient's unique condition.

[0105] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention and one or more additional therapeutic agents described above and below, optionally together with one or more inert carriers and / or diluents.

[0106] Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention.

[0107] chemical synthesis List of abbreviations: [Table 1]

[0108] Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention without limiting its scope.

[0109] General Unless otherwise stated, all reactions are carried out on commercially available equipment using methods commonly used in chemical laboratories. Air- and / or moisture-sensitive starting materials are stored under protective gas, and the corresponding reactions and manipulations with them are carried out under protective gas (nitrogen or argon).

[0110] The compounds according to the present invention are named in accordance with the IUPAC guidelines. When a compound is represented by both a structural formula and its nomenclature, the structural formula takes precedence in case of conflict.

[0111] <Chromatography> Thin layer chromatography is carried out on pre-made TLC plates coated with silica gel 60 on glass (using fluorescent indicator F-254) manufactured by Merck. For preparative NP chromatography, a Biotage Isolera Four apparatus is used together with an Interchim Puri Flash column (50 μm, 12 - 300 g) or a glass column packed with silica gel (Granula Silica Si-60A 35 - 70 μm) manufactured by Millipore. Preparative RP HPLC is carried out using columns manufactured by Waters (Sunfire C18, 10 μm, 30×100 mm Part. No. 186003971 or X-Bridge C18, 10 μm, 30×100 mm Part. No. 186003930). The compounds are eluted using various gradients of H2O / acetonitrile or H2O / MeOH with 0.2% HCOOH added to water, or various gradients using a basic aqueous buffer (1 L of water contains 5 mL of ammonium bicarbonate solution (158 g per 1 L of H2O) and 2 mL of ammonia (7 mol / MeOH solution 1 l)) instead of the water-HCOOH mixture. HPLC (reaction monitoring) for the analysis of intermediate compounds is carried out using columns manufactured by Waters and Phenomenex. In each case, the analytical instrument is equipped with a mass detector.

[0112] <HPLC Mass Spectrometry / UV Spectroscopy> Retention time / MS-ESI characterizing the example compounds according to the present invention +is determined using, for example, an HPLC-MS device (high performance liquid chromatography with a mass detector) manufactured by Agilent. The retention time tR is set to 0 for the compound eluting in the injection peak.

[0113] <Analytical HPLC method (AM)> <Method_1> HPLC: Agilent 1100 / 1200 series MS: Agilent LC / MSD SL Column: Waters X-Bridge BEH C18, 2.5 μm, 2.1 × 30 mm XP Eluent: A: 5mM NH4HCO3 / 19mM NH3 in H2O; B: ACN (HPLC grade) Detection: MS: positive and negative mode Mass range: 100-800 m / z Flow rate: 1.4ml / min Column temperature: 45℃ Gradient: 0.00-0.01 min: 5% B 0.01~1.00 minutes: 5%→100% B 1.00~1.37 minutes: 100% B 1.37~1.40 minutes: 100%→5% B

[0114] <Method_2> HPLC: Agilent 1100 / 1200 series MS: Agilent LC / MSD (API-ES+ / - 3000 V, Quadrupol, G6140) Column: Waters, XBridge C18, 2.5 μm, 2.1 × 20 mm column Solvent: A: 20mM NH4HCO3 / NH3pH 9 in H2O; B: ACN (HPLC grade) Detection: MS: positive and negative mode Mass range: 120-900 m / z Flow rate: 1.00mL / min Column temperature: 60℃ Gradient: 0.00-1.50 min: 10% → 95% B 1.50~2.00 minutes: 95% B 2.00~2.10 minutes: 95%→10% B

[0115] <Method_3> UPLC / MS: Waters Acquity-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm Solvent: A: 0.07% HCOOH in ACN; B: H2O+0.07% HCOOH Detection: MS: positive and negative mode Mass range: 100-1500 m / z Flow rate: 0.6mL / min Column temperature: 35℃ Gradient: 0.00-0.30 min: 97% B 0.30~2.20 minutes: 97%→2% B 2.20~3.30 minutes: 2% B 3.30~4.50 minutes: 2% B→97% B 4.50~4.51 minutes: 97% B

[0116] <Method_4> UPLC / MS: Waters Acquity-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm Solvent: A: H2O+0.07% HCOOH B: 0.07% HCOOH in ACN Detection: MS: positive and negative mode Mass range: 100-1500 m / z Flow rate: 0.6mL / min Column temperature: 35℃ Gradient: 0.00-0.30 min: 97% A 0.30~2.70 min: 97%→2% A 2.70-3.50 min: 2% A 3.50~3.51 min: 2%→97% A

[0117] <Method_5> UPLC / MS: Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm Solvent: A: 0.07% HCOOH in ACN; B: H2O+0.07% HCOOH Detection: MS: positive and negative mode Mass range: 100-1500 m / z Flow rate: 0.6mL / min Column temperature: 35℃ Gradient: 0.00-0.40 min: 97% B 0.40~2.50 minutes: 97%→2% B 2.50~3.40 minutes: 2% B 3.40~3.50 minutes: 2% B→97% B 3.50~4.51 minutes: 97% B

[0118] Preparation of compounds according to the invention The compounds according to the present invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the literature of organic synthesis. These methods are intended to illustrate the present invention, and the scope of its subject matter and the claimed compounds is not limited to these examples. Preferably, the compounds are obtained in a manner similar to the preparation methods described more fully below, in particular the preparation methods described in the experimental section. In some cases, the order in which the reaction steps are carried out may be changed. Variations of the reaction methods known to those skilled in the art but not described in detail here can also be used.

[0119] General methods for preparing compounds according to the invention will be apparent to those skilled in the art upon studying the following schemes. Starting materials can be prepared by methods described in the literature or herein, or can be prepared in a similar or analogous manner. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved again at a suitable stage in the reaction sequence using methods well known to those skilled in the art.

[0120] One method for preparing compounds of formula (I) is illustrated in Scheme I: Indazole B can be synthesized from ortho-methylaniline derivative A. Subsequent iodination yields 3-iodo-indazole C. Intermediate D can be obtained by, for example, a Chan-Lam coupling utilizing (6-fluoropyridin-3-yl)boronic acid. Conversion to intermediate E can be achieved, for example, via Suzuki coupling. Compound F is synthesized, for example, by aromatic nucleophilic substitution. The product is isolated by conventional means and preferably purified by chromatography.

[0121] Scheme I: [ka]

[0122] Preparation of Intermediate B B1) 7-Bromo-6-fluoro-1H-indazole [ka] To a stirred mixture of 2-bromo-3-fluoro-6-methyl-phenylamine (11 g, 53.9 mmol) and toluene (176 ml) is added potassium acetate (6.35 g, 64.7 mmol). After 30 min at room temperature, acetic acid (9.7 g, 161.7 mmol) is added and the mixture is heated to 40 °C. tert-Butyl nitrite (11.11 g, 107.8 mmol) is added and stirring is continued for 6 h. Water (150 ml) is added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. 7-Bromo-6-fluoro-1H-indazole is purified by NP chromatography. Yield: 5 g (43%). HPLC-MS: M+H=215 / 217; tR=1.89 min (Method_3)

[0123] The following intermediates are prepared in a similar manner from the corresponding substituted anilines: [Table 2]

[0124] B5) 5-chloro-7-methyl-1H-indazole [ka] To a stirred mixture of 4-chloro-2,6-dimethyl-phenylamine (5 g, 32 mmol) in acetic acid (60 ml) at 15° C., sodium nitrite (2.44 g, 35 mmol) in water (30 ml) is added. The mixture is stirred at room temperature for 19 hours. The mixture is poured into water and extracted with EtOAc. The combined organic layers are dried over Na2SO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 2.6 g (49%). HPLC-MS: M+H=167; tR=1.76 min (Method_4).

[0125] B6) 6-Fluoro-7-methyl-1H-indazole [ka] A mixture of 7-bromo-6-fluoro-1H-indazole B1 (5 g, 23.25 mmol), potassium carbonate (12.9 g, 93 mmol), trimethylboroxine (50% in THF, 23.4 g, 93 mmol), tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol), and DMF (50 ml) is stirred at 120 °C for 48 h under an argon atmosphere. At room temperature, water (100 ml) is added and the mixture is extracted with EtOAc. The combined organic layers are dried over Na2SO4, concentrated in vacuo, and the product is purified by NP HPLC. Yield: 2.4 g (69%). HPLC-MS: M+H = 151; tR = 1.58 min (Method_5).

[0126] The following intermediates are prepared in a similar manner from B3: [Table 3]

[0127] Preparation of Intermediate C C1) 6-Fluoro-3-iodo-7-methyl-1H-indazole [ka] To 6-fluoro-7-methyl-1H-indazole B6 (3 g, 20 mmol) in DMF (35 ml) at 0° C., iodine (10.1 g, 40 mmol) and K2CO3 (8.3 g, 60 mmol) are added. The mixture is stirred at room temperature for 12 h. Under ice cooling, the mixture is poured into a 10% aqueous solution of Na2SO3. The precipitate is filtered, washed with water and dried. The product is purified by NP chromatography. Yield: 4 g (73%). HPLC-MS: M+H=2.77; tR=1.90 min (Method_5).

[0128] The following intermediates are prepared in a similar manner from the corresponding intermediate B: [Table 4]

[0129] Preparation of Intermediate D D1) 6-Fluoro-1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole [ka] A mixture of 6-fluoro-3-iodo-7-methyl-1H-indazole C1 (4 g, 14.5 mmol), (6-fluoropyridin-3-yl)boronic acid (4.08 g, 29 mmol), copper(II) acetate (3.95 g, 21.75 mmol), and pyridine (3.5 ml, 43.5 mmol) in DCM (40 ml) is stirred at room temperature for 16 hours while exposed to air. The mixture is concentrated in vacuo, and the product is purified by NP chromatography. Yield: 2.5 g (47%). HPLC-MS: M+H=372; tR=2.45 min (Method_3).

[0130] The following intermediates are prepared in a similar manner from the corresponding 3-iodo-indazole (Intermediate C): [Table 5]

[0131] Preparation of Intermediate E E1) 6-fluoro-1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biindazole [ka] A mixture of 6-fluoro-1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole D1 (2.5 g, 6.7 mmol), 2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (2.1 g, 8.1 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.28 g, 0.34 mmol), and K2CO3 (1.6 g, 20.2 mmol) in dioxane (20 ml) and water (5 ml) is stirred at 100 °C for 6 hours under an argon atmosphere. At room temperature, water (100 ml) is added, and the mixture is extracted with EtOAc. The combined organic layers are dried over MgSO4, concentrated in vacuo, and the product is purified by NP HPLC. Yield: 1.2 g (48%). HPLC-MS: M+H=376; tR=2.15 min (Method_5).

[0132] The following intermediates are prepared in a similar manner from the corresponding intermediate D: [Table 6] [Example]

[0133] The following section describes one method for preparing Examples #1-#13 and Intermediate F:

[0134] F1) Ethyl 1-(5-(6-fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperidine-4-carboxylate [ka] A mixture of 6-fluoro-1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biindazole E1 (250 mg, 670 μmol), ethyl piperidine-4-carboxylate (520 mg, 3.3 mmol), and DIPEA (110 μl, 650 mmol) in DMSO (1 ml) is stirred at 110 °C for 16 h. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over MgSO and concentrated in vacuo. The title compound is purified by RP chromatography. Yield: 248 mg (73%). HPLC-MS: M+H=513; tR=1.62 min (Method_2).

[0135] The following intermediates F2-F14 are prepared in the same manner as intermediates E to F1 using the corresponding amine. In the case of the salt of the amine (e.g., the hydrochloride salt), an additional equivalent of base is used in each case. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0136] The following Examples #1-#2 are prepared in the same manner as Intermediates E-F1, utilizing the corresponding amine. In the case of the salt of the amine (e.g., the hydrochloride salt), an additional equivalent of base is used, respectively. [Table 8]

[0137] Preparation of intermediate F15: F15) 5-Fluoro-2',7-dimethyl-1-(6-(piperazin-1-yl)pyridin-3-yl)-1H,2'H-3,4'-biindazole [ka] Tert-butyl 4-(5-(5-fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperazine-1-carboxylate F14 (39 mg, 72 μmol) is stirred with TFA (400 μl) in DCM (2 ml) at room temperature for 16 hours. Toluene (10 ml) is added, the mixture is concentrated in vacuo, and the crude product (32 mg) is used directly in the next step without further purification.

[0138] Preparation of Example #3: #3) 4-(5-(5-fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperazine-1-carbaldehyde [ka] A mixture of crude 5-fluoro-2',7-dimethyl-1-(6-(piperazin-1-yl)pyridin-3-yl)-1H,2'H-3,4'-biindazole F15 (32 mg, 72 μmol) and N-formylsaccharin (23.4 mg, 109 μmol) in THF (200 μl) is stirred at room temperature for 16 hours. The mixture is concentrated in vacuo and the product is purified by RP chromatography. Yield: 16 mg (47%). HPLC-MS: M+H=470; tR=1.32 min (Method_2).

[0139] Preparation of Examples #4 to #13: #4) 1-(5-(5-fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperidine-4-carboxylic acid [ka] To ethyl 1-(5-(5-fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperidine-4-carboxylate F7 (350 mg, 690 μmol) are added THF (7 ml), water (7 ml), and KOH (390 mg; 6.9 mmol). The mixture is stirred at room temperature for 3 hours. After neutralization with 1N aqueous HCl, the mixture is extracted with DCM. The combined organic layers are dried over MgSO4, concentrated in vacuo, and the product is purified by RP HPLC. Yield: 163 mg (49%). HPLC-MS: M+H=485; tR=1.06 min (Method_2).

[0140] The following examples can be prepared in a similar manner from the corresponding ethyl or methyl esters F1-F6 and F9-F13: [Table 9-1] [Table 9-2] [Table 9-3]

[0141] Pharmacological activity Interaction with hSTING determined by differential scanning fluorimetry (DSF) In DSF, the temperature at which a protein unfolds, also called the melting temperature, Tm, is measured by the change in fluorescence of a dye that binds to the hydrophobic portion of the protein. m The shift correlates with the binding affinity of this small molecule. The target protein was human STING (hSTING, UNIPROT entry Q86WV6, residues 155-341, MW: 21578.4 Da; protein stock solution: c = 1302 μM stock solution in 20 mM Tris, 100 mM NaCl, 2 mM TCEP (pH 8.8)). The assay buffer was 20 mM Tris, 150 mM NaCl (pH 7.5), supplemented as needed. Final concentrations of components in the assay: 100 μM test compound, 5 μM target protein, "5x" SYPR Orange (from stock solution SYPRO Orange solution in DMSO (Invitrogen Cat. No. S6650-500ul), concentration "5000x").

[0142] Assay Procedure: 1) Dilutions of compound stock solutions (10 mM in DMSO) were prepared in assay buffer (20 mM Tris, 150 mM NaCl; pH 7.5). 2) 5 μl of fluorescent dye stock solution (5000× SYPRO Orange in DMSO) was mixed with 19 μl of target protein (1302 μM) and 976 μl of assay buffer. 3) 2 μl of this protein-dye-mixture (25× SYPRO Orange and 25 μM protein) was added to 8 μl of the diluted compound solution prepared in step 1. The final volume was 10 μl. 4) For every 20 compounds, two negative controls were measured. 5) A plate was prepared for duplicate measurements and centrifuged at 1000 g for 2 minutes. 6) Measurements were performed using a CFX384 Real-Time System (Bio-Rad Laboratories). The procedure consisted of 140 cycles at 0.5°C / cycle (temperature ramp 15 seconds / cycle, from 25°C to 95°C). Data analysis: Melting curves were processed with Bio-Rad CFX Manager. Peak type was set to "negative." Duplicate TM (melting temperature) measurements were averaged and standard deviations were calculated.

[0143] The changes in TM ("thermal shifts") are shown in Table 1. [Table 10]

[0144] In vitro cytokine induction measured via activation of an interferon regulatory factor-inducible reporter gene The cytokine-inducing activity of the compounds of the present invention was demonstrated by using a THP1 reporter cell line, which provided cellular EC50 values. Activation of the STING protein expressed in the cell line increases interferon production. Stable integration of an interferon regulatory factor (IRF)-inducible SEAP gene (secreted embryonic alkaline phosphatase) reporter construct allows for monitoring of a functional interferon signaling pathway. SEAP activity can be detected and quantified using Invivogen's THP1-Blue™ ISG colorimetric enzyme assay and a suitable optical density (OD) reader. This technique can be used to characterize pharmacological alterations of the STING pathway.

[0145] Several single-nucleotide polymorphisms were identified in the human STING gene. To determine the activity of the above compounds, THP1-Blue™ ISG reporter cell lines expressing different human STING variants were generated. To do so, endogenous human STING was first deleted using the CRISPR / CAS9 system. THP1-Blue ISG cells were electroporated with an ALL-IN-ONE CRISPR plasmid targeting the STING gene (purchased from Sigma, encoding a reporter gene gRNA and GFP for successful transfection). GFP-positive cells were then selected and expanded 24 hours after transfection. The cells were then dispersed in semi-solid methocel medium to allow for single-cell clonal isolation. Clones were then screened for cGAMP responsiveness using the Quanti-Blue™ reporter assay. Non-responsive clones were subsequently analyzed for STING loss by Western blotting and sequencing of the STING locus.

[0146] For overexpression of human STING variants, confirmed THP1-Blue™ ISG hSTING KO clones were transduced with individual retroviral plasmids (MSCV-ires-GFP-Blasti) encoding hSTING allelic variants (WT (H232R), HAQ, R232H, AQ, and R293Q). Transduced cells were sorted by varying GFP fluorescence levels, and STING allele expression was analyzed by Western blot. From the parental unmodified THP1-Blue ISG cell line, populations expressing ectopic STING protein (WT, HAQ, R232H, AQ, and R293Q) at levels comparable to endogenous STING levels were selected and used for compound characterization. SEAP activity was measured in THP1-Blue™ ISG cells stably expressing different human STING isoforms and an IRF-inducible SEAP reporter construct. Cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, 50 μg / ml penicillin-streptomycin, 100 μg / ml Zeocin, and 100 μg / ml Normocin in an incubator at 37°C with 95% humidity and 5% CO2.

[0147] In preparation for the assay, cells were distributed in assay plates at a density of 10,000 cells / 15 μL per well. Compounds were prepared by eight-point serial dilution in 50% aqueous DMSO with a final dilution step into medium to ensure a final DMSO concentration of 0.5% in the assay. Five μL of diluted compound was added to the plate, followed by incubation at 37° C. for 24 hours. On the day of the assay, 75 μl per well of Quanti-Blue™ reagent was added to all wells of the plate and the plate was incubated for another 30 minutes at 37° C. The OD at 620 nm was measured with an EnVision reader (PerkinElmer). EC 50Values ​​and Hill slopes were derived from an eight-point, four-parametric nonlinear curve fit with Megalab software (Boehringer Ingelheim) using the OD at 620 nM.

[0148] EC 50 Value data can be seen in Tables 2a-2e. STING HAQ-variant EC 50 Value data can be found in Table 2a. The data presented below are from the parental THP1-Blue™ ISG cell line (which endogenously expresses HAQ) or genetically engineered THP1-Blue™ ISG cell lines in which the original STING was knocked out and the HAQ-specific STING isoform was reintroduced as described above.

[0149] STING HAQ-variant EC 50 The value data can be seen in Table 2a: [Table 11]

[0150] STING H232R-variant EC 50 Value data can be seen in Table 2b: [Table 12]

[0151] STING R232H-Variant EC 50 The value data can be seen in Table 2c: [Table 13]

[0152] STING R293Q-variant EC 50 The value data can be seen in Table 2d: [Table 14]

[0153] STING AQ-variant EC 50 The value data can be seen in Table 2e: [Table 15]

[0154] Cell permeability measurement Caco-2 cells were obtained from the Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany) and cultured in Dulbecco's modified Eagle's medium (DMEM) containing (final concentrations) 10% fetal calf serum (FCS), 1% non-essential amino acids (NEAA), 2 mM glutamine, 100 U / mL penicillin, and 100 μg / mL streptomycin. Caco-2 cells were plated at 160,000 cells / cm2 in 24-well Transwell inserts (Corning, #3379) for the bidirectional permeability assay. 2 The cells were seeded at a density of 1000 and cultured for 3 weeks with the medium changed every 2 days.

[0155] For bidirectional permeability assays, 10 mM DMSO stock solutions were diluted in transport buffer containing 0.25% bovine serum albumin (final concentrations: 128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO, 1.8 mM CaCl, 4.17 mM NaHCO, 1.19 mM NaHPO, 0.41 mM NaHPO, 15 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), 20 mM glucose, pH 7.4) to a final concentration of 10 μM and added to the apical or basolateral compartment. Cells were incubated with compounds for up to 2 hours. Samples from the opposite compartment were collected at different time points.

[0156] Compound concentrations in compartments were quantified using a RapidFire-based high-throughput HPLC / MS / MS system (high-performance liquid chromatography / mass spectrometry; BioCius) customized into a fully automated, flexible platform called RIAS. In this modified instrument, the sample was drawn into a 10 μL sample loop by a vacuum pump for 250 ms, and then passed through a C4 cartridge (3.8 μL total volume; BioCius) with an aqueous mobile phase (99.9% water, 0.09% formic acid, and 0.01% TFA; flow rate 1.5 mL / min). Prior to bioanalysis, the sample was spiked with an internal standard solution and diluted with acetonitrile (ACN) for protein precipitation. Measurements were performed in multiple reaction monitoring (MRM) mode. Quantitation was performed using external calibration. A solid-phase extraction step retained the analyte for 3000 ms while removing interfering matrices (e.g., buffer components). Analytes were eluted back from the cartridge with an organic mobile phase (99.9% acetonitrile / methanol [1:1 (v:v)], 0.09% formic acid, and 0.01% TFA) in a simple step gradient for 3,000 ms and then flowed into the mass spectrometer at a flow rate of 1.25 mL / min. The cartridge was then re-equilibrated with aqueous mobile phase for 500 ms (flow rate of 1.5 mL / min). RapidFire software and customized control software were obtained from BioCius. QuickQuan 2.3, Xcalibur 2.0.7, and XDK 2.1.0.25 were used to operate a TSQ Vantage mass spectrometer (ThermoFisher, San Jose, CA) integrated into the RapidFire system. Mass spectral data processing software, QuickCalc 7.1.9, was purchased from ThermoFisher. Master software for the RIAS was programmed in-house using LabVIEW (version 8.6.1; National Instruments, Austin, TX). Data analysis was performed with AssayExplorer 3.2 (Symyx, Sunnyvale, CA), and correlation plots were visualized with Spotfire version 2.2.0 (TIBCO, Palo Alto, CA).

[0157] Apical to basolateral direction (P app,AB ) and basolateral to apical direction (P app,BA ) and the emission ratio were calculated as follows: P app,AB =Q AB / (C0 s t) P app,BA =Q BA / (C0 s t) Emission ratio=P app,BA / P app,AB where Q is the amount of compound recovered in the receiver compartment after incubation time t, C is the initial compound concentration applied to the donor compartment, and s is the surface area of ​​the Transwell insert. As quality controls, one reference P-gp substrate (apafant) and one low-permeability compound (BI internal standard, P app Approximately 3·10 -7 A kinetic energy (V) of 1000 serotonin (V) was measured for each assay plate. ... Additionally, prior to the permeability assay, transepithelial electrical resistance (TEER) values ​​were measured for each plate, and the overall recovery in the donor and receiver compartments was determined for each compound. The results can be seen in Tables 3a and 3b.

[0158] [Table 16]

[0159] Cell permeability measurement-efflux ratio: [Table 17]

Claims

1. A compound of formula (I) or a salt thereof. 【Chemistry 1】 (In the formula, B is, 5-7 membered monocyclic heterocyclyl containing 1 or 2 N atoms, a 6-membered bicyclic heterocyclyl containing one N atom, and a 6-membered monocyclic heterocyclyl containing one N atom and one heteroatom selected from the group consisting of O and S; is a group selected from the group consisting of R 1 is -H or -C 1-6 - alkyl, R 2 is —H or —halogen, R 3 is —H or —halogen, However, R 2 and / or R 3 is a halogen; R 4 is -H, -S(O 2 )-C 1-6 -Alkyl, ═O, —C(O)H, —C(O)OH, —C(O)O—C 1-6 -alkyl, -C 1-6 -Alkylene-C(O)OH, and -C(O)NH 2 is selected from the group consisting of R 5 is absent or selected from the group consisting of —H and ═O

2. R 1 But, -C 1 - 3 The compound or salt thereof according to claim 1, wherein:

3. 3. The compound or salt thereof according to claim 1 or 2, wherein B is selected from the group consisting of: 【Chemistry 2】

4. The compound or salt thereof according to any one of claims 1 to 3, wherein B is selected from the group consisting of: 【Transformation 3】

5. R 4 But -S(O 2 )-C 1-6 The compound or salt thereof according to any one of claims 1 to 4, wherein the aryl group is selected from the group consisting of -alkyl, ═O, -C(O)H, and -C(O)OH.

6. R 2 is selected from the group consisting of —H, —F, and —Cl; R 3 is selected from the group consisting of —H, —F, and —Cl; The compound or salt thereof according to any one of claims 1 to 5.

7. R 2 is —F or —Cl, R 3 is selected from the group consisting of —H, —F, and —Cl; The compound or salt thereof according to any one of claims 1 to 6.

8. R 2 is selected from the group consisting of —H, —F, and —Cl; R 3 is —F or —Cl; The compound or salt thereof according to any one of claims 1 to 6.

9. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】

10. The compound according to any one of claims 1 to 6 and 9, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 【Chemistry 5-1】 【Chemistry 5-2】

11. A compound according to any one of claims 1 to 10 in salt-free form.

12. 12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

13. 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease selected from the group consisting of inflammation, allergic and autoimmune diseases, infectious diseases, and cancer, or for use as a vaccine adjuvant.

14. 12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the compound is administered after radiation therapy.

15. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. A pharmaceutical combination comprising one or more compounds according to any one of claims 1 to 10 or pharmaceutically acceptable salts thereof, and, as another active substance, a substance selected from the group consisting of cytostatic substances, cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, viruses, immunogenic cell death inducers, cancer targeting agents, immunomodulators, antibodies, and nanobodies.

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