Heterocyclic compounds capable of activating STING

Abstract

The present invention relates to heterocyclic compounds of formula (I) capable of activating STING (Stimulating Protein of Interferon Gene). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to small molecules capable of activating STING (Stimulator of Interferon Gene) and salts thereof. Specifically, the present invention relates to heterocyclic compounds capable of activating STING. In addition, the present invention relates to pharmaceutical compositions and drug 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 inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, and for use as vaccine adjuvants. Background Art

[0002] STING is one of the pattern recognition receptors (PRRPs) that play an important role in the innate immune system, which discriminates 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 as well as malignant cells. However, pathogens and cancer cells have evolved ways to evade immune system recognition. Therefore, the goal of immunotherapy is to initiate an antigen-specific immune response or reactivate a pre-existing response against pathogenic invaders or cancer cells in certain cell types of the immune system.

[0003] Among the PRRPs, STING (also known as TMEM173, MPYS, MITA, ERIS) belongs to the nucleic acid sensor family and is an adaptor for cytosolic DNA signaling. In mammalian cells in a healthy state, DNA is compartmentalized in the nucleus. For pathogenic situations, such as the invasion of DNA-containing pathogens or in malignant cells, DNA is present in the cytoplasm. In response to this, STING is crucial for detecting the cytosolic DNA described above and inducing an immune response against pathogenic events.

[0004] STING exists as a dimer in its basal state, with the N-terminal domain anchored in the ER and the C-terminal domain residing in the cytosol. Cyclic dinucleotides (CDNs), produced by the protein cyclic GMP-AMP synthase (cGAS), are the natural ligands for STING (Ablasser et al., Nature 498, 380-384, 2013). Binding of CDNs to STING induces a conformational change that permits the binding and activation of TANK-binding kinase (TBK1) to interferon regulatory factor 3 (IRF3), followed by relocation from the ER to perinuclear endosomes (Liu et al., Science 347, no. 6227, 2630-1-2630-14, 2015). Through TBK1, phosphorylation of the transcription factors IRF3 and NF-kB leads to the expression of multiple cytokines, including type I interferons (IFNs).

[0005] Type I IFNs produced by antigen-presenting cells and other cell types are thought to be key events in the activation of T cells and subsequent differentiation into antigen-specific effector CD4 and CD8 T cells. It has been shown that the absence of type I IFNs results in reduced 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 an increase in the number of tumor-infiltrating T cells and potentially favorable clinical outcomes (Sistigu et al., Nature Medicine 20, 1301-1309, 2014).

[0006] Efficient secretion of type I IFNs in the tumor microenvironment and induction of T cell-dependent immune responses against cancer cells depend on the presence of STING, as shown in recent studies in mice (Woo et al., Immunity 41, 5, 830-842, 2014; Corrales et al., Cell Reports 11, 1018-1030, 2015; Deng et al., Immunity 41, 5, 843-852, 2014). Deletion of STING results in reduced levels of type I IFNs in the tumor microenvironment and reduced antitumor effects in several mouse tumor models, highlighting the importance of the presence of type I IFNs. On the other hand, specific activation of STING leads to improved antigen-specific T cell immune responses against cancer cells.

[0007] Type I interferons can significantly enhance antitumor immune responses by inducing the activation of both acquired and innate immune cells.

[0008] Given the importance of type I IFN in several malignancies, including viral infections, and cancer therapies, strategies that allow for specific activation of STING have therapeutic significance. STING activation can synergize with various approved chemotherapeutic agents or other anti-cancer therapies (e.g., radiotherapy) (Wu et al., Med Res Rev May 2020; 40(3):1117-1141) or with infectious disease therapies.

[0009] In the prior art, small molecule modulators of STING are described, for example, in WO2020075790. Summary of the Invention

[0010] The compounds according to the invention are novel STING activators, as demonstrated by an in vitro reporter system using the THP1-Blue reporter cell line.

[0011] In one aspect, the invention relates to compounds of formula (I)

[0012]

[0013] wherein

[0014] B is a group selected from the group consisting of:

[0015] a 5- to 7-membered monocyclic heterocyclic group containing 1 or 2 N atoms,

[0016] a 6-membered bicyclic heterocyclic group containing 1 N atom, and

[0017] a 6-membered monocyclic heterocyclic group containing 1 N atom and 1 heteroatom selected from the group consisting of O and S;

[0018] R 1 is -H or -C 1-6 alkyl;

[0019] R 2 is -H or -halogen;

[0020] R 3 is -H or -halogen;

[0021] provided that R 2 and / or R 3 is halogen;

[0022] R 4 is selected from the group consisting of: -H, -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, -C(O)OH, -C(O)O-C 1-6 alkyl, -C 1-6 alkylene-C(O)OH and -C(O)NH2 ;

[0023] R 5 is absent or is selected from the group consisting of -H and =O

[0024] or a salt thereof.

[0025] The compound of formula (I) or a salt thereof as defined herein is particularly suitable for the treatment of pathophysiological processes associated with or regulated by STING, particularly suitable for the treatment of inflammatory, allergic or autoimmune diseases, infectious diseases or cancer, or as a vaccine adjuvant.

[0026] 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 pharmaceutical combination comprising other active substances. In another embodiment, the present invention provides a general synthetic protocol for the compound of general formula (I), including examples and methods. Detailed Description

[0027] The compounds of the present invention exhibit several advantageous properties, such as favorable binding affinity for human STING, favorable cellular activity (i.e., in cells carrying different human STING alleles) as measured by cellular EC50, and favorable permeability in the cellular assays described below.

[0028] Thus, in a first aspect, the present invention provides novel compounds of formula (I), including their salts, which activate STING and thus induce cytokine production in a STING-dependent manner in vitro and / or in vivo, and have suitable pharmacological and pharmacokinetic properties for therapy (i.e., for use as a medicament).

[0029] The compounds according to the invention generally exhibit a cellular EC50 of less than 7 μM, preferably less than 4 μM, more preferably less than 2 μM, and most preferably less than 1 μM for the "HAQ" version of STING.

[0030] Furthermore, the compounds according to the invention also exhibit a cellular EC50 of less than 3 μM, preferably less than 2 μM, more preferably less than 1 μM, and most preferably less than 0.7 μM for the human STING variant "H232R" (sometimes also referred to as wild type, Yi et al., 2013; PLOS ONE 8(10)).

[0031] In addition, the compounds according to the invention also exhibit a cellular EC50 of less than 3 μM, preferably less than 2 μM, more preferably less than 1 μM, and most preferably less than 0.7 μM against the human STING variant "R232H".

[0032] In addition, the compounds according to the invention also exhibit a cellular EC50 of less than 10 μM, preferably less than 5 μM, more preferably less than 3 μM, even more preferably less than 2 μM, and most preferably less than 1 μM against the human STING variant "R293Q".

[0033] In addition, the compounds according to the invention also exhibit a cellular EC50 of less than 7 μM, preferably less than 3 μM, more preferably less than 2 μM, and most preferably less than 1 μM against the human STING variant "AQ".

[0034] "H232R", "R232H", and "R293Q" are single amino substitutions at the given positions. "AQ" is a variant consisting of two substitutions G230A and R293Q, and "HAQ" is a STING variant consisting of three substitutions (R71H, G230A, and R293Q) (Yi et al., 2013; PLOS ONE 8(10)). Activity against different variants of human STING is advantageous because the activity maximizes the probability of inducing the desired pharmacological response in patients with single nucleotide polymorphisms.

[0035] Compounds having a cellular EC50 of less than 1 μM against the human STING variants "AQ", "HAQ", and "R293Q" and less than 0.7 μM against the human STING variants "R232H" and "H232R" are preferred.

[0036] In addition, the compounds of the invention exhibit favorable binding to the human STING protein. The favorable binding affinity to human STING, as well as favorable cellular activity and / or favorable pharmacokinetic properties, enable a lower dose to be achieved for pharmacological efficacy. The lower dose has the advantage of a lower "drug load" or "drug burden" (parent drug and its metabolites) for the patient, thereby causing potentially fewer side effects and reducing the production cost of the drug.

[0037] The binding of a compound to a protein can be determined by known methods such as surface plasmon resonance, scintillation proximity assay, isothermal titration calorimetry, or differential scanning fluorimetry. In the latter test, the temperature at which the protein unfolds (also known as the melting temperature T m ) is measured by the fluorescence change of a dye that binds to the hydrophobic part of the protein. After binding of a small molecule, T mThe displacement is related to the binding affinity of the small molecule. A high binding affinity of the STING agonist is manifested as a T displacement of >10K, preferably >13K, more preferably >15K. m Displacement.

[0038] In another aspect of the present invention, the compounds of the present invention exhibit good cell permeability, promoting the targeted binding of intracellular STING protein (measured in the Caco-2 cell line) from the apical side to the basolateral side of the cell monolayer (Caco-2 A→B) greater than 5×10E-6 cm / s, preferably greater than 8×10E-6 cm / s, more preferably greater than 10×10E-6 cm / s. In addition, the compounds of the present invention show a low efflux rate from Caco cells of <8, preferably <5, more preferably <3.5 (calculated as follows), indicating good residence time inside the cell and thus promoting a longer targeted binding duration. app,AB (Measured from the apical side to the basolateral side 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. In addition, the compounds of the present invention show a low efflux rate from Caco cells of <8, preferably <5, more preferably <3.5 (calculated as follows), indicating good residence time inside the cell and thus promoting a longer targeted binding duration.

[0039] In another aspect of the present invention, the compounds of the present invention exhibit a cellular EC50 of less than 1 μM against the human STING variant "HAQ" and an efflux rate from Caco cells of <3.5. In another aspect of the present invention, the compounds of the present invention exhibit a cellular EC50 of less than 0.7 μM against the human STING variant "H232R" and an efflux rate from Caco cells of <3.5. Compounds having a cellular EC50 of less than 0.7 μM against the human STING variant "H232R", a cellular EC50 of less than 1 μM against the human STING variant "HAQ", and an efflux rate from Caco cells of <3.5 are preferred.

[0040] The compounds of the present invention according to formula (I) as defined herein

[0041]

[0042] wherein

[0043] B is a group selected from the group consisting of:

[0044] a 5- to 7-membered monocyclic heterocyclic group containing 1 or 2 N atoms,

[0045] a 6-membered bicyclic heterocyclic group containing 1 N atom, and

[0046] a 6-membered monocyclic heterocyclic group containing 1 N atom and 1 heteroatom selected from the group consisting of O and S;

[0047] R 1 is -H or -C 1-6 alkyl;

[0048] R 2 is -H or -halogen;

[0049] R 3 is -H or -halogen;

[0050] provided that R 2 and / or R 3 is halogen;

[0051] R 4 is selected from the group consisting of: -H, -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, -C(O)OH, -C(O)O-C 1-6 alkyl, -C 1-6 alkylene-C(O)OH and -C(O)NH 2 ;

[0052] R 5 is absent or is selected from the group consisting of -H and =O;

[0053] or a salt thereof, which is particularly suitable for treating pathophysiological processes associated with or regulated by STING, particularly suitable for treating inflammatory, allergic or autoimmune diseases, infectious diseases or cancer, or suitable as a vaccine adjuvant. Accordingly, in another aspect, the present invention further relates to a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use as a medicament. From the foregoing and the following description and examples, other aspects of the present invention will be apparent to those skilled in the art.

[0054] Terms and Definitions Used

[0055] Terms not specifically defined herein shall have the meaning that would be ascribed to them by those skilled in the art in view of the disclosure and context. However, as used in this specification, unless otherwise specified, the following terms have the designated meanings and comply with the following conventions.

[0056] In the groups, radicals or moieties defined below, the number of carbon atoms is usually specified before the group, e.g., C 1-6 Alkyl refers to an alkyl group or alkyl radical having 1 to 6 carbon atoms. Generally, in groups such as HO, H 2 N, (O)S, (O) 2 S, NC (cyano), HOOC, F 3 C, etc. or similar groups, those skilled in the art can see the point of attachment to one or more groups of the molecule from the free valence of the group itself. For a combined group containing two or more subunits, the last named subunit is the point of attachment of the group, e.g., the substituent "aryl-C 1-3"Alkylene" refers to an aryl group bonded to a C 1-3 alkyl group, where the C 1-3 alkyl group is bonded to the parent nucleus or to a group to which a substituent is attached.

[0057] In cases where the compounds of the present invention are described by chemical name and chemical formula, if there is any inconsistency, the chemical formula shall prevail. A wavy line in a sub-formula may be used to indicate a bond connecting to the defined parent nucleus molecule.

[0058] For example, the term "3-carboxypropyl group" represents the following substituent:

[0059]

[0060] where the carboxyl group is bonded to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" groups represent the following groups:

[0061]

[0062] A wavy line in a sub-formula may be used to indicate a bond connecting to the defined parent nucleus molecule.

[0063] 1.1.1.1 The term substituted

[0064] As used herein, the term "substituted" means that one or more hydrogens on the specified atom are replaced by a group selected from the group of defined substituents, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Similarly, the term "substituted" may be used in combination with a chemical moiety rather than a single atom, such as "substituted alkyl", "substituted aryl", or the like.

[0065] 1.1.1.2 Stereochemistry - Solvates - Hydrates

[0066] Unless otherwise specified, throughout the specification and the appended claims, a given chemical formula or name shall cover tautomers and all stereoisomers, optical isomers, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc...), and their racemates, as well as mixtures of individual enantiomers in different ratios, mixtures of diastereomers, or mixtures of any of the foregoing forms in which such isomers and enantiomers are present, and their solvates, such as hydrates.

[0067] Unless otherwise specified, "pharmaceutically acceptable salts", as more specifically defined below, shall also cover their solvates, such as hydrates.

[0068] 1.1.1.3 Stereoisomers

[0069] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separating the corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. Those skilled in the art know how to prepare optically active forms, for example, by resolution of the racemic form or by synthesis, for example, starting from optically active starting materials and / or by using chiral reagents.

[0070] The enantiomerically pure compounds or intermediates of the present invention can be prepared via asymmetric synthesis, for example, by preparing and subsequently separating suitable diastereomeric compounds or intermediates that can be separated by known methods (such as by chromatographic separation or crystallization) and / or by using chiral reagents (such as chiral starting materials, chiral catalysts or chiral auxiliaries).

[0071] In addition, those skilled in the art know how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, for example, by chromatographically separating the corresponding racemic mixtures on a chiral stationary phase; or by using a suitable resolving agent to resolve the racemic mixture, for example, by forming a diastereomeric salt of the racemic compound with an optically active acid or base, subsequently resolving the salt and releasing the desired compound from the salt; or by performing derivatization of the corresponding racemic compound with an optically active chiral auxiliary reagent, subsequently separating the diastereomers and removing the chiral auxiliary group; or by kinetic resolution of the racemate (such as by enzymatic resolution); by enantioselective crystallization from conglomerates of enantiomorphic crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0072] 1.1.1.4 Salts

[0073] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans without excessive toxicity, irritation, allergic response or other problems or complications and have a reasonable benefit / risk ratio.

[0074] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include (but are not limited to) inorganic or organic acid salts of basic residues (such as amines); alkali metal salts or organic salts of acidic residues (such as carboxylic acids); and the like.

[0075] For example, such salts include salts 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.

[0076] It can form other pharmaceutically acceptable salts with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0077] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of a suitable base or acid in water or in an organic diluent (such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile or a mixture thereof).

[0078] In addition to the salts mentioned above, salts of other acids (such as trifluoroacetate) that are suitable for purifying or isolating the compounds of the present invention also form part of the present invention.

[0079] 1.1.1.5 Halogen

[0080] The term halogen refers to fluorine, chlorine, bromine, and iodine.

[0081] 1.1.1.6 Heteroatom

[0082] Heteroatoms can exist in all possible oxidation states. For example, sulfur can exist in the form of sulfoxide (R-S(O)-R') and sulfone (-R-S(O) 2 -R').

[0083] 1.1.1.7 Alkyl

[0084] 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 another radical represents an acyclic saturated branched or straight-chain hydrocarbon group having 1 to n carbon atoms. For example, the term C 1-5 alkyl encompasses the groups H 3 C, H 3 CCH 2 , H 3 CCH 2 CH 2 , H 3 CCH(CH 3 )), H 3 CCH 2 CH 2 CH 2 , H 3 CCH 2 CH(CH 3 )), H 3 CCH(CH 3 )CH 2 , H3 CC(CH 3 ) 2 、H 3 CCH 2 CH 2 CH 2 CH 2 、H 3 CCH 2 CH 2 CH(CH 3 )、H 3 CCH 2 CH(CH 3 )CH 2 、H 3 CCH(CH 3 )CH 2 CH 2 、H 3 CCH 2 C(CH 3 ) 2 、H 3 CC(CH 3 ) 2 CH 2 、H 3 CCH(CH 3 )CH(CH 3 ) and H 3 CCH 2 CH(CH 2 CH 3 )。

[0085] 1.1.1.8 - alkylene

[0086] 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 another group, represents an acyclic saturated branched or straight-chain divalent alkyl group containing 1 to n carbon atoms. For example, the term C 1-4 alkylene includes -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -CH(CH 3 )-CH 2 -, -CH 2 -CH(CH 3)-, -CH 2 -CH 2 -CH 2 -CH 2 )-, -CH 2 -CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH 2 -CH 2 )-, -CH 2 -CH(CH 3 )-CH 2 )-, -CH 2 -C(CH 3 ) 2 )-, -C(CH 3 ) 2 -CH 2 )-, -CH(CH 3 )CH-(CH 3 )-, -CH 2 -CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )-CH 2 )-, -CH(CH 2 CH 2 CH 3 )-, -CH(CH(CH 3 )) 2 - and -C(CH 3 )(CH 2 CH 3 )-.

[0087] 1.1.1.9 Alkenyl

[0088] If at least two carbon atoms of the C 2-m alkyl group are bonded to each other by a double bond, the term "C 2-m alkenyl" is used for this group "C 2-m alkyl", where m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0089] 1.1.1.10 Alkenylene

[0090] If at least two carbon atoms of the C 2-m alkylene group are bonded to each other by a double bond, the term "C 2-m alkenylene" is used for this group "C 2-m alkylene", where m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0091] 1.1.1.11 Alkynyl

[0092] If C 2-m at least two carbon atoms of the alkyl group are bonded to each other by a triple bond, the term "C 2-m alkynyl" is used for the group "C 2-m alkyl", where m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0093] 1.1.1.12 alkynylene

[0094] If C 2-m at least two of those carbon atoms of the alkylene group are bonded to each other by a triple bond, the term "C 2-m alkynylene" is used for the group "C 2-m alkylene", where m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0095] 1.1.1.13 cycloalkyl

[0096] 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 another group represents a cyclic saturated unbranched hydrocarbon group having 3 to k carbon atoms. For example, the term C 3-7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0097] 1.1.1.14 cycloalkenyl

[0098] 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 another group represents a cyclic unsaturated but non-aromatic unbranched hydrocarbon group having 3 to k carbon atoms, where at least two carbon atoms are bonded 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 cycloheptatrieneyl.

[0099] 1.1.1.15 halo-(alkyl, alkylene or cycloalkyl)

[0100] The term "halo" added to "alkyl", "alkylene" or "cycloalkyl" (saturated or unsaturated) defines an alkyl, alkylene or cycloalkyl group in which one or more hydrogen atoms are replaced by halogen atoms selected from fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferably fluorine. Examples include: H 2 FC-, HF 2 C-, F 3 C-.

[0101] 1.1.1.16 carbocyclic group

[0102] The term "carbocyclic group", alone or in combination with another group, refers to a monocyclic, bicyclic or tricyclic structure composed of 3 to 14 carbon atoms. The term "carbocyclic group" refers to a fully saturated, partially saturated and aromatic ring system.

[0103] The term "carbocyclic group" encompasses fused, bridged and spiro ring systems.

[0104]

[0105] 1.1.1.17 Aryl

[0106] As used herein, the term "aryl", alone or in combination with another group, denotes a monocyclic carbocyclic aromatic group containing 6 carbon atoms, which is optionally further fused to a second aromatic, saturated or unsaturated five- or six-membered carbocyclic group. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl and dihydronaphthyl.

[0107] 1.1.1.18 Heterocyclic group

[0108] The term "heterocyclic group" refers to a saturated or unsaturated monocyclic or polycyclic system optionally containing an aromatic ring, which contains one or more heteroatoms selected from N, O, S, SO, SO 2 and is composed of 3 to 14 ring atoms, wherein none of the heteroatoms is part of an aromatic ring. The term "heterocyclic group" is intended to include all possible isomeric forms.

[0109] Thus, the term "heterocyclic group" includes the following exemplary structures (when each form is optionally attached by a covalent bond to any atom, it is not described as a group as long as the appropriate valence is maintained):

[0110]

[0111]

[0112] 1.1.1.19 Heteroaryl

[0113] The term "heteroaryl" refers to a monocyclic or polycyclic system containing at least one aromatic ring, which contains one or more heteroatoms selected from N, O, S, SO or SO 2 and is composed of 5 to 14 ring atoms, wherein at least one of the heteroatoms is part of an aromatic ring, and wherein the resulting ring system must be chemically stable. The term "heteroaryl" is intended to include all possible isomeric forms.

[0114] Thus, the term "heteroaryl" includes the following exemplary structures (when each form is optionally attached by a covalent bond to any atom, it is not described as a group as long as the appropriate valence is maintained):

[0115]

[0116] Many of the terms shown above may be used repeatedly to define chemical formulas or groups and, in each case, independently of one another, have a meaning given above.

[0117] The term "bicyclic system" refers to a group consisting of two linked cyclic substructures, said cyclic substructures including spiro, fused, and bridged ring systems.

[0118] Preferred embodiments

[0119] A particular embodiment of the present invention relates to a compound of formula (I)

[0120] or a salt thereof,

[0121] wherein R 1 is -C 1-3 alkyl.

[0122] Another particular embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R 1 is -CH 3 .

[0123] Another particular embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R 2 is selected from the group consisting of -H, -F, and -Cl.

[0124] Another particular embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R 3 is selected from the group consisting of -H, -F, and -Cl.

[0125] Another particular embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R 2 is selected from the group consisting of -H, -F, and -Cl, and R 3 is selected from the group consisting of -H, -F, and -Cl, provided that R 2 and / or R 3 is -F or -Cl.

[0126] Another particular embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting of: -H, -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, -C(O)OH, -C(O)O-C 1-6 alkyl.

[0127] Another particular embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R 4Selected from the group consisting of: -H, -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, -C(O)OH.

[0128] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting of: -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, -C(O)OH.

[0129] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is -C(O)OH.

[0130] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein B is a group selected from the group consisting of:

[0131] a 5- to 7-membered monocyclic heterocyclic group containing 1 or 2 N atoms,

[0132] a 6-membered bicyclic heterocyclic group containing 1 N atom, and

[0133] a 6-membered monocyclic heterocyclic group containing 1 N atom and 1 heteroatom selected from the group consisting of O and S.

[0134] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein B is selected from the group consisting of:

[0135]

[0136] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein B is selected from the group consisting of:

[0137]

[0138] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein B is selected from the group consisting of:

[0139]

[0140] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein B is selected from the group consisting of:

[0141]

[0142] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein B is selected from the group consisting of:

[0143] and wherein R 4 is selected from the group consisting of: -H, -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, -C(O)OH, and wherein R 5 is absent or is selected from the group consisting of -H and =O.

[0144] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein B is selected from the group consisting of:

[0145] and wherein R 1 is -CH 3 and R 2 is selected from the group consisting of -H, -F, and -Cl; wherein R 3 is selected from the group consisting of -H, -F, and -Cl, provided that R 2 and / or R 3 is -F or -Cl; and wherein R 4 is selected from the group consisting of: -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, -C(O)OH; and wherein R 5 is absent or is selected from the group consisting of -H and =O.

[0146] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0147]

[0148]

[0149] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0150]

[0151]

[0152] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0153]

[0154]

[0155] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0156]

[0157]

[0158] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0159]

[0160] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0161]

[0162] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0163]

[0164]

[0165] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0166]

[0167]

[0168] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0169]

[0170] Another specific embodiment of the present invention relates to a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0171]

[0172] Another specific embodiment of the present invention relates to

[0173] or a pharmaceutically acceptable salt thereof.

[0174] Another specific embodiment of the present invention relates to

[0175] or a pharmaceutically acceptable salt thereof.

[0176] Another specific embodiment of the present invention relates to

[0177] or a pharmaceutically acceptable salt thereof.

[0178] Another specific embodiment of the present invention relates to

[0179] or a pharmaceutically acceptable salt thereof.

[0180] Another specific embodiment of the present invention relates to

[0181] or a pharmaceutically acceptable salt thereof.

[0182] Another specific embodiment of the present invention relates to

[0183] or a pharmaceutically acceptable salt thereof.

[0184] Another specific embodiment of the present invention relates to

[0185] or a pharmaceutically acceptable salt thereof.

[0186] Another specific embodiment of the present invention relates to

[0187] or a pharmaceutically acceptable salt thereof.

[0188] Another specific embodiment of the present invention relates to

[0189] or a pharmaceutically acceptable salt thereof.

[0190] Another specific embodiment of the present invention relates to

[0191] or a pharmaceutically acceptable salt thereof.

[0192] Another specific embodiment of the present invention relates to

[0193] or a pharmaceutically acceptable salt thereof.

[0194] Another specific embodiment of the present invention relates to

[0195]

[0196] or a pharmaceutically acceptable salt thereof.

[0197] Another specific embodiment of the present invention relates to

[0198]

[0199] or a pharmaceutically acceptable salt thereof.

[0200] B, R 1 , R 2 , R 3 , R 4 , R 5 Any and each of the definitions in may be combined with one another. In one aspect, the present invention relates to compounds of formula (I) in salt-free form.

[0201] In one aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof for use as a medicament. In one aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof for the treatment of diseases selected from the group consisting of: inflammatory, allergic or autoimmune diseases, infectious diseases and cancer, or for use as a vaccine adjuvant. In one aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. In one aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof as other active substances selected from the group consisting of: cell growth inhibitory substances, cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, viruses, immunogenic cell death inducers, cancer targeting agents, immunomodulators, antibodies and nanobodies.

[0202] Treatment methods

[0203] In another aspect of the present invention, it has been found that compounds of general formula (I) or salts thereof are suitable for the prevention and / or treatment of diseases and / or conditions in which modulation of STING is therapeutically beneficial. Additionally, the compounds of the present invention are suitable for use as a vaccine adjuvant due to their activity.

[0204] 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.

[0205] Autoimmune diseases include (but are not limited to) systemic lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), dermatomyositis and Sjogren's syndrome (SS).

[0206] The compounds of the present invention can be used to treat inflammation in any tissue and organ of the body, including (but not limited to) musculoskeletal inflammation, vascular inflammation, nerve inflammation, digestive system inflammation, eye inflammation, reproductive system inflammation and other inflammations.

[0207] Examples of musculoskeletal inflammation treatable with the compounds of the invention include: arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendinitis, synovitis, tenosynovitis, bursitis, fibrositis (muscle fiber pain), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, pubic osteitis, and osteitis fibrosa cystica). Examples of ocular inflammation treatable with the compounds of the invention include: blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis. Examples of nervous system inflammation treatable with the compounds of the invention include: encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, and schizophrenia. Examples of inflammation of the vasculature or lymphatic system treatable with the compounds of the invention include: arthralgia, arthritis, phlebitis, vasculitis, and lymphangitis. Examples of inflammatory conditions of the digestive system treatable with the compounds of the 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 treatable with the compounds of the invention include: cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[0208] The compounds can be used to treat autoimmune conditions having an inflammatory component. Such conditions include acute disseminated alopecia universalis, Behcet's disease, Chagas' disease, chronic fatigue syndrome, autonomic disorders, 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, Grave's disease, Guillain-Barré syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjögren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0209] The compounds can be used to treat T cell-mediated hypersensitivity diseases having an inflammatory component. Such conditions include contact hypersensitivity, contact dermatitis (including contact dermatitis caused by poison ivy), urticaria, cutaneous allergy, respiratory allergy (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0210] Other inflammatory conditions treatable with the compounds described herein include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, pneumonia, prostatitis, pyelonephritis, and stomatitis, transplant rejection (involving organs such as the kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small intestine, etc., skin allograft, skin homograft, and cardiac valve xenograft, serum sickness, and graft-versus-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sézary's syndrome, congenital adrenal hyperplasia, nonsuppurative thyroiditis, cancer-related hypercalcemia, pemphigus, bullous herpetiform dermatitis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis, and iridocyclitis, choroidoretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated tuberculosis chemotherapy, adult idiopathic thrombocytopenic purpura, adult secondary thrombocytopenia, acquired (autoimmune) hemolytic anemia, adult leukemia and lymphoma, childhood acute leukemia, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid 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 lung disease, and inflammation associated with infectious conditions (e.g., sepsis).

[0211] In one aspect, the diseases or conditions treatable with the compounds of the invention are cancers. Examples of cancer diseases and conditions for which the compounds of formula (I), or salts or solvates thereof, may have potentially beneficial anti-tumor effects include (but are not limited to): lung cancer, bone cancer, pancreatic cancer, skin cancer, brain cancer, head cancer, neck cancer, uterine cancer, ovarian cancer, gastric cancer, colon cancer, colorectal cancer, breast cancer, esophageal cancer, small intestine cancer, bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, urethral cancer, prostate cancer, penile cancer, testicular cancer, ureteral cancer, bladder cancer, kidney cancer or liver cancer, cholangiocarcinoma; urothelial carcinoma; rectal cancer; anal area cancer; fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, renal pelvic cancer, renal cell carcinoma; sarcoma; soft tissue sarcoma; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatocellular carcinoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphoma; primary CNS lymphoma; CNS tumors; spinal axis tumors; squamous cell carcinoma; synovial sarcoma; malignant pleural mesothelioma; brainstem glioma; pituitary adenoma; bronchial adenoma; chondromatous hamartoma; mesothelioma; Hodgkin's Disease or a combination of one or more of the foregoing cancers.

[0212] Preferred cancers treatable with the compounds of the invention are skin cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), liver cancer, pancreatic cancer, colon cancer, colorectal cancer, brain cancer, breast cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, cholangiocarcinoma, endometrial cancer, thyroid cancer, cervical cancer, gastric cancer, head cancer, neck cancer, sarcoma, soft tissue sarcoma, esophageal cancer, head and neck cancer, rectal cancer and urothelial carcinoma, and lymphoma.

[0213] The novel compounds can be used for the prophylactic, palliative, curative or semi-curative, short-term or long-term treatment of the diseases mentioned above, optionally in combination with surgery, radiotherapy or other "state-of-the-art" compounds, such as cell growth inhibitors or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, antibodies, nanobodies, cancer targeting agents, viruses (including (but not limited to) oncolytic viruses) or immunogenic cell death inducers.

[0214] The novel compound can also be used for preventing, alleviating, curatively or semi-curatively, treating in the short or long term the diseases mentioned above by combining different administration routes of the compound (such as intravenous, intratumoral, subcutaneous, inhalation, oral, etc.), optionally also in combination with surgery, radiotherapy or other "state-of-the-art" compounds, such as cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, antibodies, nanobodies, cancer targeting agents, viruses (including (but not limited to) oncolytic viruses) or immunogenic cell death inducers. Only as an example of surgery, partial or complete tumor resection can be combined with the compounds of the present invention. Only as an example of radiotherapy, external beam radiotherapy can be combined with the compounds of the present invention.

[0215] When used as an adjuvant, in certain embodiments the compounds and compositions of the present invention can be used as adjuvants in therapeutic or prophylactic strategies employing one or more vaccines. Thus, the compounds or salts thereof of the present invention can be used together with one or more vaccines selected to stimulate an immune response against one or more predetermined antigens. The compounds or salts thereof of the present invention can be provided together with such vaccines or additionally provided in addition to such vaccines.

[0216] Such one or more vaccines can comprise inactivated or attenuated bacteria or viruses, the bacteria or viruses comprising the antigen of interest, purified antigen, an active viral or bacterial delivery vector engineered recombinantly for the expression and / or secretion of the antigen, an antigen-presenting cell (APC) vector comprising cells loaded with the antigen or transfected with a composition comprising nucleic acid encoding the antigen, a liposomal antigen delivery vehicle or a naked nucleic acid vector encoding the antigen. This list is not intended to be limiting. For example, such one or more vaccines can also comprise inactivated tumor cells or oncolytic viruses that express and secrete one or more of GM-CSF, CCL20, CCL3, IL-12p70, FLT-3 ligand, cytokines.

[0217] Accordingly, the present invention relates to a compound of general formula (I) for use as a pharmaceutical or vaccine adjuvant.

[0218] In another aspect, the present invention provides novel compounds of formula (I), including salts thereof, for use in methods of treating diseases or conditions associated with or regulated by STING.

[0219] In another aspect, the present invention provides novel compounds of formula (I) or salts thereof for use in 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.

[0220] Furthermore, the present invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of diseases and / or conditions associated with or modulated by STING. Diseases and conditions associated with or modulated by STING encompass (but are not limited to) inflammatory, allergic or autoimmune diseases (such as allergic rhinitis or asthma), infectious diseases or cancers, including (but not limited to) the specific diseases mentioned above. In addition, due to the activity of the compounds of the present invention, said compounds are suitable for use as vaccine adjuvants, including (but not limited to) the specific applications mentioned above.

[0221] Accordingly, the present invention relates to a compound of general formula (I) for use as a medicament or a vaccine adjuvant.

[0222] Furthermore, the present invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of the diseases and conditions mentioned above.

[0223] In another aspect, the present invention relates to a compound of general formula (I) for the treatment and / or prevention of the diseases and conditions mentioned above.

[0224] In another aspect, the present invention relates to a compound of general formula (I) for the treatment and / or prevention of the cancers mentioned above before and / or after tumor resection and / or radiotherapy.

[0225] In another aspect, the present invention relates to the use of compounds of general formula (I) in the preparation of a medicament for the treatment and / or prevention of the diseases and conditions mentioned above.

[0226] In another aspect, the present invention relates to a method for the treatment or prevention of the diseases and conditions mentioned above, said method comprising administering to a human an effective amount of a compound of general formula (I).

[0227] The daily applicable dosage range of the compound of general formula (I) is generally from 0.00001 to 100 mg per kg of patient body weight, for example from 0.00001 to 10 mg per kg of patient body weight. Each dosage unit may conveniently contain from 0.001 to 1000 mg, for example from 0.001 to 100 mg.

[0228] Of course, the actual therapeutically effective amount or therapeutic dose will depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration and the severity of the disease. In any case, the compound or composition is administered in a dose and manner that permits delivery of a therapeutically effective amount based on the unique condition of the patient.

[0229] In a related aspect, the present invention relates to methods for inducing, stimulating or assisting an immune response in an individual. These methods comprise administering to the individual a compound of the present invention.

[0230] On the other hand, the present invention provides the use of the compound of general formula (I) in the preparation of an immunogenic composition comprising an antigen or an antigen composition for the treatment or prevention of a disease.

[0231] On the other hand, the present invention provides a method for the treatment or prevention of a disease, the method comprising administering to a human subject suffering from or susceptible to a disease an immunogenic composition comprising an antigen or an antigen composition and a compound of general formula (I).

[0232] On the other hand, the present invention provides a vaccine composition for the treatment or prevention of a disease, comprising an antigen or an antigen composition and a compound of general formula (I).

[0233] On the other hand, the present invention provides the use of the compound of general formula (I) in the preparation of a vaccine composition comprising an antigen or an antigen composition for the treatment or prevention of a disease.

[0234] On the other hand, the present invention provides a method for the treatment or prevention of a disease, the method comprising administering to a human subject suffering from or susceptible to a disease a vaccine composition comprising an antigen or an antigen composition and a compound of general formula (I).

[0235] Pharmaceutical composition

[0236] In another aspect of the present invention, it has been found that the pharmaceutical composition of the above-mentioned compound can be formulated to be suitable for administering a therapeutically effective amount of the compound. Suitable formulations for administering the compound of formula (I) will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, cachets, injections (subcutaneous, intravenous, intramuscular, intraperitoneal, intratumoral and peritumoral), inhalants, infusions, elixirs, emulsions and powders. In addition, the compounds of the present invention 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 formulation.

[0237] Suitable tablets can be obtained, for example, by mixing one or more compounds according to formula I with known excipients such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants.

[0238] For the purposes of the present disclosure, the pharmaceutical composition can be administered by a variety of means, including parenterally, non-parenterally, by inhalation spray, topically, nasally, orally or rectally in the form of a formulation containing a pharmaceutically acceptable carrier, adjuvant and vehicle. The pharmaceutical composition of the present invention can be administered in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension.

[0239] According to another embodiment, there is provided a vaccine comprising one or more compounds of general formula (I). In another aspect, the present invention provides a vaccine adjuvant comprising a compound of general formula (I). In another aspect, the present invention provides an immunogenic composition comprising an antigen or antigenic composition and a compound of general formula (I).

[0240] In another aspect, the present invention provides an immunogenic composition comprising an antigen or antigenic composition and a compound of general formula (I) for treating or preventing a disease.

[0241] Combination therapy

[0242] The compounds of the present invention can be used alone or in combination with a pharmaceutically acceptable excipient in an amount sufficient to induce, modulate or stimulate a suitable immune response. The immune response can include (but is not limited to) specific immune responses, non-specific immune responses, specific responses and non-specific reactions, innate responses, primary immune responses, adaptive immunity, secondary immune responses, memory immune responses, immune cell activation, immune cell proliferation, immune cell differentiation and cytokine expression.

[0243] In certain embodiments, the compounds and compositions described herein are administered in combination with one or more additional compositions, said one or more additional compositions including vaccines designed to stimulate an immune response against 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, immunomodulators, where in general, immunomodulators can be understood as drugs of the general activation regulation type, and drugs that regulate and / or increase the frequency of a certain immune cell subtype, etc.

[0244] The compounds and compositions described herein can be administered before, after and / or simultaneously with additional therapeutic or prophylactic compositions or modalities.

[0245] The compounds, compositions (including any combination with one or more additional therapeutic agents) according to the present invention can be administered by mucosal (e.g., oral, sublingual, vaginal, nasal, cervical, etc.), intratumoral, intraperitoneal, peritumoral, transdermal, inhaled or parenteral (e.g., subcutaneous, intravenous, intramuscular, intraarterial, intradermal, intrathecal and epidural administration) routes.

[0246] Furthermore, the compounds, compositions (including any combination with one or more additional therapeutic agents) according to the present invention 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.

[0247] Among the possible administration methods, intraperitoneal, intratumoral, peritumoral, subcutaneous, inhalation or intravenous administration is preferred. The compounds, compositions (including any combination with one or more additional therapeutic agents) according to the invention can also be administered before, after and / or simultaneously with a combination of different administration methods. Only as an example, intratumoral or peritumoral administration can be after inhalation or intravenous administration, or inhalation or intravenous administration can be after intratumoral or peritumoral administration. In addition, such administration of the compounds by different routes can be before or after an additional therapeutic step (such as tumor resection or radiotherapy). Only as an example, the compounds of the invention can be administered after radiotherapy. In addition, the compounds of the invention can be provided by intravenous administration after radiotherapy. In addition, the compounds of the invention can be provided by intravenous administration after tumor resection. In addition, the compounds of the invention can be provided by intratumoral administration after radiotherapy. In addition, the compounds of the invention can be provided by peritumoral administration after radiotherapy. In addition, the compounds of the invention can be provided by inhalation administration after tumor resection. In addition, the compounds of the invention can be provided by intravenous administration followed by intratumoral administration, and both administrations are carried out after radiotherapy. In addition, the compounds of the invention can be provided by intratumoral administration followed by intravenous administration, and both administrations are carried out after radiotherapy. In addition, the compounds of the invention can be provided by intravenous administration followed by peritumoral administration, and both administrations are carried out after radiotherapy. In addition, the compounds of the invention can be provided by peritumoral administration followed by intravenous administration, and both administrations are carried out after radiotherapy.

[0248] Methods of co - administration with other therapeutic agents are well - known in the art.

[0249] Due to the adjuvant properties of the compounds of the invention, the compounds can also be used in combination with other therapeutic modalities (including other vaccines, adjuvants, antigens, antibodies and immunomodulators).

[0250] In addition to the compounds and their compositions of the invention described herein, the compositions or methods of the invention can further comprise one or more additional substances which, due to their nature, can be used to stimulate or otherwise harness the immune system to respond to cancer antigens present on one or more target tumor cells.

[0251] The compounds of the invention can be used in combination with immune checkpoint inhibitors, such as immune checkpoint inhibitors selected from the group consisting of: CTLA - 4 pathway antagonists, PD - 1 pathway antagonists, Tim - 3 pathway antagonists, Vista pathway antagonists, BTLA pathway antagonists, LAG - 3 pathway antagonists or TIGIT pathway antagonists.

[0252] The compounds of the present invention can be used in combination with an immune-oncology agonist, in combination with a T cell receptor agonist, or in combination with a TNF receptor superfamily agonist or antagonist.

[0253] The compounds of the present invention can be used in combination with a therapeutic antibody or a therapeutic nanobody. In some embodiments, the mechanism of action of the therapeutic antibody is antibody-dependent cell-mediated cytotoxicity (ADCC).

[0254] In other embodiments of the methods described herein, the compounds of the present invention are used in combination with chemotherapeutic agents (e.g., small molecule drug compounds) known to those skilled in the art. Accordingly, the methods further involve administering to a subject an effective amount of one or more chemotherapeutic agents as additional therapy or combination therapy.

[0255] It can also be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments or general subsets of compound (I)), or one or more additional pharmacologically active substances used in the medical uses, uses, treatments, and / or prophylactic methods disclosed herein (above and below) include (but are not limited to): hormones, hormone analogs, and antihormones (such as tamoxifen, toremifene, raloxifene, fulvestrant, medroxyprogesterone acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide); aromatase inhibitors (such as anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane); LHRH agonists and antagonists (such as goserelin acetate, luprolide); inhibitors of growth factors and / or their corresponding receptors (growth factors such as: 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, such as HER2, HER3, HER4)) and / or their corresponding receptors;Inhibitors include, for example, (anti-)growth factor antibodies, (anti-)growth factor receptor antibodies, and tyrosine kinase inhibitors such as afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV412, PF-6274484, HKI 357, olmutinib, osimertinib, almonertinib, nazartinib, lazertinib, pelitinib, erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340, necitumumab, panitumumab, cetuximab, amivantanab, pertuzumab, trastuzumab, trastuzumab emtansine, or inhibitors of mutant EGFR, inhibitors of HER2 with exon 20 mutations, and hepatocyte growth factor (HGF, c-MET, such as emibetuzumab, amivantanab, savolitinib, cabozantinib, foretinib); antimetabolites (such as methotrexate, raltitrexed, 5-fluorouracil (5-FU), capecitabine, floxuridine, gemcitabine, mercaptopurine, thioguanine, cladribine, pentostatin, cytarabine (ara-C), fludarabine, trifluridine, and the combination of tipiracil (=TAS102));Antitumor antibiotics (such as anthracyclins (e.g., doxorubicin, Doxil (liposomal doxorubicin hydrochloride), Myocet (non-PEGylated liposomal doxorubicin), daunorubicin, epirubicin, and idarubicin), mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (such as cisplatin, oxaliplatin, carboplatin); alkylating agents (such as estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); antimitotic agents (such as vinca alkaloids (e.g., vinblastine, vindesine, vinorelbin, and vincristine); and taxanes (e.g., paclitaxel, docetaxel, Abraxane)); angiogenesis inhibitors (such as tasquinimod, bevacizumab), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (such as epipodophyllotoxins (e.g., etoposide and Etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone));Serine / threonine kinase inhibitors (e.g., PDK1 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; vistusertib; AZD8055), mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors (e.g., alpelisib, serabelisib, 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, refametinib); SOS1-inhibitors (i.e., a compound that modulates / inhibits the GEF function of SOS1, e.g., by binding to SOS1 and preventing the protein-protein interaction between SOS1 and a (mutant) Ras protein, e.g., KRAS; e.g., BAY-293), inhibitors of GDP-loaded or GTP-loaded RAS and / or any of its mutants (i.e., a compound that modulates / inhibits the function of a (mutant) RAS protein, e.g., by binding to a GDP-loaded or GTP-loaded (mutant) Ras protein, e.g., KRAS, NRAS, and / or HRAS, preferably KRAS).Irreversible inhibitors of KRAS G12C (AMG-510, MRTX849, ARS-324, GDC-6036); reversible or irreversible binders to GDP-loaded (mutant) KRAS; reversible or irreversible binders to GTP-loaded (mutant) KRAS; ALK inhibitors (such as crizotinib, alectinib, entrectinib, brigatinib, ceritinib); ERK inhibitors; FLT3 inhibitors; BRD4 inhibitors; IGF-1R inhibitors; TRAILR2 agonists; Bcl-xL inhibitors; Bcl-2 inhibitors (such as venetoclax, obatoclax, navitoclax, oblimersen); Bcl-2 / Bcl-xL inhibitors; ErbB receptor inhibitors; BCR-ABL inhibitors; ABL inhibitors; Src inhibitors (such as dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU 6656, WH-4-023); rapamycin analogs (such as everolimus, temsirolimus, deforolimus, 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 of its mutants; inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any of its mutants (encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (=Example 131 in WO 2014 / 151616), LXH254, sorafenib, LY-3009120 (=Example 1 in WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265); inhibitors of receptor tyrosine kinase (RTK) and / or any of its mutants; inhibitors of SHP2 and / or any of its mutants (such as SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909); CYP17 inhibitors; radiopharmaceuticals;Proteasome inhibitors (such as carfilzomib); immunotherapeutic agents, such as immune checkpoint inhibitors (such as 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 cell-mediated cytotoxicity) enhancers (such as anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies); T cell engagers, such as PSMA×CD3, B7H6 / CD3 (disclosed in, for example, WO2021 / 064137), DLL3 / CD3 (disclosed in, for example, WO2019 / 234220), such as bispecific T cell engagers; (such as CD3×BCMA, CD3×CD33, CD3×CD19), cancer vaccines, MDM2 inhibitors, oncolytic viruses and various chemotherapeutic agents, such as amifostin, anagrelid, clodronat, filgrastin, interferons, interferon α, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer. The compounds of the present invention can be used in combination with the following: OX40 agonists, ICOS ligands, CD27 agonists, GITR agonists, Toll-like receptor agonists.

[0256] In a preferred embodiment, one or more additional pharmacologically active substances that can be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments or general subsets of compound (I)), or in a method of medical use, use, treatment, and / or prevention as disclosed herein (above and below) include: checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, epratuzumab, sintilimab, camrelizumab, tremelimumab, tislelizumab), taxanes (paclitaxel, docetaxel, albumin-bound paclitaxel (Abraxane)), T cell engagers (e.g., PSMA×CD3, B7H6 / CD3 (disclosed in, for example, WO2021 / 604137), DLL3 / CD3 (disclosed in, for example, WO2019 / 234220), e.g., bispecific T cell engagers (e.g., CD3×BCMA, CD3×CD33, CD3×CD19), cancer vaccines, MDM2 inhibitors, and oncolytic viruses.

[0257] In other embodiments of the methods described herein, the compounds of the invention are used in combination with chemotherapeutic agents and / or additional drugs (e.g., cancer-targeted therapies) for treating the indications described in the methods herein. Accordingly, the methods further involve administering to a subject an effective amount of one or more cancer-targeting agents as additional or combination therapy.

[0258] In other embodiments of the methods described herein, the compounds of the invention are used in combination with chemotherapeutic agents and / or additional drugs and / or additional therapies (e.g., radiotherapy and / or tumor resection) for treating the indications described in the methods herein.

[0259] In another aspect, the invention relates to a method for treating a disease or condition associated with or regulated by STING in a patient, the method comprising the step of administering to a human patient in need of such treatment a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of one or more of the additional therapeutic agents described above.

[0260] The combined use of a compound according to the invention with an additional therapeutic agent can be carried out simultaneously or at staggered times.

[0261] A compound according to the invention and one or more additional therapeutic agents can be present together in one formulation or independently in two identical or different formulations, e.g., as a so-called kit-of-parts.

[0262] Accordingly, in another aspect, the present invention provides a combination comprising a compound of formula (I) and at least one other therapeutic agent.

[0263] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent and one or more pharmaceutically acceptable excipients.

[0264] In another aspect, the present invention provides a combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent, said combination for use in therapy.

[0265] In another aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent, said combination for the treatment of a disease or condition in which modulation of STING is beneficial.

[0266] In another aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent, said combination for the treatment of inflammatory, allergic and autoimmune diseases, infectious diseases and cancer.

[0267] In another aspect, the present invention provides a method of treating a disease or condition in a patient in which modulation of STING is beneficial, said method comprising administering a therapeutically effective amount of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent.

[0268] In another aspect, the present invention provides a method of treating an inflammatory, allergic or autoimmune disease, an infectious disease or cancer in a patient, said method comprising administering a therapeutically effective amount of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent.

[0269] Of course the actual pharmaceutically effective amount or therapeutic dose will depend on factors known to those skilled in the art such as the age and weight of the patient, the route of administration and the severity of the disease. In any case, the combination will be administered in a dose and manner that permits delivery of a pharmaceutically effective amount based on the patient's unique condition.

[0270] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention and one or more additional therapeutic agents as described in context, and optionally one or more inert carriers and / or diluents.

[0271] Other features and advantages of the present invention will be apparent from the following detailed examples which illustrate the principles of the invention by way of example.

[0272] Chemical Synthesis

[0273] List of Abbreviations:

[0274]

[0275]

[0276] Other features and advantages of the present invention will become apparent from the following detailed examples, which illustrate the principles of the present invention without limiting its scope.

[0277] General

[0278] Unless otherwise stated, all reactions were carried out in commercially available equipment using common methods in a chemical laboratory. Starting materials sensitive to air and / or moisture were stored under a protective gas, and the corresponding reactions and operations were carried out under a protective gas (nitrogen or argon).

[0279] The compounds of the present invention are named according to the IUPAC guidelines. If a compound is represented by a structural formula together with its name, in case of conflict, the structural formula shall prevail.

[0280] Chromatography

[0281] Thin-layer chromatography was carried out on ready-made TLC plates of silica gel 60 on glass (with fluorescent indicator F-254) manufactured by Merck.

[0282] The Biotage Isolera Four device was used together with an Interchim Puri Flash column (50 μm, 12 - 300 g) or a glass column filled with silica gel manufactured by Millipore (silica particles Si-60A 35 - 70 μm) for automated preparative NP chromatography.

[0283] Preparative RP HPLC was carried out using columns manufactured by Waters (Sunfire C18, 10 μm, 30×100 mm part number 186003971 or X-Bridge C18, 10 μm, 30×100 mm part number 186003930). Different gradients of H 2 O / acetonitrile or H 2 O / MeOH (0.2% HCOOH was added to water), or an alkaline buffer aqueous solution (5 mL of ammonium bicarbonate solution (158 g / 1L H 2 O) and 2 mL of ammonia (solution of 7 mol / l in MeOH) in 1 L of water) was used instead of the water-HCOOH-mixture to elute the compounds with different gradients.

[0284] Analytical HPLC (reaction monitoring) of the intermediate compounds was carried out using columns manufactured by Waters and Phenomenex. In each case, the analytical equipment was also equipped with a mass detector.

[0285] HPLC mass spectrometry / UV spectroscopy

[0286] The retention time / MS-ESI characterizing the compounds of the examples according to the invention was determined using, for example, an HPLC-MS device (high performance liquid chromatography with a mass detector) manufactured by Agilent. + The compound eluting at the injection peak was assigned a retention time tR = 0.

[0287] Analytical HPLC method (A.M.)

[0288] Method_1

[0289] HPLC: Agilent 1100 / 1200 series

[0290] MS: Agilent LC / MSD SL

[0291] Column: Waters X-Bridge BEH C18, 2.5 μm, 2.1×30 mm XP

[0292] Eluent: A: 5 mM NH 4 HCO 3 / 19 mM NH 3 in H 2 O; B: ACN (HPLC grade)

[0293] Detection: MS: positive mode and negative mode

[0294] Mass range: 100 - 800 m / z

[0295] Flow rate: 1.4 ml / min

[0296] Column temperature: 45 °C

[0297] Gradient: 0.00 - 0.01 min: 5% B

[0298] 0.01 - 1.00 min: 5% → 100% B

[0299] 1.00 - 1.37 min: 100% B

[0300] 1.37 - 1.40 min: 100% → 5% B

[0301] Method_2

[0302] HPLC: Agilent 1100 / 1200 series

[0303] MS: Agilent LC / MSD (API-ES + / − 3000V, Quadrupol, G6140)

[0304] Column: Waters, XBridge C18, 2.5 μm, 2.1 × 20 mm column

[0305] Solvent: A: 20 mM NH 4 HCO 3 / NH 3 in H 2 O with pH 9; B: ACN (HPLC grade)

[0306] Detection: MS: positive and negative modes

[0307] Mass range: 120 - 900 m / z

[0308] Flow rate: 1.00 mL / min

[0309] Column temperature: 60 °C

[0310] Gradient: 0.00 - 1.50 min: 10% → 95% B

[0311] 1.50 - 2.00 min: 95% B

[0312] 2.00 - 2.10 min: 95% → 10% B

[0313] Method_3

[0314] UPLC / MS: Waters Acquity-UPLC-SQ detector-2

[0315] Column: AQUITY UPLC BEH C18 1.7 μm, 2.1 × 50 mm Solvent: A: 0.07% HCOOH / ACN; B: H 2 O + 0.07% HCOOH Detection: MS: positive and negative modes

[0316] Mass range: 100 - 1500 m / z

[0317] Flow rate: 0.6 mL / min

[0318] Column temperature: 35 °C

[0319] Gradient: 0.00 - 0.30 min: 97% B

[0320] 0.30 - 2.20 min: 97% → 2% B

[0321] 2.20 - 3.30 minutes: 2% B

[0322] 3.30 - 4.50 minutes: 2% B → 97% B

[0323] 4.50 - 4.51 minutes: 97% B

[0324] Method_4

[0325] UPLC / MS: Waters Acquity - UPLC - SQ detector - 2

[0326] Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm Solvent: A: H 2 O + 0.07% HCOOH B: 0.07% HCOOH / ACN Detection: MS: Positive and negative modes

[0327] Mass range: 100 - 1500 m / z

[0328] Flow rate: 0.6 ml / min

[0329] Column temperature: 35°C

[0330] Gradient: 0.00 - 0.30 minutes: 97% A

[0331] 0.30 - 2.70 minutes: 97% → 2% A

[0332] 2.70 - 3.50 minutes: 2% A

[0333] 3.50 - 3.51 minutes: 2% → 97% A

[0334] Method_5

[0335] UPLC / MS: Waters Acquity - Binary solvent manager - UPLC - SQ detector - 2 Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm

[0336] Solvent: A: 0.07% HCOOH / ACN; B: H 2 O + 0.07% HCOOH

[0337] Detection: MS: Positive and negative modes

[0338] Mass range: 100 - 1500 m / z

[0339] Flow rate: 0.6 ml / min

[0340] Column temperature: 35 °C

[0341] Gradient: 0.00 - 0.40 minutes: 97% B

[0342] 0.40 - 2.50 minutes: 97% → 2% B

[0343] 2.50 - 3.40 minutes: 2% B

[0344] 3.40 - 3.50 minutes: 2% B → 97% B

[0345] 3.50 - 4.51 minutes: 97% B

[0346] Preparation of the compounds according to the invention

[0347] 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 intended to be illustrative of the invention and do not limit the scope of the subject matter of the invention and the compounds claimed in these examples. Preferably, the compounds are obtained in a manner similar to the preparation methods more fully explained below (specifically as described in the experimental section). In some cases, the order of performing the reaction steps can be varied. Variants of reaction methods known to those skilled in the art but not described in detail herein can also be used.

[0348] Those skilled in the art studying the following schemes will be aware of the general methods for preparing the compounds according to the invention. The starting materials can be prepared by methods described in the literature or herein or in a similar or analogous manner. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved at appropriate stages within the reaction sequence using methods familiar to those skilled in the art.

[0349] An example of a method for preparing the compound of formula (I) is illustrated in Scheme I: Indazole B can be synthesized from o-methylaniline derivative A. Subsequent iodination yields 3-iodo-indazole C. Intermediate D can be obtained, for example, by Chan-Lam coupling using (6-fluoropyridin-3-yl)boronic acid. The conversion to intermediate E can be achieved via Suzuki coupling. Compound F is synthesized, for example, by nucleophilic aromatic substitution. The product is separated by conventional means and preferably purified by chromatography.

[0350] Scheme I:

[0351]

[0352] Preparation of Intermediate B

[0353] B1) 7-Bromo-6-fluoro-1H-indazole

[0354]

[0355] To a stirred mixture of 2-bromo-3-fluoro-6-methylaniline (11 g, 53.9 mmol) and toluene (176 ml) was added potassium acetate (6.35 g, 64.7 mmol). After 30 minutes at room temperature, acetic acid (9.7 g, 161.7 mmol) was added and the mixture was heated to 40 °C. tert-Butyl nitrite (11.11 g, 107.8 mmol) was added and stirring was continued for 6 hours. Water (150 ml) was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and concentrated in vacuo. 7-Bromo-6-fluoro-1H-indazole was purified by NP chromatography. Yield: 5 g (43%). HPLC-MS: M+H = 215 / 217; tR = 1.89 min (Method_3)

[0356] The following intermediates were prepared similarly from the corresponding substituted anilines:

[0357]

[0358]

[0359] B5) 5-Chloro-7-methyl-1H-indazole

[0360]

[0361] At 15 °C, sodium nitrite (2.44 g, 35 mmol) in water (30 ml) was added to a stirred mixture of 4-chloro-2,6-dimethylaniline (5 g, 32 mmol) in acetic acid (60 ml). The mixture was stirred at room temperature for 19 hours. The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The product was purified by NP chromatography. Yield: 2.6 g (49%). HPLC-MS: M+H = 167; tR = 1.76 min (Method_4).

[0362] B6) 6-Fluoro-7-methyl-1H-indazole

[0363]

[0364] Under an argon atmosphere at 120 °C, a mixture of 7-bromo-6-fluoro-1H-indazole B1 (5 g, 23.25 mmol), potassium carbonate (12.9 g, 93 mmol), trimethyl borate (50% in THF, 23.4 g, 93 mmol), tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol) and DMF (50 ml) was stirred for 48 h. Water (100 ml) was added at room temperature and the mixture was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 dried, concentrated in vacuo, and the product was purified by NP HPLC. Yield: 2.4 g (69%). HPLC-MS: M+H = 151; tR = 1.58 min (method_5).

[0365] The following intermediates were prepared similarly from B3:

[0366]

[0367] Preparation of Intermediate C

[0368] C1) 6-Fluoro-3-iodo-7-methyl-1H-indazole

[0369]

[0370] At 0 °C, iodine (10.1 g, 40 mmol) and K 2 CO 3 (8.3 g, 60 mmol) were added to 6-fluoro-7-methyl-1H-indazole B6 (3 g, 20 mmol) in DMF (35 ml). The mixture was stirred at room temperature for 12 h. While cooling with ice, the mixture was poured into 10% Na 2 S 2 O 3 aqueous solution. The precipitate was filtered, washed with water and dried. The product was purified by NP chromatography. Yield: 4 g (73%). HPLC-MS: M+H = 2.77; tR = 1.90 min (method_5).

[0371] The following intermediates were prepared similarly from the corresponding intermediate B:

[0372]

[0373] Preparation of Intermediate D

[0374] D1) 6-Fluoro-1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole

[0375]

[0376] Exposed to air at room temperature, stir a mixture of 6-fluoro-3-iodo-7-methyl-1H-indazole C1 (4 g, 14.5 mmol), (6-fluoropyridin-3-yl)boronic acid (4.08 g, 29 mmol), copper(II) acetate (3.95 g, 21.75 mmol) and pyridine (3.5 ml, 43.5 mmol) in DCM (40 ml) for 16 h. Concentrate the mixture in vacuo and purify the product by NP chromatography. Yield: 2.5 g (47%). HPLC-MS: M+H = 372; tR = 2.45 min (Method_3).

[0377] The following intermediates were prepared similarly from the corresponding 3-iodo-indazole (Intermediate C):

[0378]

[0379]

[0380] Preparation of Intermediate E

[0381] E1) 6-Fluoro-1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biindazole

[0382]

[0383] Stir a mixture of 6-fluoro-1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole D1 (2.5 g, 6.7 mmol), 2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (2.1 g, 8.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.28 g, 0.34 mmol), K 2 CO 3 (1.6 g, 20.2 mmol) in dioxane (20 ml) and water (5 ml) for 6 h under an argon atmosphere at 100 °C. Add water (100 ml) at room temperature and extract the mixture with EtOAc. Dry the combined organic layers over MgSO 4 4, concentrate in vacuo and purify the product by NP HPLC. Yield: 1.2 g (48%). HPLC-MS: M+H = 376; tR = 2.15 min (Method_5).

[0384] The following intermediates were prepared similarly from the corresponding Intermediate D:

[0385]

[0386]

[0387] Examples

[0388] In the following section, a method for preparing Examples #1 to #13 and Intermediate F is described:

[0389] F1) Ethyl 1-(5-(6-fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperidine-4-carboxylate

[0390]

[0391] Stir a mixture of 6-fluoro-1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biindazole E1 (250 mg, 670 μmol), ethyl piperidine-4-carboxylate (520 mg, 3.3 mmol), and DIPEA (110 μl, 650 mmol) in DMSO (1 ml) at 110 °C for 16 h. Dilute the mixture with water and extract with EtOAc. Dry the combined organic layers over MgSO 4 and concentrate in vacuo. Purify the title compound by RP chromatography. Yield: 248 mg (73%). HPLC-MS: M+H = 513; tR = 1.62 min (method_2).

[0392] The following Intermediates F2 to F14 are prepared from Intermediate E using the corresponding amines in a manner similar to F1. For amine salts (e.g., hydrochloride salts), use the appropriate equivalent of additional base.

[0393]

[0394]

[0395]

[0396]

[0397]

[0398] The following Examples #1 to #2 are prepared from Intermediate E using the corresponding amines in a manner similar to F1. For amine salts (e.g., hydrochloride salts), use the appropriate equivalent of additional base.

[0399]

[0400]

[0401] Preparation of Intermediate F15:

[0402] F15) 5-Fluoro-2',7-dimethyl-1-(6-(piperazin-1-yl)pyridin-3-yl)-1H,2'H-3,4'-biindazole

[0403]

[0404] At room temperature, stir tert-butyl 4-(5-(5-fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperazine-1-carboxylate F14 (39 mg, 72 μmol) in DCM (2 ml) containing TFA (400 μl) for 16 h. Add toluene (10 ml), concentrate the mixture in vacuo, and use the crude product (32 mg) directly in the next step without further purification.

[0405] Preparation of Example #3:

[0406] #3) 4-(5-(5-Fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperazine-1-carbaldehyde

[0407]

[0408] Stir a mixture of crude 5-fluoro-2',7-dimethyl-1-(6-(piperazin-1-yl)pyridin-3-yl)-1H,2'H-3,4'-biindazole F15 (32 mg, 72 μmol) and N-formylsaccharin (23.4 mg, 109 μmol) in THF (200 μl) at room temperature for 16 h. Concentrate the mixture in vacuo and purify the product by RP chromatography. Yield: 16 mg (47%). HPLC-MS: M+H = 470; tR = 1.32 min (Method_2)

[0409] Preparation of Examples #4 to #13:

[0410] #4) 1-(5-(5-Fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperidine-4-carboxylic acid

[0411]

[0412] Add THF (7 ml), water (7 ml) and KOH (390 mg; 6.9 mmol) to ethyl 1-(5-(5-fluoro-2',7-dimethyl-1H,2'H-[3,4'-biindazol]-1-yl)pyridin-2-yl)piperidine-4-carboxylate F7 (350 mg, 690 μmol). Stir the mixture at room temperature for 3 h. After neutralization with 1N aqueous HCl, extract the mixture with DCM. Combine the organic layers and dry over MgSO 4The product was dried, concentrated in vacuo and purified by RP HPLC. Yield: 163 mg (49%). HPLC-MS: M+H = 485; tR = 1.06 min (Method_2).

[0413] The following examples can be prepared analogously from the corresponding ethyl or methyl esters F1 to F6 and F9 to F13:

[0414]

[0415]

[0416]

[0417] Pharmacological activity

[0418] Interaction with hSTING determined by differential scanning fluorimetry (DSF)

[0419] In DSF, the temperature at which the protein unfolds (also called the melting temperature T m ) is measured by the fluorescence change of a dye that binds to the hydrophobic part of the protein. After binding of the small molecule, the T m shift is related to the binding affinity of the small molecule. Using human STING (hSTING, UNIPROT entry Q86WV6, residues 155 - 341, MW: 21578.4 Da; protein stock solution: c = 1302 μM in a stock solution of 20 mM Tris, 100 mM NaCl, 2 mM TCEP pH 8.8) as the target protein, 20 mM Tris, 150 mM NaCl pH 7.5 was added as the assay buffer when necessary.

[0420] Final concentrations of components in the assay: 100 μM test compound, 5 μM target protein, "5×" SYPR Orange (from a stock solution of SYPRO Orange in DMSO (invitrogen catalog number S6650 - 500 μl), concentration "5000×")

[0421] Assay procedure:

[0422] 1) Prepare dilutions of the compound stock solution (10 mM in DMSO) in the assay buffer (20 mM Tris, 150 mM NaCl; pH 7.5).

[0423] 2) Mix 5 μl of the fluorescent dye stock solution (5000× SYPRO Orange / DMSO) with 19 μl of the target protein (1302 μM) and 976 μl of the assay buffer.

[0424] 3) Add 2 μl of this protein-dye-mixture (25× SYPRO Orange and 25 μM protein) to 8 μl of the diluted compound solution prepared as in step 1. The final volume is 10 μl.

[0425] 4) Measure two negative controls for every 20 compounds.

[0426] 5) Prepare plates for duplicate measurements and centrifuge at 1000 g for 2 minutes.

[0427] 6) For the measurement, use a CFX384 real-time system (Bio-Rad). The run consists of 140 cycles at 0.5 °C / cycle (temperature ramp 15 seconds / cycle, 25 °C to 95 °C).

[0428] Data analysis: Process the melting curves in the Bio-Rad CFX Manager. The peak type is set to "negative". Average the two replicates of the TM (melting temperature) measurement and calculate the standard deviation.

[0429] The change in TM ("thermal shift") is shown in Table 1.

[0430] Table 1: Interaction with hSTING determined by DSF

[0431] Example #1 #2 #3 #4 #5 #8 #10 #11 TM[K] 21 22 21 24 26 22 19 24

[0432] In vitro cytokine induction measured via activation of an interferon regulatory factor-inducible reporter gene

[0433] The cytokine induction activity of the compounds according to the invention has been confirmed using the THP1 reporter cell line, resulting in cellular EC50 values. Activation of the STING protein expressed in the cell line leads to increased interferon production. Functional interferon signaling pathways can be monitored through stable integration of an interferon regulatory factor (IRF)-inducible SEAP (secreted embryonic alkaline phosphatase) gene reporter construct. Using Invivogen's THP1-Blue TM ISG colorimetric enzyme assay and a suitable optical density (OD) reader, the activity of SEAP can be detected and quantified. This technique can be used to characterize the pharmacological modulation of the STING pathway.

[0434] Several single nucleotide polymorphisms have been identified in the human STING gene. To determine the activity of the above compounds, THP1-Blue expressing different human STING variants has been generated TMISG reporter cell lines. For this purpose, endogenous human STING was first depleted using the CRISPR / CAS9 system: THP1-Blue ISG cells were electroporated with an all-in-one CRISPR plasmid targeting the STING gene (purchased from Sigma, encoding gRNA and GFP as a reporter gene for successful transduction). Subsequently, GFP-positive cells were sorted 24 hours after transfection and amplification. The cells were then dispersed in semi-solid methylcellulose (Methocel) medium to isolate single cell clones. Then the Quanti-Blue TM reporter assay was used to screen the clones for cGAMP responsiveness. Subsequently, non-responsive clones for STING depletion were analyzed by western blotting and sequencing of the STING locus.

[0435] For overexpression of human STING variants, the confirmed THP1-Blue TM 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 based on different GFP fluorescence levels, and STING allele expression was analyzed by western blotting. Populations expressing ectopic STING proteins (WT, HAQ, R232H, AQ, and R293Q) at levels comparable to the endogenous STING levels from the parental unmodified THP1-Blue ISG cell line were selected and used for compound characterization.

[0436] Measurements of SEAP activity were performed in THP1-Blue TM ISG cells stably expressing different human STING subtypes and an IRF-inducible SEAP reporter construct. Cells were cultured in RPMI1640 medium with 10% fetal bovine serum, 50 μg / ml penicillin-streptomycin, 100 μg / ml zeocin, and 100 μg / ml normocin in a 37 °C, 95% humidity, and 5% CO 2 incubator.

[0437] In the preparation for the assay, cells were dispensed into the assay plate at a density of 10,000 cells / 15 μl / well. Compounds were prepared by 8-point serial dilution in 50% aqueous DMSO followed by a final dilution step in the medium to ensure a final DMSO concentration of 0.5% in the assay. 5 μL of the diluted compound was added to the plate, and then incubated at 37 °C for 24 hours.

[0438] On the day of measurement, 75 μl of Quanti-Blue TM reagent was added to all wells of the plate, and the plate was incubated for an additional 30 minutes at 37 °C. The OD at 620 nm was measured on an EnVision reader (PerkinElmer).

[0439] EC 50 values and the Hill slope were derived by 8-point four-parameter non-linear curve fitting using Megalab software (Boehringer Ingelheim) with an OD of 620 nM.

[0440] EC 50 values data are shown in Tables 2a to 2e.

[0441] EC 50 values data for STING HAQ variants are shown in Table 2a. The data shown below are from the parental THP1-Blue TM ISG cell line (which endogenously expresses HAQ) or from a genetically engineered THP1-Blue TM ISG cell line in which the first STING has been knocked out and the HAQ-specific STING subtype has been reintroduced as described above.

[0442] EC 50 values data for STING HAQ variants are shown in Table 2a:

[0443]

[0444] EC 50 values data for STING H232R variants are shown in Table 2b:

[0445]

[0446] EC 50 values data for STING R232H variants are shown in Table 2c:

[0447]

[0448] EC 50 values data for STING R293Q variants are shown in Table 2d:

[0449]

[0450] EC 50 values data for STING AQ variants are shown in Table 2e:

[0451]

[0452] Cell permeability measurement

[0453] 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 Medium) containing (final concentration) 10% FCS (fetal bovine serum), 1% NEAA (non-essential amino acids), 2 mM glutamine, 100 U / mL penicillin, and 100 μg / mL streptomycin. The Caco-2 cells were seeded at a density of 160,000 cells / cm 2 onto 24-well Transwell inserts (Corning, #3379) for bidirectional permeability assays and cultured for 3 weeks, with the medium changed every other day.

[0454] For bidirectional permeability assays, a 10 mM DMSO stock solution of the test compound was diluted to a final concentration of 10 μM in transport buffer containing 0.25% bovine serum albumin (final concentration: 128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO 4 4, 1.8 mM CaCl 2 2, 4.17 mM NaHCO 3 3, 1.19 mM Na 2 2HPO 4 4, 0.41 mM NaH 2 2PO 4 4, 15 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), 20 mM glucose, pH 7.4) and added to the apical or basolateral compartments. The cells were incubated with the compound for up to 2 hours. Samples were taken from the opposite compartment at different time points.

[0455] A RapidFire-based high-throughput HPLC / MS / MS system (high performance liquid chromatography / mass spectrometry; BioCius) customized according to a fully automated flexible platform (called RIAS) was used to quantify the compound concentration in the compartment. In this modified device, the sample was aspirated into a 10 μL sample loop by a vacuum pump for 250 milliseconds and flushed onto 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). Before bioanalysis, the sample was spiked with an internal standard solution and diluted with acetonitrile (ACN) for protein precipitation. Measurements were performed in multiple reaction monitoring (MRM) mode. External calibration was used for quantification. The solid-phase extraction step retained the analyte for 3000 milliseconds while removing interfering matrices (such as buffer components). By a simple step gradient, the analyte was back-eluted from the cartridge with an organic mobile phase (99.9% acetonitrile / methanol [1:1, v:v], 0.09% formic acid, and 0.01% TFA) for 3000 milliseconds and flushed into the mass spectrometer at a flow rate of 1.25 mL / min. Subsequently, the cartridge was re-equilibrated with the aqueous mobile phase for 500 milliseconds (flow rate 1.5 mL / min). The RapidFire software and customized control software were obtained from BioCius. QuickQuan 2.3, Xcalibur 2.0.7, and XDK 2.1.0.25 were used to operate the TSQ Vantage mass spectrometer (ThermoFisher, San Jose, CA) integrated into the RapidFire system. The mass spectrometry data processing software QuickCalc 7.1.9 was purchased from ThermoFisher. The main control software of RIAS was internally programmed using LabVIEW (version 8.6.1; National Instruments, Austin, TX). Data analysis was performed in AssayExplorer 3.2 (Symyx, Sunnyvale, CA), and the correlation plot was visualized with Spotfire version 2.2.0 (TIBCO, Palo Alto, CA).

[0456] The apparent permeability coefficients in the top-to-bottom direction (P app,AB ) and bottom-to-top direction (P app,BA ) and the efflux rate were calculated as follows:

[0457] P app,AB = Q AB / (C 0 ·s·t)

[0458] P app,BA = QBA / (C 0 ·s·t)

[0459] Efflux rate = P app,BA / P app,AB

[0460] where Q is the amount of compound recovered in the receiving chamber after incubation time t, C 0 is the initial compound concentration provided to the donor chamber, and s is the surface area of the Transwell insert. As a quality control, each assay plate includes a reference P-gp substrate (apafant) and a low permeability compound (BI internal reference, P app ~3·10 -7 cm / s, no efflux). Additionally, before the permeability assay, the trans-epithelial electrical resistance (TEER) value of each plate was measured and the total recovery of each compound in the donor and receiving chambers was determined. The results can be seen in Tables 3a and 3b.

[0461] Table 3a: Cell Permeability Measurement - P appAB :

[0462]

[0463] Cell Permeability Measurement - Efflux Rate:

[0464]

Claims

1. A compound of formula (I) or a salt thereof Wherein B is a group selected from the group consisting of A 5- to 7-membered monocyclic heterocyclic group containing 1 or 2 N atoms, A 6-membered bicyclic heterocyclic group containing 1 N atom, and A 6-membered monocyclic heterocyclic group containing 1 N atom and 1 heteroatom selected from the group consisting of O and S; R 1 is -H or -C 1-6 alkyl; R 2 is -H or -halogen; R 3 is -H or -halogen; Provided that R 2 and / or R 3 is a halogen; R 4 selected from the group consisting of: -H, -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, -C(O)OH, -C(O)O-C 1-6 alkyl, -C 1-6 alkylene-C(O)OH and -C(O)NH 2 ; R 5 is absent or is selected from the group consisting of -H and =O.

2. The compound or its salt according to claim 1, wherein R 1 is -C 1-3 alkyl.

3. The compound or a salt thereof according to any one of claims 1 to 2, wherein B is selected from the group consisting of 4. The compound or a salt thereof according to any one of claims 1 to 3, wherein B is selected from the group consisting of 5. A compound or a salt thereof according to any one of claims 1 to 4, wherein R 4 is selected from the group consisting of: -S(O 2 )-C 1-6 alkyl, =O, -C(O)H, and -C(O)OH.

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

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

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

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, the compound being selected from the group consisting of 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and 9, the compound being selected from the group consisting of 11. The compound according to any one of claims 1 to 10, which is in salt-free form.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is used as a medicine.

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

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is used for the treatment of cancer, wherein the compound is administered after radiotherapy.

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

16. A pharmaceutical combination, in addition to one or more compounds or pharmaceutically acceptable salts thereof according to one or more of claims 1 to 11 as other active substances, the pharmaceutical combination further comprising a substance selected from the group consisting of: cell growth inhibitory substances, cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, viruses, immunogenic cell death inducers, cancer targeting agents, immunomodulators, antibodies and nanobodies.

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