Heterocyclic compounds capable of activating STING

Abstract

The present invention relates to heterocyclic compounds of formula (I) capable of activating STING (stimulator of interferon genes). [Formula 1] TIFF2024514361000109.tif6640(I)

Description

[Technical field]

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

[0002] STING is a type of pattern recognition receptor (PRRP) that plays a central role in the innate immune system, distinguishing between 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. Thus, 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. Among the PRRPs, STING (also known as TMEM173, MPYS, MITA, ERIS) belongs to a family of nucleic acid sensors and is an adaptor of cytosolic DNA signaling. In mammalian cells, under healthy conditions, DNA is compartmentalized in the nucleus. 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 to detect said cytosolic DNA and induce an immune response against the pathogenic event. STING exists as a dimer in the basal state, with its N-terminal domain anchored in the ER and its C-terminal domain in the cytosol. Cyclic dinucleotides (CDNs) generated by the protein cyclic GMP-AMP synthase (cGAS) are the natural ligands of STING (Ablasser et al, Nature 498, 380 - 384, 2013). Binding of CDNs to STING induces a conformational change that allows 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-kB by TBK1 results in the expression of multiple cytokines, including type I interferons (IFNs).

[0003] Type I IFN production by antigen-presenting cells and other cell types is considered a key event in T cell activation and the subsequent differentiation of antigen-specific effector CD4 and CD8 T cells. Lack of type I IFN has been shown to reduce T cell-dependent immune responses against viral infections or tumor cells (Zitvogel et al, Nature Reviews Immunology 15, 405 - 414, 2015). On the other hand, the presence of a type I IFN signature during cancer treatment is associated with increased numbers of tumor-infiltrating T cells and potentially better clinical outcomes (Sistigu et al, Nature Medicine 20, 1301 - 1309, 2014).

[0004] As shown in recent studies in mice, efficient secretion of type I IFN in the tumor microenvironment and induction of T cell-dependent immune responses against cancer cells depend on the presence of STING (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). Deletion of STING resulted in reduced type I IFN levels in the tumor microenvironment and reduced antitumor efficacy in several mouse tumor models, thereby emphasizing the importance of the presence of type I IFN. On the other hand, specific activation of STING improved antigen-specific T cell immune responses against cancer cells. Type I interferons can significantly enhance antitumor immune responses by inducing the activation of both adaptive and innate immune cells.

[0005] Given the importance of type I IFN in several malignancies and cancer treatment, including viral infections, strategies that allow specific activation of STING are of therapeutic importance. STING activation may be synergistic with other anticancer therapies, such as various approved chemotherapeutic agents or radiation therapy (Wu et al., Med Res Rev 2020 May;40(3):1117-1141), or infectious disease treatments. In the prior art, small molecule modulators of STING have been described, for example in WO2020075790. Summary of the Invention

[0006] The compounds according to the invention are novel activators of STING as demonstrated in an in vitro reporter system using the THP1-Blue reporter cell line. In one aspect, the present invention relates to a compound of formula (I) or a salt thereof:

[0007] [ka] (I) (In the formula, A is N or C; B is, 5-7 membered monocyclic heterocyclyl containing 1 or 2 N atoms; 6-membered bicyclic heterocyclyl containing one N atom; 7-11 membered bicyclic heterocyclyl containing 2 N atoms; 7-membered bicyclic heterocyclyl containing one N atom and one O atom; 6-membered monocyclic heterocyclyl containing one N atom and one heteroatom selected from the group consisting of O and S; a 9-membered bicyclic heterocyclyl containing three heteroatoms, two of which are N and one of which is O; a 9-membered bicyclic heterocyclyl containing one N atom and one S atom; Contains 3 N atoms, 2 of which are C 1-6 -10-membered bicyclic heterocyclyl substituted with alkyl; Phenyl, 9-membered bicyclic heteroaryl containing 3 N atoms; -C 1-4 -alkylene-pyrimidines, and -C 1-4 -Alkylene-OC 1-3 -Alkyl is a group selected from the group consisting of: D is 9-membered bicyclic heteroaryl containing 2 N atoms; 10-membered bicyclic heteroaryl containing one N atom, and Benzodioxole is a group selected from the group consisting of: R 1 -H, -C 1-6 -Alkyl, -CF3, -C 2-6 -Alkynyl, -OC 1-6 - selected from the group consisting of alkyl and halogen; R 2 -H, -C 1-6 -Alkyl, -C 1-6-Alkylene-OH, -C(O)OH, -C(O)OC 1-6 -Alkyl and -pyrazolyl-C 1-6 -alkyl; R 3 is -H or -C 1-6 - alkyl; R 4 -H, -C 1-3 -Alkyl, -NH2, -NHC 1-3 -Alkyl and N(C 1-3 -alkyl)2; R 5 is absent, or -H, -C 1-6 -Alkyl, -S(O2)-C 1-6 -Alkyl, -NH-S(O2)-C 1-6 -Alkyl, =O, -C(O)-C 1-6 -Alkyl, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)OC 1-6 -Alkyl, -NR 5.1 R 5.2 , -C 1-6 -Alkylene-C(O)OH, -S(O2)-NH2, -pyrolidin-2-one-1-yl, -tetrazolyl, and R 5.3 5-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O, substituted with R 5.1 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl and -C 1-6 -Alkylene-OC 1-6 -alkyl; R 5.2 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl, -C 1-6 -Alkylene-OC 1-6 -Alkyl and -C 1-6 -Alkylene-R 5.3 selected from the group consisting of; R 5.3 -H, -C1-6 -alkyl and 6-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O; R 6 is absent, or -H, -C 1-6 -alkyl, =O and -C(O)OH.

[0008] 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, allergy or autoimmune diseases, infectious diseases or cancer, or for use as vaccine adjuvants.

[0009] In another aspect, the present invention relates to a method of treatment involving a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to the use of a compound of general formula (I) as a medicament. In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of general formula (I). In another aspect, the present invention relates to the use of a compound of general formula (I) in a combination medicament comprising another active substance. In another embodiment, the present invention provides a general synthesis scheme for a compound of general formula (I), including examples and methods. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The compounds of the present invention exhibit several advantageous properties, such as 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.

[0011] Thus, in a further aspect, the present invention provides novel compounds of formula (I), including salts thereof, which activate STING and thereby induce cytokine production in vitro and / or in vivo in a STING-dependent manner and have pharmacological and pharmacokinetic properties suitable for use in therapy, i.e. as pharmaceuticals.

[0012] Compounds according to the invention typically exhibit a cellular EC50 against the STING "HAQ" version of less than 10 μM, preferably less than 7 μM, more preferably less than 5 μM, and most preferably less than 3 μM. Furthermore, the compounds according to the present invention also exhibit a cellular EC50 against the human STING variant "H232R" (sometimes referred to as wild type) of less than 10 μM, preferably less than 7 μM, more preferably less than 5 μM, and most preferably less than 3 μM (Yi et al., 2013; PLOS ONE 8(10)). Furthermore, the compounds according to the present invention also exhibit a cellular EC50 against human STING variant "R232H" of less than 10 μM, preferably less than 7 μM, more preferably less than 5 μM, and most preferably less than 3 μM. Furthermore, the compounds according to the present invention also exhibit a cellular EC50 against human STING variant "R293Q" of less than 10 μM, preferably less than 7 μM, more preferably less than 5 μM, and most preferably less than 3 μM. Furthermore, the compounds according to the present invention also exhibit a cellular EC50 against human STING variant "AQ" of less than 10 μM, preferably less than 7 μM, more preferably less than 5 μM, and most preferably less than 3 μM.

[0013] "H232R", "R232H" and "R293Q" are single amino substitutions at a given position. "AQ" is a variant with two substitutions, G230A and R293Q, and "HAQ" is a STING variant with three substitutions, R71H, G230A and R293Q (Yi et al., 2013; PLOS ONE 8(10)). Activity against different human STING variants is advantageous as it maximizes the chances of inducing the desired pharmacological response in patients with single nucleotide polymorphisms. Furthermore, the compounds of the present invention show suitable binding to human STING protein. The suitable binding affinity to human STING, combined with suitable cellular activity and / or suitable pharmacokinetic properties, can achieve lower doses for pharmacological efficacy. The reduced dose has the advantages of reducing the "drug load" or "drug burden" (parent drug and its metabolites) on the patient, which may cause reduced side effects, and reducing the production costs of the drug product. 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 tests, 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 This is reflected by a shift in

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

[0015] In another aspect of the invention, the compounds of the invention have a solubility of >40 μg / ml at pH 6.8, preferably >50 μg / ml at pH 6.8, more preferably >60 μg / ml at pH 6.8, as shown below, thereby facilitating the use of these compounds for systemic and inhaled or intratumoral administration. A compound of the invention according to general formula (I) as defined herein or a salt thereof

[0016] [ka] (I) (In the formula, A is N or C; B is, 5-7 membered monocyclic heterocyclyl containing 1 or 2 N atoms; 6-membered bicyclic heterocyclyl containing one N atom; 7-11 membered bicyclic heterocyclyl containing 2 N atoms; 7-membered bicyclic heterocyclyl containing one N atom and one O atom; 6-membered monocyclic heterocyclyl containing one N atom and one heteroatom selected from the group consisting of O and S; a 9-membered bicyclic heterocyclyl containing three heteroatoms, two of which are N and one of which is O; a 9-membered bicyclic heterocyclyl containing one N atom and one S atom; Contains 3 N atoms, 2 of which are C 1-6 -10-membered bicyclic heterocyclyl substituted with alkyl; Phenyl, 9-membered bicyclic heteroaryl containing 3 N atoms; -C 1-4 -alkylene-pyrimidines, and -C 1-4 -Alkylene-OC 1-3 -Alkyl is a group selected from the group consisting of: D is 9-membered bicyclic heteroaryl containing 2 N atoms; 10-membered bicyclic heteroaryl containing one N atom, and Benzodioxole is a group selected from the group consisting of: R 1 -H, -C 1-6 -Alkyl, -CF3, -C 2-6 -Alkynyl, -OC 1-6 - selected from the group consisting of alkyl and halogen; R 2 -H, -C 1-6 -Alkyl, -C 1-6 -Alkylene-OH, -C(O)OH, -C(O)OC 1-6 -Alkyl and -pyrazolyl-C 1-6 -alkyl; R 3 is -H or -C 1-6 - alkyl; R 4 -H, -C 1-3 -Alkyl, -NH2, -NHC 1-3 -Alkyl and N(C 1-3 -alkyl)2; R 5 is absent, or -H, -C 1-6 -Alkyl, -S(O2)-C 1-6 -Alkyl, -NH-S(O2)-C 1-6 -Alkyl, =O, -C(O)-C 1-6 -Alkyl, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)OC 1-6 -Alkyl, -NR 5.1 R 5.2 , -C 1-6 -alkylene-C(O)OH, -S(O2)-NH2, -pyrrolidin-2-one-1-yl, -tetrazolyl, and R 5.3 5-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O, substituted with R 5.1 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl and -C1-6 -Alkylene-OC 1-6 -alkyl; R 5.2 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl, -C 1-6 -Alkylene-OC 1-6 -Alkyl and -C 1-6 -Alkylene-R 5.3 selected from the group consisting of; R 5.3 -H, -C 1-6 -alkyl and 6-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O; R 6 is absent, or -H, -C 1-6 -alkyl, =O and -C(O)OH. are particularly suitable for the treatment of pathophysiological processes associated with or regulated by STING, in particular for the treatment of inflammation, allergy or autoimmune diseases, infectious diseases or cancer, or for use as a vaccine adjuvant. In view of the above, in another aspect, the present invention also relates to a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use as a medicament. Other aspects of the present invention will be apparent to the skilled artisan directly from the above and below description and examples.

[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 the context, but as used herein, unless otherwise specified, the following terms have the indicated meanings and are subject to the following conventions:

[0018] In the 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 of skill in the art will recognize the point of radical attachment to the molecule from the free valence of the group itself. In combined groups containing two or more subgroups, the last named subgroup is the point of radical attachment, e.g., the substituent "aryl-C 1-3 -Alkylene" means C 1-3 - means an aryl group bound to an alkyl group, the latter of the substituents being bound to the core or to the 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. Wavy lines may be used in subformulas to indicate bonds that are connected to a defined core molecule. For example, the term "3-carboxypropyl group" represents the following substituent:

[0020] [ka] where the carboxy group is attached to the third carbon atom of the propyl group. The term "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" represents the group: [ka] Wavy lines can be used in subformulas to indicate bonds that are connected to a defined core molecule.

[0021] 1.1.1.1 Term Replaced 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 chemical moieties other than a single atom, such as, for example, "substituted alkyl," "substituted aryl," etc.

[0022] 1.1.1.2 Stereochemistry - Solvates - Hydrates Unless expressly indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers, as well as all stereoisomers, optical isomers, geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, as well as mixtures of various proportions of the 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, etc. Unless expressly indicated, the "pharmacologically acceptable salts", as defined in more detail below, are also intended to encompass solvates thereof, such as, for example, 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 the 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, for example, by resolution of racemic forms, or by synthesis, for example, synthesis beginning with optically active starting materials and / or by the use of chiral reagents.

[0024] Enantiomerically pure compounds or intermediates of the present invention may be prepared via asymmetric synthesis, for example by the preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which may be separated by known methods (e.g. chromatographic separation or crystallization) and / or 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 mixtures, such as by chiral stationary phase chromatographic separation of the corresponding racemic mixtures; or by resolution of the racemic mixtures using a suitable resolving agent, e.g., formation of diastereomeric salts of the racemates with an optically active acid or base, followed by salt resolution and liberation of the desired compound from the salt; or by derivatization of the corresponding racemates with a chiral, optically active auxiliary reagent, followed by diastereomeric separation and removal of the chiral auxiliary; or by kinetic resolution of the racemates (e.g., enzymatic resolution); enantioselective crystallization from conglomerates of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of a chiral, optically active auxiliary.

[0025] 1.1.1.4 Salt As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit-risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds where the parent compound has been modified by making acid or base salts of the parent compound. 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 salts 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.

[0026] Additional pharma-ceutically 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 pharma- ceutically 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 other acids (eg, trifluoroacetates) that are useful for purifying or isolating the compounds of the invention also form part of this invention.

[0027] 1.1.1.5 Halogens The term "halogen" refers to fluorine, chlorine, bromine and iodine. 1.1.1.6 Heteroatoms The 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'). 1.1.1.7 Alkyl The term “C 1-n -alkyl" (where n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5 or 6), alone or in combination with other radicals, denotes an acyclic, saturated, branched or linear hydrocarbon radical having 1 to n C atoms. For example, the term C 1-5-Alkyl includes the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0028] 1.1.1.8 Alkylene The term “C 1-n -alkylene" (where n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5 or 6), alone or in combination with other radicals, denotes an acyclic, saturated, branched or straight chain divalent alkyl radical containing 1 to n carbon atoms. For example, the term C 1-4 -Alkylene includes -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-, -CH2-CH(CH3)-CH2-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH(CH2CH3)-, -CH(CH2CH3)-CH2-, -CH(CH2CH2CH3)-, -CH(CH2CH3)-CH2-, -CH(CH2CH2CH3)-, -CH(CH(CH3))2- and -C(CH3)(CH2CH3)-.

[0029] 1.1.1.9 Alkenyl The term “C 2-m -alkenyl" is "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 are joined to each other by a double bond. 1.1.1.10 Alkenylene The term “C 2-m -alkenylene" is "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 The term “C 2-m -alkynyl is "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 are joined to each other by a triple bond. 1.1.1.12 Alkynylene The term “C 2-m -alkynylene" is "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 bonded to each other by a triple bond.

[0030] 1.1.1.13 Cycloalkyl The term “C 3-k -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 other radicals, denotes a cyclic, saturated, unbranched hydrocarbon radical having 3 to k C atoms. For example, the term C 3-7 -Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 1.1.1.14 Cycloalkenyl The term “C 3-k -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 other radicals, denotes a cyclic, unsaturated but non-aromatic, unbranched hydrocarbon radical having 3 to k C atoms, at least two of which are linked to each other by a double bond. For example, the term C 3-7-Cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and cycloheptatrienyl.

[0031] 1.1.1.15 Halo-(alkyl, alkylene or cycloalkyl) The term "halo" attached to a (saturated or unsaturated) "alkyl", "alkylene" or "cycloalkyl" group defines an alkyl, alkylene or cycloalkyl group in which one or more hydrogen atoms have been replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferably fluorine. Examples include H2FC-, HF2C-, F3C-.

[0032] 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.

[0033] [ka]

[0034] 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 six carbon atoms, which may be further fused to another five- or six-membered saturated or unsaturated aromatic carbocyclic group. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, and dihydronaphthyl.

[0035] 1.1.1.18 Heterocyclyl The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic ring system of 3 to 14 ring atoms containing one or more heteroatoms selected from N, O, S, SO, SO2, which may contain an aromatic ring, and none of the heteroatoms are part of an aromatic ring. The term "heterocyclyl" is intended to include all possible isomers. Thus, the term "heterocyclyl" includes the following exemplary structures (not depicted as radicals because each form may be attached to any atom through a covalent bond as long as appropriate valences are maintained):

[0036] [ka] [ka] [ka]

[0037] 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 SO2, and consisting of 5 to 14 ring atoms, wherein at least one of the heteroatoms is part of an aromatic ring, and the resulting ring system must be chemically stable. The term "heteroaryl" is intended to include all possible isomers.

[0038] Thus, the term "heteroaryl" includes the following exemplary structures (not depicted as radicals because each form may be attached to any atom through a covalent bond as long as appropriate valences are maintained):

[0039] [ka] 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. The term "bicyclic ring system" means a group consisting of two linked cyclic moieties, including spirocyclic, fused and bridged ring systems. Preferred Embodiments A particular embodiment of the present invention is a compound of formula (I) or a salt thereof

[0040] [ka] (I) (In the formula, R 1 -C 1-6 -Alkyl, -CF3, -OC 1-6 -alkyl and halogen).

[0041] Another particular embodiment is a compound of formula (I) or a salt thereof, 1 -C 1-6 -Alkyl, -CF3, -OC 1-6 -alkyl, -Br and -Cl). Another particular embodiment is a compound of formula (I) or a salt thereof, 1 -C 1-6 -alkyl, -CF3, -Br and -Cl). Another particular embodiment is a compound of formula (I) or a salt thereof, 1 -C 1-6 -Alkyl, -CF3, -OC 1-6 -alkyl, halogen; R 4 is -H or -C 1-3 -alkyl).

[0042] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, 2 is -H). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R3 is -H). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 2 is -H, R 3 is -H). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 4 is -H or -C 1-3 -alkyl).

[0043] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 5 -H, -C 1-6 -Alkyl, -S(O2)-C 1-6 -Alkyl, =O, -C(O)H, -C(O)NH2, -C(O)OH, -C(O)OC 1-6 -Alkyl, -NR 5.1 R 5.2 , and R 5.3 R is selected from the group consisting of 5-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O, substituted with 5.1 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl and -C 1-6 -Alkylene-OC 1-6 -alkyl; R 5.2 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl, -C 1-6 -Alkylene-OC 1-6 -Alkyl and -C 1-6 -Alkyl-R 5.3 R 5.3 is -H or -C 1-6 -alkyl).

[0044] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 5 -H, -C 1-6 -Alkyl, -S(O2)-C 1-6 -Alkyl, -NH-S(O2)-C1-6 -Alkyl, =O, -C(O)-C 1-6 -Alkyl, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)OC 1-6 -Alkyl, -NR 5.1 R 5.2 , -C 1-6 -alkylene-C(O)OH, -S(O2)-NH2, -pyrrolidin-2-one-1-yl, and R 5.3 R is selected from the group consisting of 5-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O, substituted with 5.1 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl and -C 1-6 -Alkylene-OC 1-6 -alkyl; R 5.2 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl, -C 1-6 -Alkylene-OC 1-6 -Alkyl and -C 1-6 -Alkylene-R 5.3 R 5.3 -H, -C 1-6 -alkyl, and 6-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O.

[0045] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 5 -H, -C 1-6 -Alkyl, -S(O2)-C 1-6 -Alkyl, =O, -C(O)H, C(O)NH2, -C(O)OH, -C(O)OC 1-6 -Alkyl and -NR 5.1 R 5.2 R 5.1 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl and -C 1-6 -Alkyl-OC 1-6-alkyl; R 5.2 -H, -C 1-6 -Alkyl, -C(O)-C 1-6 -Alkyl and -C 1-6 -Alkylene-OC 1-6 -alkyl). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 5 -H, -C 1-6 -Alkyl, -S(O2)-C 1-6 -Alkyl, =O, -C(O)H, -C(O)NH2, -C(O)OH and -C(O)OC 1-6 -alkyl).

[0046] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 5 are -C(O)H, C(O)NH2, -C(O)OH and -C(O)OC 1-6 -alkyl). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 5 is -C(O)OH or -C(O)OC 1-3 -alkyl). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 5 is absent when required by valence). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 6 is -H or -C(O)OH.

[0047] Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 6 is absent when required by valence). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein R 5 is -H, R 6 is -H). Another particular embodiment of the present invention relates to compounds of formula (I) or salts thereof, wherein A is N. Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein B is selected from the group consisting of 5-7 membered monocyclic heterocyclyl containing one or two N atoms, 6 membered bicyclic heterocyclyl containing one N atom, 7-11 membered bicyclic heterocyclyl containing 2-3 N atoms, 7 membered bicyclic heterocyclyl containing one N atom and one O atom, 6 membered monocyclic heterocyclyl containing one N atom and one heteroatom selected from the group consisting of O and S, 9 membered bicyclic heterocyclyl containing three heteroatoms, two of which are N and one is O, 9 membered bicyclic heterocyclyl containing one N atom and one S atom, and 3 N atoms, two of which are C. 1-6 -alkyl-substituted 10-membered bicyclic heterocyclyl. Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein B is

[0048] [ka] wherein the group is a group selected from the group consisting of Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein B is

[0049] [ka] wherein the group is a group selected from the group consisting of Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein B is

[0050] [ka] (selected from the group consisting of:

[0051] Another particular embodiment of the present invention relates to compounds of formula (I) or salts thereof, wherein D is selected from the group consisting of 9-membered bicyclic heteroaryl containing 2 N atoms and 10-membered bicyclic heteroaryl containing 1 N atom. Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0052] [ka] (selected from the group consisting of: Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0053] [ka] (selected from the group consisting of: Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0054] [ka] R 1 -C 1-6 -Alkyl, -CF3, -OC 1-6 -alkyl, halogen; R 2 is -H, R 3 is -H, R 4 is -H or -C 1-3 -alkyl). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0055] [ka] (selected from the group consisting of: Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0056] [ka] (selected from the group consisting of: Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0057] [ka] (is). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0058] [ka] R 2 is -H, R 3 is -H). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0059] [ka] R 1 is selected from the group consisting of -Br and -Cl; R 2 is -H, R 3 is -H). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0060] [ka] R 1 -C 1-6 -Alkyl, -CF3, -OC 1-6 -alkyl, -Br and -Cl). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0061] [ka] R 1 -C 1-6 -Alkyl, -CF3, -OC 1-6 -alkyl, -Br and -Cl; R 2 is -H, R 3 is -H). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0062] [ka] and R 1 -C 1-6 -Alkyl, -CF3, -OC 1-6 -alkyl, halogen; R 2 is -H, R 3 is -H). Another particular embodiment of the present invention is a compound of formula (I) or a salt thereof, wherein D is

[0063] [ka] and R 1 -C 1-6 -Alkyl, -CF3, -OC 1-6 -alkyl, halogen; R 2 is -H, R 3 is -H, R 4 is -H or -C 1-3 -alkyl). Another particular embodiment of the present invention comprises

[0064] [ka] [ka] [ka] [ka] [ka] or a salt thereof, wherein the compound is selected from the group consisting of: Another particular embodiment of the present invention comprises

[0065] [ka] [ka] or a salt thereof, wherein the compound is selected from the group consisting of: In one aspect, the present invention relates to a compound of formula (I) or a salt thereof:

[0066] [ka] (I) In the formula, as depicted in the structural representation of formula (I), A is a part of B, i.e., B includes A. For example, when A is a heteroatom, this heteroatom can be the only heteroatom of B when B is heterocyclyl. Also, for example, when B is a heterocyclyl defined by a certain number of members (e.g., 5-7 members, 6 members, etc.), A is one such member. Also, as another example, when B is a 6-membered monocyclic heterocyclyl containing one N atom, A can be this N atom.

[0067] In one aspect, the present invention provides a compound of formula (I) or a salt thereof, 1-4 -alkylene-pyrimidine and -C 1-4 -Alkylene-OC 1-3 -alkyl, with the proviso that A is nitrogen. A, B, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 5.1 , R 5.2 , R 5.3 , R 6 Any and each of the definitions may be combined with each other. In one aspect, the present invention relates to compounds of formula (I) in salt-free form. In one aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a medicament. In one aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. In one aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically 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 inhibitor, an antiangiogenic substance, a steroid, a virus, an immunogenic cell death inducer, a cancer targeting agent, an immunomodulator, an antibody and a nanobody.

[0068] Treatment In another aspect of the present invention, it is found that the compounds of general formula (I) or salts thereof may be useful for the prevention and / or treatment of diseases and / or conditions in which modulation of STING is of therapeutic benefit.Furthermore, the compounds of the present invention are suitable as vaccine adjuvants due to their activity. 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.

[0069] Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), dermatomyositis, and Sjogren's syndrome (SS). 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.

[0070] Examples of musculoskeletal inflammation that can be treated with the compounds of the present invention include arthritis (e.g., 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 (e.g., Paget's disease, osteitis pubis, and osteitis fibrosus cyst).Examples of ocular inflammation that can be treated with the compounds of the present invention include blepharitis, cutis palpebrae, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.Examples of nervous system inflammation that can be treated with the compounds of the present invention include encephalitis, Guillain-Barre 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, enterocolitis, 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.

[0071] The compounds can be used to treat autoimmune conditions with an inflammatory component, including 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 colonic necrosis factor syndrome, and the like. In some embodiments, the conditions described herein include inflammatory bowel disease, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus syndrome, optic neuritis, ordothyroiditis, 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, mole hair, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0072] The compounds can be used to treat T cell-mediated hypersensitivity disorders that have an inflammatory component. Such conditions include 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).

[0073] Other inflammatory conditions that can be treated with the compounds include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibromyalgia, gingivitis, glossitis, hepatitis, suppurative hidradenitis, 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, Sexary syndrome, congenital adrenal hyperplasia, non-dense thyroiditis, cancer. hypercalcemia associated with chronic obstructive pulmonary disease, 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 oiridocyclitis, 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 enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, parenchymal organ transplant rejection, 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 pulmonary disease, and inflammation associated with infectious conditions (e.g., sepsis).

[0074] 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 salts or solvates thereof may have a potentially beneficial anti-tumor effect include cancer of the lung, bone, pancreas, skin, brain, head, neck, uterus, ovaries, stomach, colon, colorectum, breast, esophagus, small intestine, intestine, endocrine system, thyroid, parathyroid, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney or liver, bile duct; urothelial cancer; rectal cancer; anal cancer; fallopian tube, endometrium, cervix, vagina, vulva, rectum ... These include, but are not limited to, carcinoma of the hilum, renal pelvis, or renal cell; sarcoma; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatoma; 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 hanlartoma; mesothelioma; Hodgkin's disease or a combination of one or more of the above cancers.

[0075] Preferred cancers which may 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, endometrium, thyroid, cervix, stomach, head, neck, sarcoma, sarcoma of soft tissue, esophagus, head and neck cancer, rectal and urothelial cancer, and lymphoma. The new compounds can be used in any combination with surgery, radiotherapy or other "modern" compounds such as cytostatic or cytotoxic substances, cell growth inhibitors, anti-angiogenic substances, 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. The new compounds can 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 different administration routes for the compounds, such as intravenous, intratumoral, subcutaneous, inhalation, oral administration routes, for the prevention, palliative, curative or semi-curative, short-term or long-term treatment of the above 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.

[0076] In certain embodiments, the compounds and compositions can be used as adjuvants in therapeutic or prophylactic strategies that use vaccines in their role as adjuvants.Thus, the compounds of the present invention or their salts can be used together with one or more vaccines that are selected to stimulate immune response against 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.

[0077] Such vaccines can include inactivated or attenuated bacteria or viruses, including the antigen of interest, purified antigen, live virus or bacterial delivery vectors recombinantly engineered to express and / or secrete the antigen, antigen presenting cell (APC) vectors including cells loaded with the antigen or transfected with compositions including nucleic acids 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 can 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. Thus, the present invention relates to compounds of general formula (I) for use as a medicament or vaccine adjuvant.

[0078] In a further aspect, the present invention provides novel compounds of formula (I), including salts thereof, for use in a method of treatment of a disease or condition associated with or modulated by STING. In a further aspect, the present invention provides novel 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 a vaccine adjuvant.

[0079] Furthermore, the present invention relates to the use of compounds of general formula (I) for treating and / or preventing diseases and / or conditions associated with or regulated by STING. Diseases and conditions associated with or regulated 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 described above. Furthermore, the compounds of the present invention are suitable as vaccine adjuvants due to their activity, including but not limited to the specific applications described above. Thus, the present invention relates to compounds of general formula (I) for use as a medicament or vaccine adjuvant. Furthermore, the present invention relates to the use of the compounds of general formula (I) for treating and / or preventing the abovementioned diseases and pathologies.

[0080] In a further aspect, the present invention relates to the compounds of general formula (I) for use in the treatment and / or prevention of the abovementioned diseases and pathologies. In a further aspect, the present invention relates to compounds of general formula (I) for use before or after tumor resection and / or radiotherapy in the treatment and / or prevention of the abovementioned cancers. In a further aspect, the present invention relates to the use of compounds of general formula (I) for preparing a medicinal product for the treatment and / or prevention of the abovementioned diseases and pathologies. In a further aspect, the present invention relates to a method for treating or preventing 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 0.00001-100 mg per kg of patient body weight, for example 0.00001-10 mg per kg of body weight. Each dosage unit can conveniently contain 0.001-1000 mg, for example 0.001-100 mg. The actual therapeutically effective amount or therapeutic dose will, of course, depend on factors known by those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the compound or composition will be administered in a dose and in a manner that allows for the delivery of 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 the step of administering to the individual a compound of the invention.

[0081] In a further 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. In a further aspect, the present invention provides a method of treating or preventing a disease comprising the step of 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 a further aspect, the present invention provides a vaccine composition comprising an antigen or antigenic composition and a compound of general formula (I) for use in the treatment or prevention of disease. In a further 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 an antigenic composition for the treatment or prevention of a disease. In a further aspect, the present invention provides a method of treating or preventing a disease comprising the step of administering to a human subject suffering from or susceptible to the disease a vaccine composition comprising an antigen or antigenic composition and a compound of general formula (I).

[0082] Pharmaceutical Compositions In another aspect of the present invention, it is found that pharmaceutical compositions of said compounds can be formulated suitable for administering therapeutically effective amounts of said compounds.The preparations suitable for administering the compounds of formula (I) are clear 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 peritumor), 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.

[0083] Suitable tablets can be obtained, for example, by mixing one or more compounds of formula I with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. For purposes of this disclosure, pharmaceutical compositions can be administered by a variety of means, including oral, parenteral, inhalation spray, topical, nasal, oral, or rectal administration, as formulations containing pharma- ceutical acceptable carriers, adjuvants, and vehicles. Pharmaceutical compositions of the present disclosure can be administered in the form of injectable sterile preparations, such as injectable sterile aqueous or oleaginous suspensions. According to another embodiment, there is provided a vaccine comprising one or more compounds of general formula (I). In a further aspect, the present invention provides a vaccine adjuvant comprising a compound of general formula (I). In a further aspect, the present invention provides an immunogenic composition comprising an antigen or antigenic composition and a compound of general formula (I). In a further 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.

[0084] Combination Therapy The compounds of the invention can be used alone or combined with a pharma- ceutically acceptable excipient in an amount sufficient to induce, modify, or stimulate an appropriate immune response, which can 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 certain 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, etc., which may be understood to be general activation-modulatory agents in general as well as agents that modulate and / or increase the frequency of certain immune cell subtypes.

[0085] The compounds described herein and compositions thereof can be administered before, after, and / or simultaneously with additional therapeutic or prophylactic compositions or therapeutic or prophylactic modalities. The compounds, compositions according to the present invention, including any combination with one or more additional therapeutic agents, can be administered by mucosal (e.g., oral, sublingual, intravaginal, nasal, cervical, etc.), intratumoral, intraperitoneal, peritumor, 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.

[0086] Among the possible administration methods, intraperitoneal, intratumoral, peritumoral, subcutaneous, inhalation or intravenous administration are preferred. The compounds, compositions according to the invention can also be administered before, after and / or simultaneously by a combination of different 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, administration of the compounds via such different routes can be performed before or after additional therapeutic steps, such as tumor resection or radiation therapy. By way of example only, the compounds of the invention can be administered after radiation therapy. Furthermore, the compounds of the invention can be given by intravenous administration after radiation therapy. Furthermore, the compounds of the invention can be given by intratumoral administration after tumor resection. Furthermore, the compounds of the invention can be given by peritumoral administration after radiation therapy. Furthermore, the compounds of the invention can be given by inhalation administration after tumor resection. Furthermore, the compounds of the invention can be given by intravenous administration followed by intratumoral administration, both administrations being performed after radiation therapy. Additionally, the compounds of the present invention can be administered intratumorally and then intravenously, both of which are administered after radiation therapy. Additionally, the compounds of the present invention can be administered intravenously and then peritumoral, both of which are administered after radiation therapy. Additionally, the compounds of the present invention can be administered peritumorally and then intravenously, both of which are administered after radiation therapy.

[0087] Methods for co-administration with additional therapeutic agents are well known in the art. Because of the adjuvant properties of the compounds of the 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 which, by their nature, can act to stimulate or otherwise harness the immune system to respond to cancer antigens present on targeted tumor cells.

[0088] The compounds of the 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. The compounds of the invention can be used in combination with cancer immunoagonists, in combination with T-cell receptor agonists, or in combination with TNF receptor superfamily agonists or antagonists.

[0089] 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 cellular cytotoxicity (ADCC).

[0090] 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). Thus, the methods further include administering to the subject an effective amount of one or more chemotherapeutic agents as an additional or combination treatment. Additional pharmacologically active substances that may also be used together / in combination with the compounds of formula (I) or pharma- ceutically acceptable salts thereof (including any individual embodiment or general subset of compound (I)), or in the medical uses, methods of use, treatment and / or prophylaxis 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, octreotide); aromatase inhibitors (e.g., anastrozole, letrozole, lia ... zole, vorozole, exemestane, atamestane); LHRH agonists and antagonists (e.g. goserelin acetate, luprolide); inhibitors of growth factors and / or their corresponding receptors (growth factors are e.g. 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 are e.g. (anti)growth factor antibodies, (anti)growth factor receptor antibodies, and tyrosine kinase inhibitors, e.g. afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, Olmutinib, Osimertinib, Almonertinib, Nazartinib, Lazertinib, Peritinib, Erlotinib, Gefitinib, Icotinib, Sapitinib, Lapatinib, Barlitinib, Vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340, necitumumab, panitumumab, cetuximab, amivantanab, pertuzumab, trastuzumab, trastuzumab emtansine, or inhibitors of mutant EGFR, HER2 with exon 20 mutations, and hepatocyte growth factor (HGF) / c-MET, such as emibetuzumab, amivantamab, savolitinib, cabozantinib, and foretinib;Antimetabolites (e.g. methotrexate, raltitrexed, 5-fluorouracil (5-FU), capecitabine, floxuridine, gemcitabine, mercaptopurine, thioguanine, cladribine, pentostatin, cytarabine (ara C), fludarabine, trifluridine and tipiracil combination (=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); alkylating agents (e.g., estramustine, meclorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosporin, RAs, such as carmustine and lomustine, thiotepa; mitotic inhibitors (e.g., vinca alkaloids, such as vinblastine, vindesine, vinorelbine, and vincristine; and taxanes, such as paclitaxel, docetaxel, and 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, torin 1, dactosilib, GDC-0349, vs-5584; bistuertib;AZD8055), mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors (e.g., alpelisib, ceravelisib, GDC-0077, HH-CYH33, AMG 511, buparlisib, dactolisib, pictilisib, taselisib), dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDK4 / 6 (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, leuproretinib, Fametinib; SOS1-inhibitors (i.e. compounds which modulate / inhibit the GEF functionality of SOS1, for example by binding to SOS1 and interfering with the protein-protein interaction between SOS1 and a (mutated) Ras protein, for example KRAS; e.g. BAY-293); inhibitors of GDP- or GTP-loaded RAS and / or any mutants thereof (i.e. compounds which modulate / inhibit the functionality of a (mutated) RAS protein, for example by binding to a GDP- or GTP-loaded (mutated) RAS protein, for example KRAS, NRAS and / or HRAS, preferably KRAS); KRAS Irreversible inhibitors of G12C (AMG-510, MRTX849, ARS-324, GDC-6036);reversible or irreversible binders to GDP-loaded (mutated) KRAS;reversible or irreversible binders to GTP-loaded (mutated) 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; A-Raf and / or B-Raf and / or C-Raf and / or their Inhibitors of any mutation (encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (= Example 131 of WO 2014 / 151616), LXH254, sorafenib, LY-3009120 (= Example 1 of WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265); receptor tyrosine kinase (RTK) and inhibitors of SHP2 and / or any variants thereof (e.g., SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909); CYP17 inhibitors; radiopharmaceuticals; proteasome inhibitors (e.g., carfilzomib); immunotherapeutics 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, sintilimab, camrelizumab, toribalimab, tislelizumab); ADCC (antibody-dependent cellular cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies);These include, but are not limited to, T cell engagers such as PSMAxCD3, B7H6 / CD3 (e.g., as disclosed in WO 2021 / 064137), DLL3 / CD3 (e.g., as disclosed in WO 2019 / 234220), bispecific T cell engagers (e.g., BiTEs such as CD3xBCMA, CD3xCD33, CD3xCD19), cancer vaccines, MDM2-inhibitors, oncolytic viruses, and various chemotherapeutic agents such as amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, 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, Toll-like receptor agonists.;

[0091] In a preferred embodiment, additional pharmacologically active substances which may also be used together / in combination with the compound of formula (I) or a pharma- ceutically acceptable salt thereof (including all individual embodiments or general subsets of compound (I)) or in the medical uses, methods of use, treatment and / or prophylaxis disclosed herein (above and below) include checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab, scinti These include, for example, anti-CD35 inhibitors such as ribavirin, tamab, camrelizumab, 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 (BiTEs®), such as CD3xBCMA, CD3xCD33, CD3xCD19, cancer vaccines, MDM2 inhibitors, and oncolytic viruses.

[0092] 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. Thus, the methods further include administering to the subject an effective amount of one or more cancer targeting agents as an additional or combined treatment. In additional embodiments of the methods described herein, the compounds of the invention are used in combination with chemotherapeutic agents and / or additional agents to treat the indications described in the methods herein, and / or additional therapies such as radiation therapy and / or tumor resection. 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.

[0093] The use of the compounds according to the invention in combination with an additional therapeutic agent may be simultaneous or staggered. The compound according to the invention and the one or more additional therapeutic agents may be present both together in one formulation or separately in two identical or different formulations, e.g. as a so-called kit of parts. Therefore, in a further aspect, the present invention provides a combination comprising a compound of general formula (I) and at least one further therapeutic agent.

[0094] A further aspect of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one additional therapeutic agent and one or more pharma- ceutically acceptable excipients. In a further aspect, the present invention provides a combination comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one further therapeutic agent for use in therapy. In a further aspect, the present invention provides a combination comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one further therapeutic agent for use in the treatment of a disease or condition in which modulation of STING is beneficial. In a further aspect, the present invention provides a combination comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one further therapeutic agent for use in the treatment of inflammation, allergy and autoimmune diseases, infectious diseases and cancer. In a further aspect, the present invention provides a method of treating a disease or condition in a patient in which modulation of STING is beneficial, the method comprising the step of administering a therapeutically effective amount of a combination comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one other therapeutic agent. In a further aspect, the present invention provides a method of treating inflammation, allergy or autoimmune disease, infectious disease or cancer in a patient, the method comprising the step of administering a therapeutically effective amount of a combination comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one other therapeutic agent.

[0095] The actual pharmacologic effective amount or therapeutic dose will, of course, depend on factors known by those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the combination is administered in a dose and in a manner that allows for the delivery of a pharmacologic effective amount based on the patient's unique condition.

[0096] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the invention and one or more additional therapeutic agents as described above and below, together with optionally one or more inert carriers and / or diluents.

[0097] Other features and advantages of the present invention will become apparent from the following more detailed embodiments which illustrate, by way of example, the principles of the invention. chemical synthesis

[0098] [Table 1] 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.

[0099] 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). The compounds according to the invention are named according to IUPAC guidelines. When a compound is to be represented by both a structural formula and its nomenclature, the structural formula will control in case of conflict.

[0100] Chromatography Thin layer chromatography is performed on prefabricated silica gel 60 on glass TLC plates manufactured by Merck (with fluorescent indicator F-254). A Biotage Isolera Four instrument is used for automated preparative NP chromatography with Interchim Puri Flash columns (50 μm, 12-300 g) or glass columns packed with silica gel (Granula Silica Si-60A 35-70 μm) manufactured by Millipore. Preparative RP HPLC is performed using columns made by Waters (Sunfire C18, 10 μm, 30×100 mm Part. No. 186003971 or X-Bridge C18, 10 μm, 30×100 mm Part. No. 186003930). Compounds are eluted using various gradients of HO / acetonitrile or HO / MeOH with 0.2% HCOOH added to water, or using basic aqueous buffer instead of water-HCOOH mixture (1 L water contains 5 mL of ammonium bicarbonate solution (158 g per L HO) and 2 mL of ammonia (7 mol / l solution in MeOH)). Analytical HPLC (reaction monitoring) of intermediate compounds is carried out using columns made by Waters and Phenomenex Inc. The analytical equipment is also equipped with a mass detector in each case.

[0101] 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 of the compound eluting in the injection peak is set to 0.

[0102] Analytical HPLC method (AM) Method_1 HPLC: Agilent 1100 / 1200 series MS: Agilent LC / MSD SL Column: Waters X-Bridge BEH C18, 2.5μm, 2.1×30mm XP Eluents: A: 5mM NH4HCO3 / 19mM NH3 in H2O; B: ACN (HPLC grade) Detection: MS: positive and negative modes Mass range: 100-800m / 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

[0103] Method_2 HPLC: Agilent 1100 / 1200 series MS: Agilent LC / MSD (API-ES + / - 3000V, Quadrupol, G6140) Column: Waters, XBridge C18, 2.5μm, 2.1×20mm column Solvents: A: 20mM NH4HCO3 / NH3 in H2O pH 9; B: ACN (HPLC grade) Detection: MS: positive and negative modes Mass range: 120-900m / 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

[0104] Method_3 HPLC: Agilent 1260 system MS: 1200 Series LC / MSD (MM-ES+APCI + / - 3000 V, Quadrupol, G6130) Column: YMC; Part. No. TA12S03-0302WT; Triart C18, 3 μm, 12 nm; 30 × 2.0 mm column Eluent: A: HO + 0.11% HCOOH; B: MeCN + 0.1% HCOOH (HPLC grade) Detection signal: UV 254nm (bandwidth 10, reference off) Mass range: 150-750m / z Flow rate: 1.4mL / min Column temperature: 45℃ Gradient: 0.0-1.0 min: 15% → 100% B 1.0~1.23 minutes: 100% B

[0105] Method_4 UPLC / MS: Waters Acquity-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm Solvent: A: 0.05% HCOOH in ACN; B: H2O + 0.05% HCOOH Detection: MS: positive and negative modes Mass range: 100-1500m / 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 4.50~4.51 minutes: 2% B → 97% B

[0106] Method_5 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 modes Mass range: 100-1500m / 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 4.50~4.51 minutes: 2% B → 97% B

[0107] Method_6 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 modes Mass range: 100-1500m / 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

[0108] Method_7 HPLC: Agilent 1100 / 1200 system MS: 1200 Series LC / MSD (MM-ES + APCI + / - 3000 V, Quadrupol, G6130B) Column: Waters, Part.No. 186003389, XBridge BEH C18, 2.5μm, 2.1×30mm) column Eluent: A: 5mM NH4HCO3 / 18mM NH3(pH=9.2); B: ACN(HPLC grade) Detection signal: UV 254nm, 230nm, 214nm (bandwidth 8, reference off) Mass range: 150-750m / z Flow rate: 1.4mL / min Column temperature: 45℃ Gradient: 0.0-1.0 min 15% → 95% B 1.0~1.3 minutes 95% B

[0109] Method_8 HPLC: Agilent 1100 / 1200 system MS: 1200 Series LC / MSD (MM-ES + APCI + / - 3000 V, Quadrupol, G6130B) Column: Waters, Part.No. 186003389, XBridge BEH C18, 2.5μm, 2.1×30mm) column Eluent: A: 5mM NH4HCO3 / 18mM NH3(pH=9.2); B: ACN(HPLC grade) Mass range: positive / negative 150~750 Detection signal: UV 254nm, 230nm, 214nm (bandwidth 8, reference off) Flow rate: 1.4mL / min Column temperature: 45℃ Gradient: 0.0-1.0 min: 15% → 95% B 1.0~1.3 minutes: 95% B

[0110] Preparation of compounds according to the invention The compounds according to the invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature. These methods are illustrative of the invention, and do not limit the subject matter and the scope of the claimed compounds 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. Variants of reaction methods known to those skilled in the art, but not described in detail here, may also be used. General methods for preparing compounds according to the invention will be apparent to those skilled in the art upon studying the following schemes. The starting materials can be prepared by methods described in the literature or herein, or can be prepared in a similar or analogous manner. Conventional protecting groups can be used to protect any functional groups of the starting materials or intermediates. 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.

[0111] One method for preparing compounds of formula (I) is illustrated in Scheme I. From ortho-methylaniline derivative A, indazole B can be synthesized. Subsequent iodination gives 3-iodo-indazole C. Intermediate D can be obtained by utilizing (6-fluoropyridin-3-yl)boronic acid, for example, via Chan-Lam coupling. Conversion to intermediate E can be achieved, for example, via Suzuki coupling. Finally, compound F is synthesized, for example, via aromatic nucleophilic substitution. The product is isolated by conventional means and preferably purified by chromatography. Scheme I:

[0112] [ka] Preparation of intermediate B B1 7-Methyl-6-nitro-1H-indazole

[0113] [ka] A mixture of 2,6-dimethyl-3-nitro-phenylamine (2.0 g, 12 mmol) in acetic acid (177 ml) is cooled to 5° C. Sodium nitrite (1.08 g, 15.6 mmol) in water (4 ml) is added dropwise. The mixture is stirred for 24 h and concentrated in vacuo. The title compound is obtained by recrystallization from methanol. Yield 0.7 g (34%). HPLC-MS: M+H=178; tR=1.85 min (Method_4) B2 7-Methyl-1H-indazole-6-carboxylate methyl

[0114] [ka] To a mixture of 3-amino-2,4-dimethyl-benzoic acid methyl ester (5.0 g, 27.9 mmol) in water (15 ml) is added aqueous concentrated HCl (7 ml) at 0° C., followed by NaNO2 (2.3 g, 33.5 mmol in water (4 ml)) and sodium tetrafluoroborate (4.0 g, 36.3 mmol in water (4 ml)). The mixture is stirred for 45 min. The solid is collected by filtration, rinsed with diethyl ether, dried and dissolved in chloroform (40 ml). Under stirring, potassium acetate (2.2 g, 22.3 mmol) and 18-crown-6 (synonym: 1,4,7,10,13,16-hexaoxacyclooctadecane; 0.22 g, 0.84 mmol) are added and stirring is continued for 2 h at room temperature. Water (70 ml) is added and the mixture is extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated in vacuo and rinsed with pentane. Yield 3.5 g (66%). HPLC-MS: M+H=191; tR=1.85 min (Method_5). B3 (7-Methyl-1H-indazol-6-yl)methanol

[0115] [ka] To methyl 7-methyl-1H-indazole-6-carboxylate B2 (3.5 g, 18.4 mmol) in THF (40 ml) is added lithium aluminum hydride (1.05 g, 27.6 mmol) at 0° C. After stirring at room temperature for 5 min, 4N aqueous NaOH (1 ml) is added. The mixture is extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. Yield of crude product: 3.0 g (99%). HPLC-MS: M+H=163; tR=1.47 min (Method_5). Preparation of intermediate C C1 (3-iodo-7-methyl-1H-indazol-6-yl)methanol

[0116] [ka] To (7-methyl-1H-indazol-6-yl)-methanol B3 (0.35 g, 2.16 mmol) in DMF (6 ml) is added iodine (298 mg, 4.32 mmol) and K2CO3 (895 mg, 6.47 mmol) at 0° C. After stirring at room temperature for 2 h, EtOAc (100 ml) is added and the mixture is extracted with water, 10% Na2S2O3 aqueous solution and brine. The combined organic layers are dried over Na2SO4 and concentrated in vacuo. Yield of crude product: 0.3 g (48%). HPLC-MS: M+H=289; tR=1.75 min (Method_5). In a similar manner, the following intermediates are prepared from intermediate B:

[0117] [Table 2]

[0118] [ka] To a stirred solution of (3-iodo-7-methyl-1H-indazol-6-yl)-methanol C1 (100 mg, 347 μmol) in DMF (2 ml) at 0° C., imidazole (35 mg, 521 μmol) and TBDMS chloride (63 mg, 417 μmol) are added. The mixture is stirred at room temperature for 16 h and then partitioned between EtOAc and ice water. The organic layer is dried over MgSO4, concentrated in vacuo and the product is purified by NP chromatography. Yield: 70 mg (50%). HPLC-MS: M+H=403; tR=2.85 min (Method_5). Preparation of intermediate D D1 1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole

[0119] [ka] A mixture of 3-iodo-7-methyl-1H-indazole (17 g, 65.9 mmol), (6-fluoropyridin-3-yl)boronic acid (15.8 g, 112 mmol), copper(II) acetate (17.9 g, 98.8 mmol) and pyridine (10.4 g, 132 mmol) in DCM (340 ml) is stirred at room temperature for 16 h with exposure to air. The solids are filtered off, the mixture is concentrated in vacuo and the product is purified by RP chromatography. Yield: 14 g (60%). HPLC-MS: M+H=354; tR=1.50 min (Method_2) In a similar manner, the following intermediates are prepared from the corresponding 3-iodo-indazole (Intermediate C):

[0120] [Table 3-1] [Table 3-2]

[0121] [ka] To 6-{[(tert-butyldimethylsilyl)oxy]methyl}-1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole D9 (50 mg, 101 μmol) in THF (2 ml) is added tetra-N-butylammonium fluoride (1 mol / l in THF, 202 μl, 202 μmol). The mixture is stirred at room temperature for 16 h. A saturated aqueous solution of ammonium chloride is added and the mixture is extracted with EtOAc. The organic layer is dried over MgSO4, concentrated in vacuo and the product is purified by RP chromatography. Yield: 26 mg (68%). HPLC-MS: M+H=384; tR=1.82 min (Method_6) Preparation of intermediate E E1 1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biindazole

[0122] [ka] A mixture of 1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole D1 (1.0 g, 2.8 mmol), 2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (1.1 g, 4.2 mmol), 1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (0.21 g, 0.28 mmol), Na2CO3 (0.9 g, 8.5 mmol) in dioxane (20 ml) and water (5 ml) is stirred at 110° C. for 2 h under 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 vacuum and the product is purified by RP HPLC. Yield: 0.8 g (79%). HPLC-MS:M+H=358;tR=0.997min (Method_1) In a similar manner, the following intermediates are prepared from intermediate D utilizing the corresponding boronic acid derivatives:

[0123] [Table 4-1] [Table 4-2]

[0124] Additional intermediate E is synthesized as follows. E10 1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-6-amine

[0125] [ka] To 1-(6-fluoro-pyridin-3-yl)-7,2'-dimethyl-6-nitro-1H,2'H-[3,4']biindazolyl E2 (0.5 g, 1.2 mmol) in methanol (5 ml) and THF (5 ml) is added palladium on carbon (41 mg, 0.39 mmol). The mixture is hydrogenated at room temperature for 16 h (hydrogen pressure 50 psi). The reaction is filtered through Celite and washed with methanol (50 mL). The filtrate is concentrated in vacuo and the crude product is used without further purification. Yield: 0.35 g (76%). HPLC-MS: M+H=373; tR=1.96 min (Method_5). E11 1-(6-fluoropyridin-3-yl)-6-iodo-2',7-dimethyl-1H,2'H-3,4'-biindazole

[0126] [ka] To 1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-6-amine E10 (0.1 g, 270 μmol) in water (1 ml) is added aqueous concentrated HCl (1 ml) at 0°C, followed by sodium nitrite (20 mg; 295 μmol) in water (1 ml). The reaction mixture is stirred at room temperature for 1 h. Sodium tetrafluoroborate (43 mg, 394 μmol) is added and stirring is continued for 10 min. The mixture is filtered and the solid is washed with 10% NaBF4 solution and diethyl ether and dried under vacuum. This is added to a mixture of iodine (68 mg, 270 μmol) and potassium iodide (70 mg, 414 μmol) in DMSO (2 ml) together with 1 ml of DMSO. The mixture is stirred at room temperature for 1 h and then at 45° C. for 30 min, after which FeSO4*7H2O (90 mg, 324 μmol) is added and stirred for another 30 min. The mixture is poured into aqueous sodium thiosulfate solution and extracted with EtOAc. The combined organic layers are washed with aqueous sodium thiosulfate solution and water, dried over Na2SO4 and concentrated in vacuo. Yield of crude product: 50 mg (39%). HPLC-MS: M+H=484; tR=2.59 min (Method_5). E12 1-(6-fluoropyridin-3-yl)-2',7-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)-1H,2'H-3,4'-biindazole

[0127] [ka] E11 E12 A mixture of 1-(6-fluoropyridin-3-yl)-6-iodo-2',7-dimethyl-1H,2'H-3,4'-biindazole E11 (100 mg, 200 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (52 mg, 240 μmol), ({[1,1'-biphenyl]-2-yl}amino)palladium ilium dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphane methanesulfonate (8 mg, 10 μmol), K3PO4 (87 mg, 400 μmol), dioxane (1 ml) and water (0.5 ml) is stirred at 80° C. for 16 hours under an argon atmosphere. At room temperature, water (30 ml) is added and the mixture is extracted with DCM. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give 50 mg (56%) of crude E12, which is used in the next step without further purification. Additional intermediates E can be obtained via intermediate S by following an alternate sequence of the synthetic steps shown in Scheme 1.

[0128] [ka]

[0129] S1 7-Methoxy-2'-methyl-1H,2'H-3,4'-biindazole A mixture of 3-iodo-7-methoxy-1H-indazole C4 (500 mg, 1.62 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (512 mg, 1.94 mmol), ({[1,1'-biphenyl]-2-yl}amino)palladium ilium dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphane methanesulfonate (126 mg, 162 μmol), K3PO4 (695 mg, 3.24 mmol), dioxane (5 ml) and water (1 ml) is stirred under argon atmosphere at 80° C. for 16 hours. At room temperature, the mixture is diluted with DCM and extracted with water. The organic layer is dried over Na2SO4, concentrated in vacuo and the intermediate 7-methoxy-2'-methyl-1H,2'H-3,4'-biindazole is purified by NP chromatography. Yield: 256 mg (57%). HPLC-MS: M+H=279; tR=0.55 min (Method_7). The following intermediate S2 is synthesized in a similar manner to S1.

[0130] [Table 5]

[0131] E13 1-(6-fluoropyridin-3-yl)-7-methoxy-2'-methyl-1H,2'H-3,4'-biindazole To 7-methoxy-2'-methyl-1H,2'H-3,4'-biindazole S1 (256 mg, 920 μmol) is added (6-fluoropyridin-3-yl)boronic acid (259 mg, 1.84 mmol), copper(II) acetate (167 mg, 920 μmol) and pyridine (218 μl, 2.8 mmol) in DCM (5 ml) and DMF (2.25 ml). The mixture is stirred at room temperature for 60 h with exposure to air. The solids are filtered off, the filtrate is concentrated in vacuo and the product is purified by NP chromatography. Yield: 185 mg (54%). HPLC-MS: M+H=374; tR=0.70 min (Method_7) Additionally, intermediate D can be boronylated to intermediate T, which can then undergo Suzuki coupling with, for example, a heteroaryl bromide, to provide another intermediate E. T1 3-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-(6-fluoropyridin-3-yl)-7-methyl-1H-indazole

[0132] [ka] To 1-(6-fluoro-pyridin-3-yl)-3-iodo-7-methyl-1H-indazole D1 (17 g, 48.1 mmol) in dioxane (170 ml) is added bisneopentylglycolatodiborane (16.3 g, 72.2 mmol), potassium acetate (14.2 g, 144 mmol), dichlorobis(triphenylphosphine)palladium(II) (3.38 g, 4.8 mmol) under argon atmosphere and the mixture is stirred at 100° C. for 16 h. At room temperature, EtOAc and water are added and the aqueous layer is extracted with EtOAc. The combined organic layers are concentrated in vacuum and rinsed with petroleum ether. The crude product is used in the next step without further purification. Yield of crude product: 4 g (25%). E14 1-(6-fluoropyridin-3-yl)-7-methyl-3-{pyrazolo[1,5-a]pyridin-4-yl}-1H-indazole

[0133] [ka] A mixture of 3-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-(6-fluoropyridin-3-yl)-7-methyl-1H-indazole T1 (50 mg, 147 μmol), 4-bromopyrazolo[1,5-a]pyridine (44 mg, 223 μmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 15 μmol), Na2CO3 (47 mg, 443 μmol) in dioxane (1 ml) and water (250 μl) is stirred at 110° C. for 1 h under argon atmosphere. At room temperature, water (20 ml) is added and the mixture is extracted with DCM. The combined organic layers are dried over MgSO4, concentrated in vacuum and the product is purified by RP HPLC. Yield: 35 mg (69%). HPLC-MS:M+H=344;tR=0.993 min (Method_1)

[0134] In a similar manner, the following intermediates are prepared from intermediate T1 by coupling with the corresponding heteroaryl bromides: E15 and E18 are prepared utilizing U2 and U3, respectively.

[0135] [Table 6]

[0136] [ka] At room temperature, DMF (100 ml) is purged with propyne gas for 10 min under an argon atmosphere. 3-Bromo-2-iodopyridine (10 g, 35.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (2.47 g, 3.52 mmol) and copper(I) iodide (669 mg, 3.52 mmol) are added and the mixture is stirred for 4 h. The mixture is diluted with 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: 4.0 g (58%). HPLC-MS: M+H=196; tR=1.94 min (Method_5). U2 4-Bromo-2-methylpyrazolo[1,5-a]pyridine

[0137] [ka] To a stirred mixture of 3-bromo-2-prop-1-ynyl-pyridine U1 (6.0 g; 30.6 mmol) in DCM (55 ml) is added O-(mesitylsulfonyl)hydroxylamine (9.88 g, 45.9 mmol) in DCM (5 ml) at 0° C. The mixture is stirred at room temperature for 4 h before the solvent is removed under reduced pressure. To the crude material is added DMF (60 ml) and K2CO3 (12.7 g, 91.8 mmol) at room temperature and the mixture is stirred for 16 h. Water is added and the mixture is extracted with diethyl ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP chromatography. Yield: 900 mg (14%). HPLC-MS: M+H=211; tR=2.10 min (Method_5) U3) 5-Bromo-N,N-dimethylisoquinolin-3-amine

[0138] [ka] A mixture of 5-bromo-3-chloroisoquinoline (100 mg, 412 μmol), dimethylamine hydrochloride (2.45 g, 30 mmol), NMP (3 ml) and DIPEA (5.1 ml, 30 mmol) is heated to 200° C. for 15 h. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP chromatography. Yield: 69 mg (67%). HPLC-MS: M+H=251 / 253; tR=1.045 min (Method_1). EXAMPLES

[0139] Preparation of Examples #1-#45 and Intermediate F: #1) 3-(5-(2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate methyl

[0140] [ka] A mixture of 1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biindazole E1 (20 mg, 56 μmol), methyl 3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (10 mg, 56 μmol) and DIPEA (50 μl, 0.29 mmol) in DMSO (0.1 ml) is stirred at 80° C. for 16 h. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP chromatography. Yield: 13 mg (48%). HPLC-MS: M+H=479; tR=1.47 min (Method_2) In the same manner, the following examples are prepared from intermediate E utilizing the corresponding amines. In the case of the salt of the amine (eg hydrochloride salt), an additional equivalent of base is used in each case.

[0141] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9]

[0142] [Table 8-1] [Table 8-2]

[0143] [ka] 4-(tert-butyl 5-(2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate F1 (42 mg, 78 μmol) is stirred with TFA (400 μl) in DCM (2 ml) at room temperature for 2 h. Toluene (10 ml) is added, the mixture is concentrated in vacuo and the product is purified by RP chromatography. Yield: 12 mg (35%). HPLC-MS: M+H=438; tR=1.36 min (Method_2) In the same manner, prepare the following examples from F2 to F6, respectively.

[0144] [Table 9]

[0145] Preparation of Examples #51-#54: #51 4-(5-(2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperazine-1-carbaldehyde

[0146] [ka]

[0147] A mixture of formic acid (2 μl; 53 μmol) and N-methylmorpholine (6 μl; 57 μmol) in DCM (200 μl) is cooled to 0° C. Isobutyl chloroformate (7 μl; 54 μmol) is added and the RM is stirred for 2 h at 20° C. 2′,7-Dimethyl-1-[6-(piperazin-1-yl)pyridin-3-yl]-1H,2′H-3,4′-biindazole #46 (10 mg, 24 μmol) is added and stirring is continued for 16 h at RT.

[0148] The mixture is concentrated in vacuo and the product is purified by RP chromatography. Yield: 7 mg (66%). HPLC-MS: M+H=452; tR=1.31 min (Method_2) In the same manner, prepare the following examples from #45, #48 and #49, respectively.

[0149] [Table 10]

[0150] [ka]

[0151] To 3-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-amine #47 (46 mg, 106 μmol) in DCM (200 μl) and NMP (200 μl) is added DIPEA (103 μl, 636 μmol) and acetyl chloride (10 μl, 139 μmol) at room temperature. The mixture is stirred for 40 min, concentrated in vacuo and the product is purified by RP HPLC. Yield: 18 mg (36%). HPLC-MS: M+H=478; tR=1.26 min (Method_2) #56 N-[1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)piperidin-4-yl]methanesulfonamide

[0152] [ka] A mixture of 1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)piperidin-4-amine #50 (45 mg, 103 μmol), triethylamine (250 μl, 1.8 mmol), NMP (750 μl) and methanesulfonyl chloride (18 μl, 235 μmol) is stirred at room temperature for 1 h. The mixture is concentrated in vacuo and the product is purified by RP HPLC. Yield: 23 mg (43%). HPLC-MS: M+H=516; tR=1.36 min (Method_2).

[0153] Preparation of Examples #57-#71: #57 1-(5-(2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperidine-4-carboxylic acid

[0154] [ka] To ethyl 1-(5-(2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperidine-4-carboxylate #31 (40 mg; 81 μmol) is added THF (1 ml), MeOH (800 μl), water (200 μl) and LiOH (19 mg; 793 μmol). The mixture is stirred at room temperature for 2 h. After neutralization with 1N aqueous HCl, the mixture is extracted with EtOAc. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product is purified by RP HPLC. Yield: 35 mg (93%). HPLC-MS: M+H=467; tR=1.03 min (Method_2) In the same manner, prepare the following examples from #32, #1, #33-#44, respectively.

[0155] [Table 11-1] [Table 11-2] [Table 11-3]

[0156] Further examples are obtained by additional chemical transformations. #72 3-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0157] [ka]

[0158] To a mixture of 3-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)-3-azabicyclo-[3.1.0]hexane-6-carboxylic acid #1 (20 mg, 43 μmol), DIPEA (22 μl, 129 μmol) in NMP (500 μl) is added HATU (25 mg, 66 μmol) and the mixture is stirred at RT for 10 min. Ammonium chloride (10 mg, 187 μmol) is added and stirring is continued for 16 h. The mixture is concentrated in vacuo and the product is purified by RP chromatography. Yield: 11 mg (55%). HPLC-MS: M+H=464; tR=1.28 min (Method_2). Starting from intermediate S2, building block V is used to synthesize example #73. V1 5-Bromo-2-(4-methanesulfonylphenyl)pyridine

[0159] [ka] A mixture of 2,5-dibromopyridine (50 mg, 211 μmol), (4-methanesulfonylphenyl)boronic acid (42 mg, 211 mmol) and tetrakis(triphenyl-phosphine)palladium (25 mg, 21 μmol), dioxane (1 ml) and aqueous sodium carbonate solution (2 mol / l, 264 μl, 528 μmol) is stirred at 80° C. for 2 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 MgSO4, concentrated in vacuo and the product is purified by RP HPLC. Yield: 43 mg (65%). HPLC-MS: M+H=312 / 314; tR=0.57 min (Method_8) V2 [6-(4-methanesulfonylphenyl)pyridin-3-yl]boronic acid

[0160] [ka] A mixture of 5-bromo-2-(4-methanesulfonylphenyl)pyridine V1 (450 mg, 1.44 mmol), bis(pinacolato)diboron (732 mg, 2.88 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (121 mg, 144 μmol) and potassium acetate (707 mg, 7.2 mmol) in dioxane (9 ml) is stirred at 80° C. for 1 h under argon atmosphere. The solids are filtered off, the filtrate is concentrated in vacuo and the product is purified by RP chromatography. Yield: 245 mg (61%). HPLC-MS: M+H=278; tR=0.24 min (Method_2) #73 1-[6-(4-methanesulfonylphenyl)pyridin-3-yl]-2',7-dimethyl-1H,2'H-3,4'-biindazole

[0161] [ka] To a mixture of 2',7-dimethyl-1H,2'H-3,4'-biindazole S2 (26 mg, 99 μmol) in ACN (1 ml) and DCM (1 ml) pyridine (24 μl, 300 μmol), [6-(4-methanesulfonylphenyl)pyridin-3-yl]boronic acid V2 (87 mg, 303 μmol) and copper(II) acetate (27 mg, 149 μmol) are added. The mixture is stirred at 80° C. for 3 days. The solids are filtered off, the filtrate is concentrated in vacuo and the product is purified by RP chromatography. Yield: 4.3 mg (9%). HPLC-MS: M+H=494; tR=0.74 min (Method_8).

[0162] Example #74 is synthesized via W1. W1 3-(5-{2'-methyl-7-[2-(trimethylsilyl)ethynyl]-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate methyl

[0163] [ka] Dichlorobis(triphenylphosphine)palladium(II) (13 mg, 19 μmol) is added to a mixture of methyl 3-(5-{7-bromo-2'-methyl-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)-3-azabicyclo-[3.1.0]hexane-6-carboxylate #37 (100 mg, 184 μmol), ethynyltrimethylsilane (181 mg, 1.8 mmol), copper(I) iodide (4 mg, 21 μmol), DIPEA (94 μl, 550 μmol) and NMP (2 ml) at room temperature under argon atmosphere and stirred at 50° C. for 4 h. The mixture is concentrated in vacuum and the product is purified by RP HPLC. Yield: 24 mg (23%). HPLC-MS: M+H=561; tR=1.214 min (Method_1)

[0164] #74 3-(5-{7-ethynyl-2'-methyl-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0165] [ka] To methyl 3-(5-{2'-methyl-7-[2-(trimethylsilyl)ethynyl]-1H,2'H-[3,4'-biindazol]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate W1 (24 mg; 43 μmol) is added THF (1 ml), MeOH (800 μl), water (200 μl) and LiOH (10 mg, 412 μmol). The mixture is stirred at room temperature for 2 h, concentrated in vacuo and the product is purified by RP HPLC. Yield: 2 mg (10%). HPLC-MS: M+H=475; tR=0.777 min (Method_1).

[0166] In Examples #1, 26, 28, 29, 30, 37, 38, 41, 42, 44, 47, 55, 59, 64, 65, 68, 69, 71, 72, 74, the following reported values ​​represent isomers containing the (1R,5S,6R)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid or (1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-amine moiety. In the case of Example #6, data for the (R) isomer is shown.

[0167] Pharmacological activity Interaction with hSTING determined by Differential Scanning Fluorometry (DSF) In DSF, 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. mThe shift correlates with the binding affinity of this small molecule. Human STING (hSTING, 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)) was used as the target protein, and 20 mM Tris, 150 mM NaCl (pH 7.5) was added appropriately when necessary as the assay buffer. Final concentrations of components in the assay: 100 μM test compound, 5 μM target protein, 5x SYPR Orange (from stock solution of SYPRO orange in DMSO (Invitrogen Cat. No. S6650-500ul), at 5000x concentration). 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 (SYPRO Orange 5000x 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 (25x 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) Plates were prepared for duplicate measurements and centrifuged at 1000g for 2 minutes. 6) The measurement was performed using a CFX384 Real-Time System (Bio-Rad Laboratories). The process consisted of 140 cycles at 0.5°C / cycle (temperature ramp 15 sec / cycle, from 25°C to 95°C). Data analysis: Melting curves were processed with Bio-Rad CFX Manager. Peak shape was set to "negative". Duplicate TM (melting temperature) measurements were averaged and standard deviations were calculated.

[0168] The changes in TM ("thermal shifts") are shown in Table 1. [Table 12]

[0169] In vitro cytokine induction measured via activation of an interferon regulatory factor-inducible reporter gene The cytokine-inducing activity of the compounds according to the invention has been demonstrated by using THP1 reporter cell line and obtaining cellular EC50 values. Activation of STING protein expressed in cell line increases interferon production. Stable integration of interferon regulatory factor (IRF)-inducible SEAP gene (secreted embryonic alkaline phosphatase) reporter construct allows monitoring of functional interferon signaling pathway. Using Invivogen's THP1-Blue™ ISG colorimetric enzyme assay and a suitable optical density (OD) reader, SEAP activity can be detected and quantified. This technique allows characterization of pharmacological alterations of the STING pathway.

[0170] 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, the CRISPR / CAS9 system was used to first delete endogenous human STING. THP1-Blue ISG cells were electroporated with ALL-IN-ONE CRISPR plasmid (purchased from Sigma, encoding GFP and gRNA of reporter gene for successful transfection) targeting the STING gene. GFP-positive cells were then selected and expanded 24 hours after transfection. The cells were then dispersed in semi-solid methocel medium to allow 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.

[0171] For overexpression of human STING variants, confirmed THP1-Blue™ ISG hSTING KO clones were transduced with individual retroviral plasmids (MSCV-ires-GFP-Blasti) encoding allelic variants of hSTING (WT (H232R), HAQ, R232H, AQ and R293Q). Transduced cells were sorted by different 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. Measurement of SEAP activity was performed 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.

[0172] In preparation for the assay, cells were distributed into assay plates at a density of 10000 cells / 15 μL per well. Compounds were prepared by 8-point serial dilution in 50% aqueous DMSO and final dilution step into medium to ensure a final DMSO concentration of 0.5% in the assay. 5 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).

[0173] EC 50Values ​​and Hill slopes were derived from an eight-point, four-parametric non-linear curve fit with Megalab software (Boehringer Ingelheim) using the OD at 620 nM. EC 50 Value data can be seen in Tables 2a-2e. STING HAQ-Variant EC 50 Value data can be found in Table 2a. Data presented below is from the parental THP1-Blue™ ISG cell line (which endogenously expresses HAQ) or 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.

[0174] [Table 13]

[0175] [Table 14]

[0176] [Table 15]

[0177] [Table 16]

[0178] [Table 17]

[0179] 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 DMEM (Dulbecco's modified Eagle's medium) containing (final concentrations) 10% FCS (fetal calf serum), 1% NEAA (non-essential amino acids), 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 bidirectional permeability assays. 2 The cells were seeded at a density of 100×1000 and cultured for 3 weeks with the medium changed every 2 days.

[0180] For bidirectional permeability assays, 10 mM DMSO stock solutions were diluted in transport buffer (final concentrations: 128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4, 0.41 mM NaH2PO4, 15 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), 20 mM glucose, pH 7.4) containing 0.25% bovine serum albumin to a final concentration of 10 μM of test compounds and added to the apical or basolateral compartment. Cells were incubated with compounds for up to 2 hours. Samples from the opposite compartment were taken at different time points.

[0181] Compound concentrations in the 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 and flexible platform called RIAS. In this modified setup, the sample was aspirated by a vacuum pump into a 10 μL sample loop for 250 ms and run through a C4 cartridge (3.8 μL bed 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, samples were spiked with an internal standard solution and diluted with acetonitrile (ACN) for protein precipitation. Measurements were operated in multiple reaction monitoring (MRM) mode. Quantification was performed using external calibration. A solid-phase extraction step retained the analytes for 3000 ms while removing interfering matrices (e.g., buffer components). Analytes were eluted back from the cartridge in a simple step gradient with organic mobile phase (99.9% acetonitrile / methanol [1:1 (v:v)], 0.09% formic acid, and 0.01% TFA) for 3,000 ms and run 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. A TSQ Vantage mass spectrometer (ThermoFisher, San Jose, CA) integrated into a RapidFire system was operated using QuickQuan 2.3, Xcalibur 2.0.7, and XDK 2.1.0.25. Mass spectral data processing software QuickCalc 7.1.9 was purchased from ThermoFisher. The 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).

[0182] In the apical-to-basolateral direction (P app,AB ) and in the 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, C0 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 profile (V / cm / sec, no efflux) was included for each assay plate. Additionally, transepithelial electrical resistance (TEER) values ​​were measured for each plate prior to the permeability assay, and the total recovery in the donor and receiver compartments was determined for each compound. The results can be seen in Tables 3a and 3b.

[0183] [Table 18]

[0184] [Table 19]

[0185] Solubility measurement Aqueous solubility was determined by diluting 10 mM stock solutions of compounds in DMSO to a final concentration of 250 μM in aqueous McIlvaine buffer (pH 6.8) or acetonitrile / water (1:1) as a reference. Samples were shaken in 96-well plates (Whatman Uniplate® 96-well, 750 μL, polypropylene, round bottom) at room temperature for 24 hours. Plates were then centrifuged at 3,000 rpm for 2 minutes. 250 μL of each sample was transferred to a Millipore MultiScreenHTS filter plate with polycarbonate membrane (pore size 0.45 μm). Filtrates were collected by centrifugation at 3,000 rpm for 2 minutes. Dissolved concentrations were determined by UPLC / UV (ultra-performance liquid chromatography / ultraviolet) on a Waters ACQUITY UPLC® SQD system equipped with a Waters ACQUITY UPLC® BEH 2.1×50 mm C18 column, particle size 1.7 μm, using a short gradient (5→95% B, total cycle time 1.7 min) of water / 0.1% formic acid as solvent A and acetonitrile / 0.1% formic acid as solvent B. A photodiode array UV detector was operated at 254 nm to measure compound signals. Solubility was determined with a one-point calibration by comparing peak areas against reference standards using Waters Empower software. Results can be seen in Table 4.

[0186] [Table 20] TIFF0007634112000097.tif21147 TIFF0007634112000098.tif21140

Claims

1. A compound of formula (I) or a salt thereof. 【Chemistry 1】 (I) (In the formula, A is N or C; B is, 5-7 membered monocyclic heterocyclyl containing 1 or 2 N atoms; 6-membered bicyclic heterocyclyl containing one N atom; 7-11 membered bicyclic heterocyclyl containing two N atoms; a 7-membered bicyclic heterocyclyl containing one N atom and one O atom; 6-membered monocyclic heterocyclyl containing one N atom and one heteroatom selected from the group consisting of O and S; a 9-membered bicyclic heterocyclyl containing three heteroatoms, two of which are N and one of which is O; a 9-membered bicyclic heterocyclyl containing one N atom and one S atom; Contains 3 N atoms, 2 of which are C 1-6 - 10-membered bicyclic heterocyclyl substituted by alkyl, Phenyl, 9-membered bicyclic heteroaryl containing 3 N atoms; is a group selected from the group consisting of: D is 9-membered bicyclic heteroaryl containing two N atoms; a 10-membered bicyclic heteroaryl containing one N atom, and Benzodioxole is a group selected from the group consisting of: R 1 is -H, -C 1-6 -Alkyl, -CF 3 , -C 2-6 -alkynyl, -O-C 1-6 - selected from the group consisting of alkyl and halogen; R 2 is -H, -C 1-6 -alkyl, -C 1-6 -Alkylene-OH, -C(O)OH, -C(O)O-C 1-6 -Alkyl and -pyrazolyl-C 1-6 - alkyl; R 3 is -H or -C 1-6 - alkyl; R 4 is -H, -C 1-3 -Alkyl, -NH 2 , -NHC 1-3 -Alkyl and N(C 1-3 -alkyl) 2 selected from the group consisting of: R 5 is absent, or -H, -C 1-6 -Alkyl, -S(O 2 ) -C 1-6 -Alkyl, -NH-S(O 2 ) -C 1-6 -Alkyl, ═O, —C(O)—C 1-6 -Alkyl, -C(O)H, -C(O)OH, -C(O)NH 2 , -C(O)O-C 1-6 -Alkyl, -NR 5.1 R 5.2 , -C 1-6 -Alkylene-C(O)OH, -S(O 2 )-NH 2 , -pyrrolidin-2-one-1-yl, -tetrazolyl, and R 5.3 5-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O, substituted with R 5.1 is -H, -C 1-6 -alkyl, -C(O)-C 1-6 -Alkyl and -C 1-6 -Alkylene-O-C 1-6 - alkyl; R 5.2 is -H, -C 1-6 -alkyl, -C(O)-C 1-6 -alkyl, -C 1-6 -Alkylene-O-C 1-6 -Alkyl and -C 1-6 -Alkylene-R 5.3 selected from the group consisting of: R 5.3 is -H, -C 1-6 - alkyl and 6-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O; R 6 is absent, or -H, -C 1-6 -alkyl, ═O, and —C(O)OH.

2. R 1 But, -C 1-6 -Alkyl, -CF 3 , -O-C 1-6 - selected from the group consisting of alkyl and halogen; R 4 is -H or -C 1-3 - alkyl, The compound according to claim 1 or a salt thereof.

3. D. 【Chemistry 2】 selected from the group consisting of: R 1 But, -C 1-6 -Alkyl, -CF 3 , -O-C 1-6 -alkyl, -Br and -Cl; R 2 is -H; R 3 is -H; The compound according to claim 1 or a salt thereof.

4. D. 【Chemistry 3】 2. The compound according to claim 1, or a salt thereof, selected from the group consisting of:

5. D. 【Chemistry 4】 2. The compound according to claim 1, or a salt thereof, selected from the group consisting of:

6. R 5 But -H, -C 1-6 -Alkyl, -S(O 2 ) -C 1-6 -Alkyl, =O, -C(O)H, -C(O)NH 2 , -C(O)OH, -C(O)OC 1-6 -Alkyl, -NR 5.1 R 5.2 , and R 5.3 5-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of N and O, substituted with R 5.1 But -H, -C 1-6 -alkyl, -C(O)-C 1-6 -Alkyl and -C 1-6 -Alkylene-O-C 1-6 - alkyl is selected from the group consisting of: R 5.2 But -H, -C 1-6 -alkyl, -C(O)-C 1-6 -alkyl, -C 1-6 -Alkylene-O-C 1-6 -Alkyl and -C 1-6 -Alkyl-R 5.3 selected from the group consisting of: R 5.3 is -H or -C 1-6 - alkyl, The compound according to claim 1 or a salt thereof.

7. B, 【Chemistry 5】 2. The compound according to claim 1, or a salt thereof, selected from the group consisting of:

8. B, 【Chemistry 6】 2. The compound according to claim 1, or a salt thereof, selected from the group consisting of:

9. B, 【Chemistry 7】 2. The compound according to claim 1, or a salt thereof, selected from the group consisting of: 【Request 10】 【Chemical 8-1】 【Chemistry 8-2】 2. The compound of claim 1, selected from the group consisting of:

11. The compound of claim 1 which is not in the form of a salt.

12. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharma- ceutically acceptable salt thereof.

13. 13. A pharmaceutical composition comprising the compound of claim 1 or a pharma- ceutical acceptable salt thereof for use in the treatment of a disease selected from the group consisting of inflammation, allergy and autoimmune diseases, infectious diseases and cancer, or for use as a vaccine adjuvant.

14. 13. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, administered following radiation therapy.

15. The pharmaceutical composition according to any one of claims 12 to 14, further comprising a pharma- ceutically acceptable carrier.

16. The pharmaceutical composition according to any one of claims 12 to 14, further comprising, as another active substance, a substance selected from the group consisting of a cytostatic substance, a cytotoxic substance, a cell growth inhibitor, an anti-angiogenic substance, a steroid, a virus, an immunogenic cell death inducer, a cancer targeting agent, an immunomodulator, an antibody, and a nanobody.

17. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

18. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

19. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

20. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

21. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

22. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

23. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

24. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

25. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

26. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

27. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

28. A compound represented by the following formula:

29. A compound represented by the following formula:

30. A compound represented by the following formula:

31. A compound represented by the following formula:

32. A compound represented by the following formula:

33. A compound represented by the following formula:

34. A compound represented by the following formula:

35. A compound represented by the following formula:

36. A compound represented by the following formula:

37. A compound represented by the following formula:

38. A compound represented by the following formula:

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