Use of heterocyclic compounds capable of activating sting

Abstract

This invention relates to a heterocyclic compound of formula (I) capable of activating the interferon gene stimulator (STING).

Description

Technical Field

[0001] This invention relates to small molecules capable of activating the interferon gene stimulating factor (STING) and its salts. Specifically, this invention relates to heterocyclic compounds capable of activating STING. Furthermore, this invention relates to pharmaceutical compositions and combinations comprising such compounds, and their use in methods for treating diseases related to or regulated by STING. Specifically, the pharmaceutical compositions of this invention are suitable for treating inflammatory, allergic, and autoimmune diseases, infectious diseases, and cancer, and are suitable as vaccine adjuvants. Prior Technology

[0002] STING is one of the pattern recognition receptors (PRRPs) that plays an important role in the innate immune system. It identifies pathogens and host cells by detecting extracellular and intracellular danger signals, including damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). This recognition process constitutes the first line of defense against viral and bacterial infections and malignant cells. However, pathogens and cancer cells have evolved means to evade recognition by the immune system. Therefore, the goal of immunotherapy is to initiate antigen-specific immune responses against pathogen invaders or cancer cells or to reactivate pre-existing responses in certain cell types of the immune system.

[0003] In PRRP, STING (also known as TMEM173, MPYS, MITA, and ERIS) belongs to the nucleic acid sensor family and is a transducer for cytoplasmic DNA communication. In healthy mammalian cells, DNA is separated in the nucleus. In pathogenic situations, such as when DNA-containing pathogens invade, or in malignant cells, DNA is present in the cytoplasm. In this paper, STING is crucial for detecting the cytoplasmic DNA described above and for inducing an immune response against pathogenic events.

[0004] In its basal state, STING exists as a dimer, with its N-terminal domain anchored in the ER and its C-terminal domain residing in the cytoplasm. Cyclic dinucleotide (CDN), generated by cyclic GMP-AMP synthase (cGAS), is the natural ligand of STING (Ablasser et al., Nature 498, 380-384, 2013). The binding of CDN to STING induces a conformational change, enabling the binding and activation of TANK-binding kinase (TBK1) and interferon regulatory factor 3 (IRF3), followed by relocalization from the ER to the perinuclear endosome (Liu et al., Science 347, Vol. 6227, 2630-1-2630-14, 2015). Phosphorylation of transcription factors IRF3 and NF-κB via TBK1 induces the expression of various interferons, including type I interferon (IFN).

[0005] Type I IFN, generated by antigen-presenting cells and other cell types, is considered a key event in T cell activation and thus differentiates into antigen-specific effector CD4 and CD8 T cells. Studies have shown that a lack of type I IFN leads to a decrease in 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 type I IFN markers 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] The effective secretion of type I IFNs in the tumor microenvironment and the induction of T cell-dependent immune responses against cancer cells depend on the presence of STING, as demonstrated 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). The absence of STING leads to reduced levels of type I IFNs in the tumor microenvironment and decreased 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 enhances antigen-specific T cell immune responses against cancer cells.

[0007] Type I interferon can significantly enhance anti-tumor immune responses by inducing the activation of both acquired and innate immune cells.

[0008] Given the importance of type I IFN in the treatment of several malignant diseases (including viral infections) and cancer, the focus of treatment is on strategies that allow for specific activation of STING. STING activation can be combined with various approved chemotherapy agents or other anticancer therapies (such as radiotherapy) (Wu et al., Med Res Rev 2020 May;40(3):1117-1141) or with infectious disease therapies.

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

[0010] The compounds of the present invention are novel activators of STING, as demonstrated in in vitro reporter systems using the THP1-Blue reporter cell line.

[0011] In one state, the present invention relates to compounds of formula (I), in [A] represents N or C. [B] refers to groups selected from the following groups: 5-7 member monocyclic heterocyclic groups containing 1 or 2 nitrogen atoms A 6-membered bicyclic heterocyclic group containing one nitrogen atom. 7-11 member bicyclic heterocyclic groups containing 2 nitrogen atoms A 7-membered bicyclic heterocyclic group containing one nitrogen atom and one oxygen atom. A 6-membered monocyclic heterocyclic group containing one nitrogen atom and one heteroatom selected from the groups of O and S. A 9-membered bicyclic heterocyclic group containing 3 heteroatoms, two of which are N and the other is O. A 9-membered bicyclic heterocyclic group containing one nitrogen atom and one sulfur atom. A 10-membered bicyclic heterocyclic group containing 3 nitrogen atoms, of which 2 nitrogen atoms are substituted with C1-6 alkyl groups. Phenyl, A 9-membered bicyclic heteroaryl group containing 3 nitrogen atoms. -C1-4 alkyl-pyrimidine, [and] -C1-4 alkyl-O-C1-3 alkyl; [D] is a group selected from the following groups: A 9-membered bicyclic heteroaryl group containing 2 nitrogen atoms. A 10-membered bicyclic heteroaryl group containing one nitrogen atom. [and] Benzodioxane; [R, 1 The group consisting of -H, -C1-6 alkyl, -CF3, -C2-6 ynyl, and -O-C1-6 alkyl is selected from the following groups: [and] halogens; [ ] [R, 2 The group consisting of -H, -C1-6 alkyl, -C1-6 alkyl-OH, -C(O)OH, -C(O)O-C1-6 alkyl is selected from the following groups: -H, -C1-6 alkyl, -C1-6 alkyl-OH, -C(O)OH, -C(O)O-C1-6 alkyl. [and]-pyrazolyl-C1-6 alkyl; [ ] [R, 3 , ] is -H [or]-C1-6 alkyl; [R, 4 The group consisting of -H, -C1-3 alkyl, -NH2, and -NHC1-3 alkyl is selected from the following groups: [and]N(C1-3 alkyl)2; [R, 5 , ] does not exist [Or] selected from the following groups: -H, -C1-6 alkyl, -S(O2)-C1-6 alkyl, -NH-S(O2)-C1-6 alkyl, =O, -C(O)-C1-6 alkyl, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)O-C1-6 alkyl, -NR5.1R5.2, -C1-6 alkyl-C(O)OH, -S(O2)-NH2, -pyrrolidin-2-one-1-yl, -tetrazolyl, [and] R5.3-substituted 5-membered heteroaryl groups having one or two heteroatoms selected from the groups of N and O; [R, 5.1The group consisting of -H, -C1-6 alkyl, and -C(O)-C1-6 alkyl is selected from the following groups: [and]-C1-6 alkyl-O-C1-6 alkyl; [R, 5.2 The group consisting of -H, -C1-6 alkyl, -C(O)-C1-6 alkyl, -C1-6 alkyl, -O-C1-6 alkyl [and]-C1-6 alkyl-R5.3; [R, 5.3 The group consisting of -H, -C1-6 alkyl groups is selected from the following groups: [and] a 6-membered heteroaryl group having one or two heteroatoms selected from the groups of N and O; [R, 6 , ] does not exist [Or] It is selected from the following groups: -H, -C1-6 alkyl, =O [and]-C(O)OH; Or its salt.

[0012] Compounds of formula (I) or salts thereof, as defined herein, are particularly suitable for the treatment of pathophysiological processes associated with or regulated by STING, specifically for the treatment of inflammatory, allergic or autoimmune diseases, infectious diseases or cancer, or for use as vaccine adjuvants.

[0013] In another embodiment, the invention relates to a treatment method involving a compound of formula (I) or a salt thereof. In another embodiment, the invention relates to the use of a compound of general formula (I) as a pharmaceutical agent. In another embodiment, the invention relates to a pharmaceutical composition comprising at least one compound of general formula (I). In another embodiment, the invention relates to the use of a compound of general formula (I) in a pharmaceutical composition comprising other active substances. In another embodiment, the invention provides a general synthetic process for compounds of general formula (I), including examples and methods. Implementation

[0014] The compounds of the present invention exhibit several advantageous properties in cellular analysis, such as a favorable binding affinity for human STING, favorable cellular activity as measured by cellular EC50 (i.e., in cells carrying different human STING alleles), and favorable permeability.

[0015] Therefore, in another embodiment, the present invention provides a novel (I) compound comprising its salt, which activates STING and thus induces interferon production in vitro and / or in vivo in a STING-dependent manner, and has suitable pharmacological and pharmacokinetic properties for use in a therapy, i.e., for use as a pharmaceutical agent.

[0016] The compounds according to the invention generally exhibit a cellular EC50 of less than 10 µM, more preferably less than 7 µM, more preferably less than 5 µM, and most preferably less than 3 µM for the STING "HAQ" form.

[0017] Furthermore, the compounds according to the invention also show lower than 10 µM, more preferably lower than 7 µM, more preferably lower than 5 µM, and most preferably lower than 3 µM for human STING variant "H232R" (sometimes also referred to as wild type, Yi et al., 2013; PLOS ONE 8(10)).

[0018] Furthermore, the compounds according to the present invention also show lower than 10 µM, more preferably lower than 7 µM, more preferably lower than 5 µM, and most preferably lower than 3 µM cellular EC50 for the human STING variant "R232H".

[0019] Furthermore, the compounds according to the present invention also show lower than 10 µM, more preferably lower than 7 µM, more preferably lower than 5 µM, and most preferably lower than 3 µM cellular EC50 for the human STING variant "R293Q".

[0020] Furthermore, the compounds according to the present invention also show that for human STING variant "AQ", the cellular EC50 is below 10 µM, preferably below 7 µM, more preferably below 5 µM, and most preferably below 3 µM.

[0021] "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)). The activity of different variants of human STING is advantageous because it maximizes the probability of inducing the desired pharmacological response in patients with single nucleotide polymorphisms.

[0022] Furthermore, the compounds of this invention exhibit favorable binding to human STING protein. This favorable binding affinity to human STING, along with favorable cellular activity and / or favorable pharmacokinetic properties, allows for lower doses to achieve the pharmacological efficacy required. Lower doses offer the advantage of lower "drug loading" or "drug burden" (parent drug and its metabolites) for patients, resulting in potentially fewer side effects and reduced pharmaceutical manufacturing costs.

[0023] The binding of compounds to proteins can be determined using known methods, such as surface plasma resonance, scintillation proximity analysis, isothermal titration calorimetry, or differential scanning luminescence. In the latter test, the temperature at which the protein unfolds (also known as the melting temperature Tm) is measured by the fluorescence change of the dye bound to the hydrophobic portion of the protein. After small molecule binding, the Tm shift is related to the binding affinity of this small molecule. The high binding affinity of STING activators is reflected by a Tm shift of >10 K, preferably >13 K, and more preferably >15 K.

[0024] In another embodiment of the invention, the compounds exhibit good cell permeability, facilitating targeted binding of intracellular STING proteins. For example, as measured in Caco-2 cell lines, Papp AB, measured from the top to the bottom outer side of the cell monolayer (Caco-2 A→B), is higher than 5 × 10E-6 cm / s, preferably higher than 8 × 10E-6 cm / s, and more preferably higher than 10 × 10E-6 cm / s. Furthermore, the compounds exhibit a low efflux rate from Caco cells (calculated as shown below) of <8, preferably <5, and more preferably <3.5, indicating a good intracellular residence time and thus promoting a longer duration of targeted binding.

[0025] In another embodiment of the invention, the solubility of the compounds of the invention is > 40 µg / ml at pH 6.8, preferably > 50 µg / ml at pH 6.8, and more preferably > 60 µg / ml at pH 6.8, as shown below, thereby facilitating the use of these compounds for systemic and inhalation or intratumoral administration.

[0026] Compounds of general formula (I) as defined herein, in [A] represents N or C. [B] refers to groups selected from the following groups: 5-7 member monocyclic heterocyclic groups containing 1 or 2 nitrogen atoms A 6-membered bicyclic heterocyclic group containing one nitrogen atom. 7-11 member bicyclic heterocyclic groups containing 2 nitrogen atoms A 7-membered bicyclic heterocyclic group containing one nitrogen atom and one oxygen atom. A 6-membered monocyclic heterocyclic group containing one nitrogen atom and one heteroatom selected from the groups of O and S. A 9-membered bicyclic heterocyclic group containing 3 heteroatoms, two of which are N and the other is O. A 9-membered bicyclic heterocyclic group containing one nitrogen atom and one sulfur atom. A 10-membered bicyclic heterocyclic group containing 3 nitrogen atoms, of which 2 nitrogen atoms are substituted with C1-6 alkyl groups. Phenyl, A 9-membered bicyclic heteroaryl group containing 3 nitrogen atoms. -C1-4 alkyl-pyrimidine, [and] -C1-4 alkyl-O-C1-3 alkyl; [D] is a group selected from the following groups: A 9-membered bicyclic heteroaryl group containing 2 nitrogen atoms. A 10-membered bicyclic heteroaryl group containing one nitrogen atom. [and] Benzodioxane; [R, 1 The group consisting of -H, -C1-6 alkyl, -CF3, -C2-6 ynyl, and -O-C1-6 alkyl is selected from the following groups: [and] halogens; [ ] [R, 2 The group consisting of -H, -C1-6 alkyl, -C1-6 alkyl-OH, -C(O)OH, -C(O)O-C1-6 alkyl is selected from the following groups: -H, -C1-6 alkyl, -C1-6 alkyl-OH, -C(O)OH, -C(O)O-C1-6 alkyl. [and]-pyrazolyl-C1-6 alkyl; [ ] [R, 3 , ] is -H [or]-C1-6 alkyl; [R, 4The group consisting of -H, -C1-3 alkyl, -NH2, and -NHC1-3 alkyl is selected from the following groups: [and]N(C1-3 alkyl)2; [R, 5 , ] does not exist [Or] selected from the following groups: -H, -C1-6 alkyl, -S(O2)-C1-6 alkyl, -NH-S(O2)-C1-6 alkyl, =O, -C(O)-C1-6 alkyl, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)O-C1-6 alkyl, -NR5.1R5.2, -C1-6 alkyl-C(O)OH, -S(O2)-NH2, -pyrrolidin-2-one-1-yl, -tetrazolyl, [and] R5.3-substituted 5-membered heteroaryl groups having one or two heteroatoms selected from the groups of N and O; [R, 5.1 The group consisting of -H, -C1-6 alkyl, and -C(O)-C1-6 alkyl is selected from the following groups: [and]-C1-6 alkyl-O-C1-6 alkyl; [R, 5.2 The group consisting of -H, -C1-6 alkyl, -C(O)-C1-6 alkyl, -C1-6 alkyl, -O-C1-6 alkyl [and]-C1-6 alkyl-R5.3; [R, 5.3 The group consisting of -H, -C1-6 alkyl groups is selected from the following groups: [and] a 6-membered heteroaryl group having one or two heteroatoms selected from the groups of N and O; [R, 6 , ] does not exist [Or] It is selected from the following groups: -H, -C1-6 alkyl, =O [and]-C(O)OH; Or its salts, particularly suitable for treating pathophysiological processes associated with or regulated by STING, specifically suitable for treating inflammatory, allergic or autoimmune diseases, infectious diseases or cancer, or suitable as vaccine adjuvants. Thus, in another aspect, the invention further relates to compounds of formula (I) as defined herein, or their pharmaceutically acceptable salts, for use as pharmaceutical agents. Other aspects of the invention will become apparent to those skilled in the art directly from the foregoing and following description and examples.

[0027] Terms and definitions used herein that are not specifically defined herein shall be given the meanings that a person skilled in the art would assign to them in light of the invention and the context. However, as used herein, unless otherwise stated, the following terms have designated meanings and shall be governed by the following conventions.

[0028] In the groups, radicals, or moiety defined below, the number of carbon atoms is usually indicated before the group name; for example, C1-6 alkyl means an alkyl group having 1 to 6 carbon atoms. Generally, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, or similar groups, those skilled in this art can see the group connection point of the molecule from the free valence of the group itself. For composite groups containing two or more subgroups, the last subgroup named is the group connection point; for example, the substituent "aryl-C1-3 alkyl" means that the aryl group is bonded to a C1-3 alkyl group, which in turn is bonded to the core or the group to which the substituent is attached.

[0029] If the compounds of this invention are described by chemical name and chemical formula, in case of any inconsistency, the chemical formula shall prevail. The wavy line in the formula may be used to indicate bonds connected to the core molecule as defined.

[0030] For example, the term "3-carboxypropyl-" indicates the following substituents: The carboxyl group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" represent the following groups:

[0031] The wavy line in the formula can be used to indicate the bond that is connected to the core molecule as defined.

[0032] 1.1.1.1 The term "substituted" as used herein means that one or more hydrogen atoms on a specified atom are replaced by a group selected from a substituent, provided that the replacement does not exceed the normal valence of the specified atom and that the substitution produces a stable compound. Similarly, the term "substituted" may be used in conjunction with a chemical part rather than a single atom, such as "substituted alkyl", "substituted aryl", or the like.

[0033] 1.1.1.2 Stereochemicals - Solvents - Hydrates Unless specifically specified, throughout this specification and the accompanying patent application, the given chemical formula or name shall cover tautomers and all stereo, optical and geometric isomers (e.g., mirror-image isomers, non-mirror-image isomers, E / Z isomers, etc.), their racemic derivatives, and mixtures of individual mirror-image isomers in different proportions, mixtures of non-mirror-image isomers, or mixtures in which such isomers and mirror-image isomers are present in any of the aforementioned forms, and their solvates, such as hydrates.

[0034] Unless specifically specified, "medically acceptable salts" as defined in more detail below should also include their solvates, such as hydrates.

[0035] 1.1.1.3 Stereoisomes Generally speaking, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example by separating corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. The art knows how to prepare optically active forms, such as by resolving the racemic form or by synthesis (e.g., starting from optically active starting materials and / or by using antagonistic reagents).

[0036] The mirror-isomer pure compounds or intermediates of the present invention can be prepared by means of asymmetric synthesis, for example by preparation and subsequent separation of suitable non-mirror-isomer compounds or intermediates that can be separated by known methods (e.g., by chromatography or crystallization), and / or by using antipodal reagents (such as antipodal starting materials, antipodal catalysts or antipodal auxiliaries).

[0037] Furthermore, those skilled in this art know how to prepare mirror-isomerically pure compounds from corresponding racemic mixtures, such as by separating the corresponding racemic mixture by chromatography on an antipodal stationary phase; or by resolving the racemic mixture using a suitable eluent, for example by forming non-mirror-isomer salts with the racemic compound and an optically active acid or base, followed by resolving the salts and releasing the desired compound from them; or by derivatizing the corresponding racemic compound with an optically active antipodal auxiliary reagent, followed by separating the non-mirror-isomers and removing the antipodal auxiliary groups; or by kinetic resolving of the racemic mixture (e.g., by enzymatic resolving); by mirror-selective crystallization from aggregates of isomorphic crystals under suitable conditions; or by (partial) crystallization from a suitable solvent in the presence of an optically active antipodal auxiliary agent.

[0038] 1.1.1.4 As used herein, the phrase “medically acceptable” means that such compounds, materials, compositions and / or dosage forms are suitable for contact with human tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, within the bounds of reasonable medical judgment, and in proportion to a reasonable benefit / risk ratio.

[0039] As used herein, "medically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by preparing its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues, such as inorganic or organic acid salts of amines; acidic residues, such as alkali metal or organic salts of carboxylic acids; and the like.

[0040] For example, such salts include those derived from: benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentian acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0041] It can form other medically acceptable salts with cations from ammonia, L-arginine, calcium, 2,2'-imine diethanol, L-lysine, magnesium, N-methyl-D-glucosamine, potassium, sodium, and tris(hydroxymethyl)aminomethane.

[0042] The pharmaceutically acceptable salts of this invention can be synthesized by conventional chemical methods from a parent compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of an aqueous solution or an organic diluent solution (such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) or a mixture thereof.

[0043] In addition to those mentioned above, other acid salts (e.g., trifluoroacetate salts) suitable for purifying or separating the compounds of the present invention also constitute a part of the present invention.

[0044] 1.1.1.5 Halogen Terminology Halogen refers to fluorine, chlorine, bromine and iodine.

[0045] 1.1.1.6 Heteroatoms Heteroatoms can exist in all possible oxidation stages. For example, sulfur can exist in the form of monoxide (RS(O)-R') and monoxide (-RS(O)2-R').

[0046] 1.1.1.7 The alkyl term "C1-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 group represents a non-cyclic saturated branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, the term C1-5 alkyl encompasses the groups H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0047] 1.1.1.8 The term "C1-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 group, refers to a non-cyclic saturated branched chain or straight-chain divalent alkyl group containing 1 to n carbon atoms. For example, the term C1-4 enylalkyl includes -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-, -CH2-CH(CH3)-CH2-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH(CH2CH3)-, -CH(CH2CH2CH3)-CH2-, -CH(CH(CH3))2- and -C(CH3)(CH2CH3)-.

[0048] 1.1.1.9 Alkenyl If at least two carbon atoms of a C2-m alkyl group are bonded to each other by double bonds, the term "C2-m alkenyl" is used for the group "C2-m alkyl", where m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0049] 1.1.1.10 Enylene If at least two carbon atoms of a C2-m enylene group are bonded to each other by a double bond, the term "C2-m enylene" is used for the group "C2-m enylene", where m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0050] 1.1.1.11 Alkynyl If at least two carbon atoms of a C2-m alkyl group are bonded to each other by a paratactic bond, the term "C2-m alkynyl" is used for the group "C2-m alkyl", where m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0051] 1.1.1.12 Entynyl group: The term "C2-m entynyl group" is used for the group "C2-m entynyl group" if at least two of the carbon atoms of the C2-m entynyl group are bonded to each other by a paratactic bond, wherein m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0052] 1.1.1.13 The cycloalkyl term "C3-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 C3-7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0053] 1.1.1.14 The cycloalkenyl term "C3-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, wherein at least two carbon atoms are bonded to each other by double bonds. For example, the term C3-7 cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and cyclohepttrienyl.

[0054] 1.1.1.15 Halogen - (alkyl, alkylene, or cycloalkyl) The term "halogen" added to "alkyl," "alkylene," or "cycloalkyl" (saturated or unsaturated) is defined as an alkyl, alkylene, or cycloalkyl group in which one or more hydrogen atoms are replaced by a halogen atom selected from: fluorine, chlorine, or bromine, preferably fluorine and chlorine, especially fluorine. Examples include: H2FC-, HF2C-, F3C-.

[0055] 1.1.1.16 The term "carbocyclic group" refers to a monocyclic, bicyclic, or tricyclic structure consisting of 3 to 14 carbon atoms, alone or in combination with another group. The term "carbocyclic group" refers to fully saturated, partially saturated, and aromatic ring systems. The term "carbocyclic group" encompasses fused, bridged, and spirocyclic systems.

[0056] 1.1.1.17 Aryl As used herein, the term "aryl" alone or in combination with another group refers to a six-carbon-ring aromatic monocyclic group, which, where appropriate, is further fused with a second aromatic, saturated, or unsaturated five- or six-membered carbocyclic group. Aryl groups include, but are not limited to, phenyl, dihydroindenyl, indenyl, naphthyl, anthraceneyl, phenanthryl, tetrahydronaphthyl, and dihydronaphthyl.

[0057] 1.1.1.18 The term "heterocyclic group" means, where applicable, an aromatic ring containing one or more heteroatoms selected from N, O, S, SO, and SO2, and consisting of 3 to 14 ring atoms in a saturated or unsaturated monocyclic or polycyclic system, wherein none of the heteroatoms is part of an aromatic ring. The term "heterocyclic group" is intended to include all possible isomers.

[0058] Therefore, the term "heterocyclic group" includes the following exemplary structures (not depicted as groups because each form is connected to any atom via covalent bonds, as long as the appropriate valence is maintained):

[0059] 1.1.1.19 The term "heteroaryl" means a monocyclic or polycyclic system comprising 5 to 14 ring atoms, containing at least one aromatic ring and one or more heteroatoms selected from N, O, S, SO, or SO2, wherein at least one of the heteroatoms is part of an aromatic ring, and the resulting ring system must be chemically stable. The term "heteroaryl" is intended to include all possible isomers.

[0060] Therefore, the term "heteroaryl" includes the following exemplary structures (not depicted as groups, as each form may be covalently bonded to any atom, as long as the appropriate valence is maintained):

[0061] Many of the terms given above can be used repeatedly to define chemical formulas or groups, and in each case, each independently has one of the meanings given above.

[0062] The term "bicyclic system" refers to a group consisting of two conjoined cyclic substructures, including spirocyclic, fused, and bridging ring systems.

[0063] A preferred embodiment of the present invention relates to a compound of formula (I) or a salt thereof. The R1 group is selected from the following groups: -C1-6 alkyl, -CF3, -O-C1-6 alkyl and halogens.

[0064] Another specific embodiment relates to a compound of formula (I) or a salt thereof, wherein R1 is selected from the group consisting of -C1-6 alkyl, -CF3, -O-C1-6 alkyl, -Br and -Cl.

[0065] Another specific embodiment relates to a compound of formula (I) or a salt thereof, wherein R1 is selected from the group consisting of -C1-6 alkyl, -CF3, -Br and -Cl.

[0066] Another specific embodiment relates to a compound of formula (I) or a salt thereof, wherein R1 is selected from the group consisting of -C1-6 alkyl, -CF3, -O-C1-6 alkyl, halogen, and wherein R4 is -H or -C1-3 alkyl.

[0067] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R2 is -H.

[0068] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R3 is -H.

[0069] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R2 is -H and wherein R3 is -H.

[0070] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R4 is -H or -C1-3 alkyl.

[0071] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R5 is selected from the group consisting of: -H, -C1-6 alkyl, -S(O2)-C1-6 alkyl, =O, -C(O)H, -C(O)NH2, -C(O)OH, -C(O)O-C1-6 alkyl, -NR5.1R5.2, and a 5-membered heteroaryl group substituted with R5.3 having one or two heteroatoms selected from the group consisting of N and O; R5.1 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl and -C1-6 alkyl-O-C1-6 alkyl; R5.2 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl, -C1-6 alkyl-O-C1-6 alkyl and -C1-6 alkyl-R5.3; and R5.3 is -H or -C1-6 alkyl.

[0072] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R5 is selected from the group consisting of: -H, -C1-6 alkyl, -S(O2)-C1-6 alkyl, -NH-S(O2)-C1-6 alkyl, =O, -C(O)-C1-6 alkyl, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)O-C1-6 alkyl, -NR5.1R5.2, -C1-6 alkyl-C(O)OH, -S(O2)-NH2, -pyrrolidone-2-one-1-yl, and a 5-membered heteroaryl group substituted with R5.3 having one or two heteroatoms selected from the group consisting of N and O; and wherein R5.1 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl and -C1-6 alkyl-O-C1-6 alkyl; and R5.2 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl, -C1-6 alkyl-O-C1-6 alkyl and -C1-6 alkyl-R5.3; and R5.3 is selected from the group consisting of: -H, -C1-6 alkyl and a 6-membered heteroaryl group having one or two heteroatoms selected from the groups consisting of N and O.

[0073] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R5 is selected from the group consisting of: -H, -C1-6 alkyl, -S(O2)-C1-6 alkyl, =O, -C(O)H, C(O)NH2, -C(O)OH, -C(O)O-C1-6 alkyl and -NR5.1R5.2; and wherein R5.1 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl and -C1-6 alkyl-O-C1-6 alkyl; and wherein R5.2 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl and -C1-6 alkyl-O-C1-6 alkyl.

[0074] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R5 is selected from the group consisting of: -H, -C1-6 alkyl, -S(O2)-C1-6 alkyl, =O, -C(O)H, -C(O)NH2, -C(O)OH and -C(O)O-C1-6 alkyl.

[0075] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R5 is selected from the group consisting of -C(O)H, C(O)NH2, -C(O)OH and -C(O)O-C1-6 alkyl.

[0076] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R5 is -C(O)OH or -C(O)O-C1-3 alkyl.

[0077] Another specific embodiment of the invention relates to a compound of formula (I) or a salt thereof, wherein R5 is absent (if required by valence).

[0078] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R6 is -H or -C(O)OH.

[0079] Another specific embodiment of the invention relates to a compound of formula (I) or a salt thereof, wherein R6 is absent (if required by valence).

[0080] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein R5 is -H and R6 is -H.

[0081] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein A is N.

[0082] 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: a 5-7 member monocyclic heterocyclic group containing 1 or 2 N atoms; a 6 member bicyclic heterocyclic group containing 1 N atom; a 7-11 member bicyclic heterocyclic group containing 2-3 N atoms; a 7 member bicyclic heterocyclic group containing 1 N atom and 1 O atom; a 6 member monocyclic heterocyclic group containing 1 N atom and 1 heteroatom selected from the group consisting of O and S; a 9 member bicyclic heterocyclic group containing 3 heteroatoms, wherein 2 heteroatoms are N and the other is O; a 9 member bicyclic heterocyclic group containing 1 N atom and 1 S atom; and a 10 member bicyclic heterocyclic group containing 3 N atoms, wherein 2 N atoms are substituted with C1-6 alkyl groups.

[0083] Another specific embodiment of the invention relates to a compound of formula (I) or a salt thereof, wherein B is selected from a group of the group consisting of: .

[0084] Another specific embodiment of the invention relates to a compound of formula (I) or a salt thereof, wherein B is selected from a group of the group consisting of: .

[0085] 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: .

[0086] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein the D group is selected from the group consisting of: a 9-membered bicyclic heteroaryl containing 2 N atoms; and a 10-membered bicyclic heteroaryl containing 1 N atom.

[0087] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: .

[0088] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: .

[0089] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: . R1 is selected from the group consisting of: -C1-6 alkyl, -CF3, -O-C1-6 alkyl, halogen, and R2 is -H, R3 is -H, and R4 is -H or -C1-3 alkyl.

[0090] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: .

[0091] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: .

[0092] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is .

[0093] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: And R2 is -H, and R3 is -H.

[0094] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: Furthermore, R1 is selected from the group consisting of -Br and -Cl, R2 is -H, and R3 is -H.

[0095] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: Furthermore, R1 is selected from the following groups: -C1-6 alkyl, -CF3, -O-C1-6 alkyl, -Br, and -Cl.

[0096] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is selected from the group consisting of: Furthermore, R1 is selected from the group consisting of: -C1-6 alkyl, -CF3, -O-C1-6 alkyl, -Br and -Cl; and R2 is -H; and R3 is -H.

[0097] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is Furthermore, R1 is selected from the group consisting of: -C1-6 alkyl, -CF3, -O-C1-6 alkyl, halogen, and R2 is -H, and R3 is -H.

[0098] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, wherein D is R1 is selected from the group consisting of: -C1-6 alkyl, -CF3, -O-C1-6 alkyl, halogen, and R2 is -H, R3 is -H, and R4 is -H or -C1-3 alkyl.

[0099] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, which is selected from the group consisting of: .

[0100] Another specific embodiment of the present invention relates to a compound of formula (I) or a salt thereof, which is selected from the group consisting of: .

[0101] In one embodiment, the present invention relates to compounds of formula (I) or salts thereof. As depicted in the structural diagram of formula (I), A is a part of B, meaning B includes A. For example, when A is a heteroatom, this heteroatom can be the only heteroatom in B, when B is a heterocyclic group. Furthermore, for example, if B is a heterocyclic group defined by a certain number of members (e.g., 5-7 members, 6 members, etc.), then A is one of these members. Furthermore, as another example, if B is a 6-membered monocyclic heterocyclic group containing one N atom, then A can be this N atom.

[0102] In one embodiment, the present invention relates to a compound of formula (I) or a salt thereof, wherein B is a group selected from -C1-4 alkyl-pyrimidine and -C1-4 alkyl-O-C1-3 alkyl, and the limiting condition is that A is nitrogen.

[0103] Any one of the definitions of A, B, D, R1, R2, R3, R4, R5, R5.1, R5.2, R5.3, and R6, and each of them can be combined with each other.

[0104] In one embodiment, the present invention relates to compounds of formula (I) in their salt-free form.

[0105] In one embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, used as a pharmaceutical agent. In another embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, used to treat diseases selected from the group consisting of inflammatory, allergic or autoimmune diseases, infectious diseases, and cancers, or used as a vaccine adjuvant. In another embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, as another active substance selected from the group consisting of: cell growth inhibitors, cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, viruses, immunogenic cell death inducers, cancer targets, immunomodulators, antibodies, and nanoantibodies.

[0106] In another aspect of the invention, compounds of general formula (I) or salts thereof have been found to be suitable for the prevention and / or treatment of diseases and / or symptoms in which regulation of STING has a therapeutic benefit. Additionally, the compounds of the invention are suitable as vaccine adjuvants due to their activity.

[0107] Diseases and symptoms 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.

[0108] Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), dermatomyositis, and Sjogren's syndrome (SS).

[0109] The compounds of this invention can be used to treat inflammation of any tissue and organ in the body, including but not limited to inflammation of the muscles and bones, blood vessels, nerves, digestive system, eyes, reproductive system, and other types of inflammation.

[0110] Examples of musculoskeletal inflammations that can be treated with the compounds of the present invention include: arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendinitis, synovitis, tenosynovitis, bursitis, fibrositis (muscle fiber pain), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and cystic fibrosis). Examples of ocular inflammations that can be treated with the compounds of the present invention include: blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, dry eye syndrome, scleritis, trichiasis, and uveitis. Examples of neurological inflammations that can be treated with the compounds of the present invention include: encephalitis, Guillain-Barré syndrome, meningitis, neuromuscular rigidity, narcolepsy, multiple sclerosis, myelitis, and schizophrenia. Examples of inflammations of the vascular structure or lymphatic system that can be treated with the compounds of the present invention include: arthritis, joint stiffness, phlebitis, vasculitis, and lymphangitis. Examples of inflammatory conditions of the digestive system that can be treated with the compounds of the present invention include: cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), ileitis, and proctitis. Examples of inflammatory conditions of the reproductive system that can be treated with the compounds of the present invention include: cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian cysts, urethritis, vaginitis, vulvitis, and vulvar pain.

[0111] These compounds can be used to treat autoimmune diseases with inflammatory components. These conditions include acute diffuse alopecia universalis, Behcet's disease, Chagas' disease, chronic fatigue syndrome, autonomic nervous system dysfunction, 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, Graves-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, strabismus myoclonus syndrome, optic neuritis, and Ord's thyroiditis. Thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Hughley's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, scleroderma, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and leukoplakia.

[0112] These compounds can be used to treat T-cell-mediated hypersensitivity disorders with inflammatory components. Such conditions include contact hypersensitivity, contact dermatitis (including contact dermatitis caused by kudzu), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0113] Other inflammatory conditions that can be treated with these compounds include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, pneumonia, prostatitis, pyelonephritis, and stomatitis; transplant rejection (involving organs such as kidneys, liver, heart, lungs, pancreas (e.g., islet cells), bone marrow, cornea, small intestine, skin allogeneic transplants, skin allogeneic transplants, and heart valve xenotransplants, serum disorders, and graft-versus-host disease); acute pancreatitis; chronic pancreatitis; acute respiratory distress syndrome; and Sezary's syndrome. Syndrome), congenital adrenal hyperplasia, non-suppurative thyroiditis, cancer-related hypercalcemia, pemphigus, bullous herpes-like dermatitis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity, allergic conjunctivitis, keratitis, ocular herpes zoster, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated pulmonary 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. Better treatment options include treatment for the following: 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 such as sepsis.

[0114] In one embodiment, the disease or symptom to be treated with the compound of the present invention is cancer. Examples of cancer diseases and symptoms for which the compound of formula (I) or its salts or solvates may have potentially beneficial antitumor effects include, but are not limited to: cancers of the lungs, bones, pancreas, skin, brain, head, neck, uterus, ovary, stomach, large intestine, colon and rectum, breast, ovary, esophagus, small intestine, intestine, endocrine system, thyroid gland, parathyroid gland, adrenal gland, urethra, prostate, penis, testicles, ureter, bladder, kidney or liver, bile duct; urethral epithelial cancer; rectal cancer; anal cancer; fallopian tube, endometrium, cervix, vagina, vulva, renal pelvis, renal cells. Tumor; sarcoma; soft tissue sarcoma; myxoma; rhabdomyosarcoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; liver cancer; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphoma; primary CNS lymphoma; CNS vesicle; spinal axis tumor; 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 aforementioned cancers.

[0115] Preferred cancers that can be treated with the compounds according to the present invention include skin cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, brain cancer, breast cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, bile duct cancer, endometrial cancer, thyroid cancer, cervical cancer, stomach cancer, head cancer, neck cancer, sarcoma, soft tissue sarcoma, esophageal cancer, head and neck cancer, rectal and urethral epithelial cancer, and lymphoma.

[0116] These novel compounds can be used for the prevention, palliative, curative or semi-curative, short-term or long-term treatment of the diseases mentioned above, and may be combined with surgical, radiotherapy or other "current state-of-the-art" compounds, such as cell growth or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, antibodies, nanoantibodies, cancer targets, viruses (including but not limited to oncolytic viruses) or immunogenic cell death inducers.

[0117] These novel compounds can also be used to prevent, palliative, curative, or semi-curative, short-term or long-term treat the diseases mentioned above by combining them with different routes of administration (e.g., intravenous, intratumoral, subcutaneous, inhalation, oral, etc.), and, as appropriate, with surgical, radiotherapy, or other "current state-of-the-art" compounds, such as cell growth or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, antibodies, nanoantibodies, cancer targets, viruses (including but not limited to oncolytic viruses), or immunogenic cell death inducers. As an example of surgery, partial or complete tumor resection can be combined with the compounds of this invention. As an example of radiotherapy, external beam radiotherapy can be combined with the compounds of this invention.

[0118] In its role as an adjuvant, in some embodiments, the compounds and compositions of the present invention can be used as adjuvants in therapeutic or preventative strategies employing vaccines. Therefore, the compounds of the present invention or salts thereof can be used with one or more vaccines selected to stimulate an immune response against one or more predetermined antigens. The compounds of the present invention or salts thereof can be provided together with / in addition to such vaccines.

[0119] Such vaccines may contain inactivated or attenuated bacteria or viruses containing the antigen of interest, purified antigen, recombinantly engineered live viral or bacterial delivery vectors to express and / or secrete antigens, antigen-presenting cell (APC) vectors containing cells loaded with antigens or transfected with a composition containing nucleic acids encoding antigens, lipid antigen delivery media, or naked nucleic acid vectors encoding antigens. This list is not intended to be restrictive. By way of example, such vaccines may also contain inactivated tumor cells or oncolytic viruses that express and secrete one or more of GM-CSF, CCL20, CCL3, IL-12p70, FLT-3 ligands, and intercytokines.

[0120] Therefore, the present invention relates to a compound of general formula (I) which is used as a pharmaceutical or vaccine adjuvant.

[0121] In another embodiment, the present invention provides a novel compound of formula (I), including its salt, used in a method of treating diseases or symptoms associated with or regulated by STING.

[0122] In another embodiment, the present invention provides a novel compound of formula (I) or a salt thereof for treating inflammatory, allergic or autoimmune diseases, such as allergic rhinitis or asthma, for treating infectious diseases or cancer, or for use as a vaccine adjuvant.

[0123] Furthermore, this invention relates to the use of a compound of general formula (I) for the treatment and / or prevention of diseases and / or symptoms associated with or regulated by STING. Diseases and symptoms associated with or regulated by STING encompass, but are not limited to, inflammatory, allergic, or autoimmune diseases, such as allergic rhinitis or asthma, infectious diseases, or cancer, including but not limited to the specific diseases mentioned above. Furthermore, due to their activity, the compounds of this invention are suitable as vaccine adjuvants, including but not limited to the specific applications mentioned above.

[0124] Therefore, the present invention relates to a compound of general formula (I) which is used as a pharmaceutical or vaccine adjuvant.

[0125] Furthermore, this invention relates to the use of a compound of general formula (I) for the treatment and / or prevention of the diseases and symptoms mentioned above.

[0126] In another embodiment, the present invention relates to a compound of general formula (I) for the treatment and / or prevention of the diseases and symptoms mentioned above.

[0127] In another embodiment, the present invention relates to a compound of general formula (I) for treating and / or preventing the cancers mentioned above before or after tumor resection and / or radiotherapy.

[0128] In another embodiment, the present invention relates to the use of a compound of general formula (I) for the preparation of a medicament for the treatment and / or prevention of the diseases and symptoms mentioned above.

[0129] In another embodiment, the present invention relates to a method for treating or preventing the diseases and symptoms mentioned above, the method comprising administering to a human an effective amount of a compound of general formula (I).

[0130] The daily dose range for compounds of general formula (I) is typically 0.00001 to 100 mg per kg of body weight, for example, 0.00001 to 10 mg per kg of patient body weight. Each dose unit may contain 0.001 to 1000 mg, for example, 0.001 to 100 mg.

[0131] The actual therapeutically effective dose or dosage will naturally depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of disease. In any case, the compound or composition will be administered in a dosage and manner permissible for delivering a therapeutically effective amount, based on the patient's unique condition.

[0132] In one related context, the present invention relates to methods for inducing, stimulating, or assisting an immune response in an individual. These methods involve administering the compounds of the present invention to the individual.

[0133] In another embodiment, the present invention provides the use of a compound of general formula (I) for manufacturing an immunogenic composition comprising an antigen or antigenic composition for the treatment or prevention of a disease.

[0134] In another embodiment, the present invention provides a method for treating or preventing a disease, comprising administering to a human individual suffering from or susceptible to a disease an immunogenic composition comprising an antigen or an antigenic composition and a compound of general formula (I).

[0135] In another embodiment, the present invention provides a vaccine composition comprising an antigen or an antigen composition and a compound of general formula (I) for the treatment or prevention of disease.

[0136] In another embodiment, the present invention provides the use of a compound of general formula (I) for manufacturing a vaccine composition comprising an antigen or an antigenic composition for treating or preventing a disease.

[0137] In another embodiment, the present invention provides a method for treating or preventing a disease, comprising administering to a human individual suffering from or susceptible to a disease a vaccine composition comprising an antigen or an antigenic composition and a compound of formula (I).

[0138] [ ] In another embodiment of the invention, pharmaceutical compositions of the compounds mentioned above are found to be formulated to administer a therapeutically effective amount of the compounds. Formulations suitable for administering compounds of formula (I) will be apparent to those skilled in the art and include, for example: tablets, pills, capsules, suppositories, lozenges, sugar-coated tablets, solutions, syrups, elixirs, capsules, injectable solutions (subcutaneous, intravenous, intramuscular, intraperitoneal, intratumoral, and peritumoral), inhalants, infusions, elixirs, emulsions, and powders. Furthermore, the compounds according to the invention can be administered via targeted delivery platforms, such as antibody-drug conjugates, nano-antibody-drug conjugates, peptide-drug conjugates, virus-like particles, or nanoparticle formulations.

[0139] Suitable tablets can be obtained, for example, by mixing one or more compounds according to Formula I with known excipients (e.g., inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants).

[0140] For the purposes of this invention, the pharmaceutical compositions can be administered by a variety of means, including in the form of formulations containing pharmaceutically acceptable carriers, adjuvants, and mediators, via enteral, non-enteral, inhalation spray, topical, nasal, oral, or rectal administration. The pharmaceutical compositions of this invention can be in the form of sterile injectable formulations, such as sterile injectable aqueous or oil suspensions.

[0141] According to another embodiment, a vaccine is provided that comprises one or more compounds of general formula (I). In another embodiment, the present invention provides a vaccine adjuvant that comprises a compound of general formula (I). In yet another embodiment, the present invention provides an immunogenic composition comprising an antigen or antigen composition and a compound of general formula (I).

[0142] In another embodiment, the present invention provides an immunogenic composition comprising an antigen or antigenic composition and a compound of general formula (I) for the treatment or prevention of disease.

[0143] Combination therapy: The compounds of this invention can be used independently or in combination with pharmaceutically acceptable excipients in amounts sufficient to induce, modulate, or stimulate an appropriate immune response. Immune responses may include, but are not limited to, specific immune responses, nonspecific immune responses, specific and nonspecific responses, innate responses, primary immune responses, acquired immunity, secondary immune responses, memory immune responses, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

[0144] In some embodiments, the compounds and compositions thereof described herein are administered in combination with one or more additional compositions, including vaccines intended 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 targets; immunogenic cell death inducers; and immunomodulators, wherein immunomodulators can be understood as agents of commonly used activation-regulating types and agents that regulate and / or increase the frequency of a particular immune cell subtype, etc.

[0145] The compounds and their compositions described herein may be administered before, after, and / or simultaneously with other therapeutic or preventative compositions or modalities.

[0146] The compounds and compositions of the present invention, including any combination with one or more additional therapeutic agents, may be administered via mucosal (e.g., oral, sublingual, vaginal, nasal, cervical, etc.), intratumoral, intraperitoneal, peritumoral, percutaneous, inhalation, or non-intestinal (e.g., subcutaneous, intravenous, intramuscular, intra-arterial, intradermal, intrathecal, and epidural) routes.

[0147] Furthermore, compounds and compositions according to the present invention, including any combination with one or more additional therapeutic agents, can be delivered via a targeted delivery platform, such as an antibody-drug conjugate, a nano-antibody-drug conjugate, a peptide-drug conjugate, a virus-like particle, or a nanoparticle.

[0148] Among possible administration methods, intraperitoneal, intratumoral, peritumoral, subcutaneous, inhalation, or intravenous administration are preferred. The compounds and compositions according to the invention, including any combination with one or more additional therapeutic agents, can also be administered before, after, and / or simultaneously with combinations of different administration methods. As an example only, inhalation or intravenous administration can be administered after intratumoral or peritumoral administration, or intratumoral or peritumoral administration can be administered after inhalation or intravenous administration. Furthermore, such administration of the compounds via different routes can be before or after additional therapeutic steps (such as tumor resection or radiotherapy). As an example only, the compounds of the invention can be administered after radiotherapy. Furthermore, the compounds of the invention can be administered intravenously after radiotherapy. Furthermore, the compounds of the invention can be administered intravenously after tumor resection. Furthermore, the compounds of the invention can be administered intratumorally after radiotherapy. Furthermore, the compounds of the invention can be administered peritumorally after radiotherapy. Furthermore, the compounds of the invention can be administered by inhalation after tumor resection. Furthermore, the compounds of the present invention can be administered intravenously, followed by intratumoral administration, with both administrations occurring after radiotherapy. (This text is repeated four times in the original.)

[0149] The method of co-administering with additional therapeutic agents is well known in this technique.

[0150] Due to the adjuvant properties of the compounds of this invention, they can also be used in combination with other therapeutic modalities (including other vaccines, adjuvants, antigens, antibodies and immunomodulators).

[0151] In addition to the compounds and compositions thereof described herein, the compositions or methods of the present invention may further comprise one or more other substances that, due to their properties, can be used to stimulate or otherwise utilize the immune system to respond to cancer antigens present on targeted tumor cells.

[0152] The compounds of this 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.

[0153] The compounds of this invention can be used in combination with immunocarcinogenic agonists, T-cell receptor agonists, or TNF receptor superfamily agonists or antagonists.

[0154] The compounds of this invention can be used in combination with therapeutic antibodies or therapeutic nanoantibodies. In some embodiments, the mechanism of action of the therapeutic antibody is antibody-dependent cell-mediated cytotoxicity (ADCC).

[0155] In additional embodiments of the methods described herein, the compounds of the invention are used in combination with chemotherapeutic agents (e.g., small molecule pharmaceutical compounds) as known to those skilled in the art. Therefore, the methods further involve administering an effective amount of one or more chemotherapeutic agents to an individual as additional or combined treatment.

[0156] It can also be combined with the style [(I)] A compound or a pharmaceutically acceptable salt thereof (including compounds) [(I)] together or in combination with any individual embodiments or general subset thereof, or additional pharmacologically active substances used in medical uses, applications, treatments and / or preventive methods as disclosed herein (above and below), including but not limited to: hormones, hormone analogs and anti-hormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate). Acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide; aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane); LHRH agonists and antagonists (e.g., goserelin acetate, luprolide); growth factors and / or their corresponding receptor inhibitors (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). Human epidermal growth factor (HER, such as HER2, HER3, HER4) and / or its corresponding receptors (IGF, human epidermal growth factor, and / or its corresponding receptors).Inhibitors include (anti)growth factor antibodies, (anti)growth factor receptor antibodies, and tyrosine kinase inhibitors, such as afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, and HKI. 357. Omoltinib, 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 Entazoline Inhibitors of emtansine, or mutant EGFR, inhibitors of HER2 with exon 20 mutations, and hepatocyte growth factor (HGF, c-MET, such as emibetuzumab, amiranumab, savoritinib, cabozantinib, foretinib); antimetabolites (such as methotrexate, raltitrexed, 5-fluorouracil (5-FU), capecitabine, fluxuridine, gemcitabine, mecaptopurine, thioguanine, cladribine, pentostatin, cytarabine). C) A combination of fludarabine, trifluridine, and tipiracil (= TAS102)Antitumor antibiotics (such as anthracycline, doxorubicin, doxil (polyethylene glycol liposomal doxorubicin hydrochloride), myocet (non-polyethylene glycol liposomal doxorubicin), daunorubicin, epirubicin, idarubicin, mitomycin-C, bleomycin, actinomycin D) (dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas (such as carmustin and lomustin), thiotepa); antimitotic agents (e.g., vinca alkaloids). Alkaloids, such as vinblastine, vindesin, vicorylbin, and vincristine; and taxanes, such as paclitaxel, docetaxel, and nab-paclitaxel (Abraxane); angiogenesis inhibitors (such as tasquinimod and bevacizumab), microtubule inhibitors; DNA synthesis inhibitors, PARP inhibitors, and topoisomerase inhibitors (such as epipodophyllotoxin, such as etoposide, etopophos, teniposide, amsacrin, topotecan, irinotecan, and mitoxantrone);Serine / threonine kinase inhibitors (e.g., PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors), mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, torin 1, dactosilib, GDC-0349, vs-5584; vistusertib; AZD8055), mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors (e.g., alpelisib, serabelisib, GDC-0077, HH-CYH33, AMG) 511. Buparlisib, dactolisib, pictilisib, taselisib, mTOR / PI3K dual inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600), Aurora kinase inhibitors); tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors); protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimics, MCL-1). (e.g., AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477), MDM2, MDM2 / MDMX); MEK inhibitors (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib); SOS1 inhibitors (i.e., compounds that regulate / inhibit the GEF function of SOS1 by binding to SOS1 and preventing protein-protein interactions between SOS1 and (mutant) Ras proteins (e.g., KRAS);Examples include BAY-293), inhibitors of GDP-loaded or GTP-loaded RAS and / or any mutant thereof (i.e., compounds that regulate / inhibit the function of (mutant) RAS proteins by binding to GDP-loaded or GTP-loaded (mutant) RAS proteins (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 of GDP-loaded (mutant) KRAS; and GTP-loaded (mutant)... Reversible or irreversible KRAS binders; ALK inhibitors (e.g., crizotinib, alectinib, entrectinib, brigatinib, ceritinib); ERK inhibitors; FLT3 inhibitors; BRD4 inhibitors; IGF-1R inhibitors; TRAILR2 agonists; Bcl-xL inhibitors; Bcl-2 inhibitors (e.g., venetoclax, omeprazole). Batoclax, Navitoclax, Oblimersen; Bcl-2 / Bcl-xL inhibitors; ErbB receptor inhibitors; BCR-ABL inhibitors; ABL inhibitors; Src inhibitors (e.g., dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU...). 6656, WH-4-023); rapamycin analogues (e.g., everolimus, temsirolimus, ridaforolimus, sirolimus); androgen synthesis inhibitors; androgen receptor inhibitors; DNMT inhibitors; HDAC inhibitors; ANG1 / 2 inhibitors; histone deacetylases; IL6 inhibitors; JAK and / or any mutant inhibitors;Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any of their 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); receptor tyrosine kinase. Inhibitors of kinase (RTK) and / or any mutant thereof; inhibitors of SHP2 and / or any mutant thereof (e.g., SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909); CYP17 inhibitors; radiopharmaceuticals; proteasome inhibitors (e.g., carfilzomib); immunotherapeutic agents, such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, SIRPα antibodies and TIM3 binding molecules / immunoglobulins (ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001) (e.g., spartalizumab), AMG-404, ezabenlimab, sintilimab, camrelizumab, toribalimab, tislelizumab); antibody-dependent cell-mediated cytotoxicity (ADCC) enhancers (e.g., anti-CD33 antibody, anti-CD37 antibody, anti-CD20 antibody);T-cell conjugates, such as PSMA x CD3, B7H6 / CD3 (as disclosed in, for example, WO2021 / 064137), DLL3 / CD3 (as disclosed in, for example, WO2019 / 234220), such as bispecific T-cell conjugates (BiTEs®), such as CD3 x BCMA, CD3 x CD33, CD3 x CD19, cancer vaccines, MDM2 inhibitors, oncolytic viruses, and various chemotherapeutic agents, such as amifostin, anagrelor, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer. The compounds of this invention can be used in combination with the following: OX40 agonists, ICOS ligands, CD27 agonists, GITR agonists, and Toll-like receptor agonists.

[0157] In a preferred embodiment, additional pharmacologically active substances that may also be used together with or in combination with compounds of formula (I) or with a pharmaceutically acceptable salt thereof (including all individual embodiments or general subsets of compound (I)) or used in medical uses, applications, treatments and / or preventive methods as disclosed herein (above and below) include: checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avitumab, durvalumab, pilizumab, PDR-001 (= spartazumab), AMG-404, ebbenlimumab, stilimumab, camrelizumab, torebaliumab, tislelizumab), taxanes (paclitaxel, docetaxel, albumin-bound paclitaxel (abrazan)), T-cell binding agents (e.g., PSMA x CD3, B7H6 / CD3) (as disclosed in, for example, WO2021 / 604137, DLL3 / CD3 (as disclosed in, for example, WO2019 / 234220), such as bispecific T-cell conjugates (BiTEs®) (such as, for example, CD3 x BCMA, CD3 x CD33, CD3 x CD19), cancer vaccines, MDM2 inhibitors and oncolytic viruses.

[0158] In other embodiments of the methods described herein, the compounds of the invention are used in combination with chemotherapeutic agents and / or additional agents for treating indications as described in the methods herein (e.g., targeted cancer therapies). Therefore, the methods further involve administering an effective amount of one or more targeted cancer agents to an individual as additional or combined treatment.

[0159] In other embodiments of the methods described herein, the compounds of the present invention are used in combination with chemotherapeutic agents and / or additional agents and / or additional therapies (such as radiation therapy and / or tumor resection) for treating indications as described herein.

[0160] In yet another embodiment, the invention relates to a method for treating a disease or condition in a patient that is related to or regulated by STING, comprising the steps of administering to a human patient in need of such treatment a therapeutically effective amount of the compound of the invention and a therapeutically effective amount of one or more additional therapeutic agents described above.

[0161] The use of compounds according to the invention in combination with additional therapeutic agents can be performed simultaneously or at staggered times.

[0162] The compounds according to the invention and one or more additional therapeutic agents may coexist in one formulation or independently in two identical or different formulations, for example as so-called kits.

[0163] Therefore, in another embodiment, the present invention provides a combination comprising a compound of general formula (I) and at least one other therapeutic agent.

[0164] Another aspect of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more of at least one other therapeutic agent and a pharmaceutically acceptable excipient.

[0165] In another embodiment, the present invention provides a combination for use in therapy comprising a compound of formula (I) or a medically acceptable salt thereof and at least one other therapeutic agent.

[0166] In another embodiment, the present invention provides a combination for treating diseases or symptoms in which STING is beneficial, comprising a compound of formula (I) or a medically acceptable salt thereof and at least one other therapeutic agent.

[0167] In another embodiment, the present invention provides a combination for treating inflammatory, allergic and autoimmune diseases, infectious diseases and cancer, comprising a compound of formula (I) or a medically acceptable salt thereof and at least one other therapeutic agent.

[0168] In another embodiment, the present invention provides a method for treating a disease or condition in which STING is beneficial to a patient, comprising administering a combination of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent.

[0169] In another embodiment, the present invention provides a method for treating patients with inflammatory, allergic or autoimmune diseases, infectious diseases or cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a combination of at least one other therapeutic agent.

[0170] The actual medically effective or therapeutic dose will naturally depend on factors known to those skilled in the technique, such as the patient's age and weight, route of administration, and severity of disease. In any case, the combination will be administered according to the patient's unique condition, using the dosage and method that allows for the delivery of a medically effective dose.

[0171] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound according to the invention and one or more additional therapeutic agents as described in the context, together with one or more inert carriers and / or diluents, as appropriate.

[0172] Other features and advantages of the present invention will become apparent from the following more detailed examples, which illustrate the principles of the invention by way of example.

[0173] Chemical synthesis

[0174] List of abbreviations ACN Acetonitrile AM Analytical methods Bu Butyl conc. Concentrated / Essential d sky DCM dichloromethane DIPEA Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP N,N-Dimethylpyridine-4-amine DMF N,N-Dimethylformamide DMSO Dimethicone Et Ethyl EtOAc Ethyl acetate h Hour HATU N-[(dimethylamino)-(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)-methylene]-N-methylmethane-ammonium N-oxide of hexafluorophosphate HPLC High performance liquid chromatography iPr Isopropyl M molar concentration mp Melting point Me methyl min minute mL milliliters MS mass spectrometry N normal NMP N-methylpyrrolidone NMR Nuclear resonance spectroscopy NP Right phase ppm parts per million prep Preparative Rf Retention factor RP Reverse phase RT room temperature tert Level 3 TBDMS Tertiary butyldimethylsilyl TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography tR Duration of stay

[0175] Other features and advantages of the invention will become apparent from the following more detailed examples, which illustrate the principles of the invention but do not limit its scope.

[0176] Unless otherwise stated, all reactions were carried out using methods commonly used in chemical laboratories on commercially available equipment. 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).

[0177] The compounds according to the present invention are named in accordance with the IUPAC guidelines. If a compound is represented by both a structural formula and its terminology, in the event of a conflict, the structural formula shall prevail.

[0178] [Chromatography] [ ] Thin-layer chromatography was performed on a ready-made silicone 60 TLC disk on glass (with fluorescent indicator F-254) manufactured by Merck.

[0179] The Biotage Isolera Four instrument, together with Interchim Puri Flash columns (50 µm, 12-300 g) or glass columns filled with Millipore-manufactured silica (partial silicon dioxide Si-60A 35-70 µm), is used for automated preparative NP chromatography.

[0180] Preparative RP-HPLC was performed using columns manufactured by Waters (Sunfire C18, 10 µm, 30 x 100 mm, part number 186003971; or X-Bridge C18, 10 µm, 30 x 100 mm, part number 186003930). Compounds were dissolved using different gradients of H₂O / acetonitrile or H₂O / MeOH, wherein 0.2% HCOOH was added to water, or different gradients were used, with alkaline buffer solutions (1 L of water containing 5 mL of ammonium bicarbonate solution (158 g / 1 L H₂O) and 2 mL of ammonia (7 mol / L solution in MeOH)) instead of water-HCOOH mixtures.

[0181] Intermediate compounds were processed using tubing manufactured by Waters and Phenomenex. [Analytical] [HPLC () [Reaction Monitoring] In all cases, the analytical equipment also includes a quality detector.

[0182] [HPLC] Mass spectrometry UV [spectrum] [ ] The residence time / MS-ESI+ of the example compounds according to the present invention was determined using, for example, an HPLC-MS device (high performance liquid chromatography with a mass detector) manufactured by Agilent. The residence time tR = 0 for compounds dissociated at the injection peak is given.

[0183] [Analytical] [HPLC] [Law] [(]AM [)]

[0184] [method] [_1] HPLC: Agilent 1100 / 1200 series MS: Agilent LC / MSD SL Tubing string: Waters X-Bridge BEH C18, 2.5 µm, 2.1 x 30 mm XP Solvents: A: H₂O + 5 mM NH₄HCO₃ / 19 mM NH₃; B: ACN (HPLC grade) Detection: MS: Positive and Negative Modes Mass range: 100 - 800 m / z Flow rate: 1.4 ml / min Column temperature: 45℃ Gradient: 0.00 - 0.01 min: 5% B 0.01 - 1.00 min: 5% à 100% B 1.00 - 1.37 min: 100% B 1.37 - 1.40 min: 100% à 5% B

[0185] [method] [_2, <s> < / s> , ] HPLC: Agilent 1100 / 1200 series MS: Agilent LC / MSD (API-ES + / - 3000 V, Quadrupol, G6140) Tubing string: Waters, XBridge C18, 2.5 µm, 2.1 x 20 mm tubing Solvents: A: H₂O + 20 mM NH₄HCO₃ / NH₃ pH 9; B: ACN (HPLC grade) Detection: MS: Positive and Negative Modes Mass range: 120 - 900 m / z Flow rate: 1.00 mL / min Column temperature: 60℃ Gradient: 0.00 - 1.50 min: 10% à 95% B 1.50 - 2.00 min: 95% B 2.00 - 2.10 min: 95% à 10% B

[0186] [method] [_3] HPLC Agilent 1260 system MS 1200 Series LC / MSD (MM-ES+APCI + / - 3000 V, Quadrupol, G6130) YMC column; part number TA12S03-0302WT; Triart C18, 3 µm, 12 nm; 30 x 2.0 mm column Solvent A: H₂O + 0.11% HCOOH; Solvent B: MeCN + 0.1% HCOOH (HPLC level) Detection signal UV 254 nm (bandwidth 10, reference off) Mass range: ±150 - 750 m / z Flow rate 1.4 mL / min Column temperature: 45℃ Gradient 0.0 - 1.0 min 15% → 100% B 1.0 - 1.23 min 100% B

[0187] [method] [_4] UPLC / MS: Waters Acquity-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7 µm, 2.1 x 50 mm Solvents: A: ACN + 0.05% HCOOH; B: H2O + 0.05% HCOOH Detection: MS: Positive and Negative Modes Mass range: 100 - 1500 m / z Flow rate: 0.6 mL / min Column temperature: 35℃ Gradient: 0.00 - 0.30 min: 97% B 0.30 - 2.20 min: 97% à 2% B 2.20 - 3.30 min: 2% B 3.30 - 4.50 min: 2% B 4.50 - 4.51 min: 2% B to 97% B

[0188] [method] [_5] UPLC / MS: Waters Acquity-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7 µm, 2.1 x 50 mm Solvents: A: ACN + 0.07% HCOOH; B: H2O + 0.07% HCOOH Detection: MS: Positive and Negative Modes Mass range: 100 - 1500 m / z Flow rate: 0.6 mL / min Column temperature: 35℃ Gradient: 0.00 - 0.30 min: 97% B 0.30 - 2.20 min: 97% à 2% B 2.20 - 3.30 min: 2% B 3.30 - 4.50 min: 2% B 4.50 - 4.51 min: 2% B to 97% B

[0189] [method] [_6] UPLC / MS: Waters Acquity-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7 µm, 2.1 x 50 mm Solvents: A: H₂O + 0.07% HCOOH, B: ACN + 0.07% HCOOH Detection: MS: Positive and Negative Modes Mass range: 100 - 1500 m / z Flow rate: 0.6 mL / min Column temperature: 35℃ Gradient: 0.00 - 0.30 min: 97% A 0.30 - 2.70 min: 97% à 2% A 2.70 - 3.50 min: 2% A 3.50 - 3.51 min: 2% à 97% A

[0190] [method] [_7] HPLC Agilent 1100 / 1200 system MS 1200 Series LC / MSD (MM-ES + APCI + / - 3000 V, Quadrupol, G6130B) Waters tubing, Part No. 186003389, XBridge BEH C18, 2.5 µm, 2.1 x 30 mm) Solvent A: 5 mM NH4HCO3 / 18 mM NH3 (pH = 9.2); Solvent B: ACN (HPLC grade) Detection signals UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off) Mass range: 150 - 750 m / z Flow rate 1.4 mL / min Column temperature 45℃ Gradient 0.0 - 1.0 min 15% à 95% B 1.0 - 1.3 min 95% B

[0191] [method] [_8] HPLC Agilent 1100 / 1200 system MS 1200 Series LC / MSD (MM-ES + APCI + / - 3000 V, Quadrupol, G6130B) Waters tubing, Part No. 186003389, XBridge BEH C18, 2.5 µm, 2.1 x 30 mm) Solvent A: 5 mM NH4HCO3 / 18 mM NH3 (pH = 9.2); Solvent B: ACN (HPLC grade) Quality range ±150 - 750 Detection signals UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off) Flow rate 1.4 mL / min Column temperature 45℃ Gradient 0.0 - 1.0 min 15% à 95% B 1.0 - 1.3 min 95% B

[0192] [ ] Compounds according to the invention can be prepared using synthetic methods known to those skilled in the art and described in the organic synthesis literature. These are intended as illustrative of the invention and not to limit its subject matter or the scope of the claimed compounds to these examples. Preferably, compounds are obtained in a manner similar to the preparation methods explained more fully below (specifically, as described in the experimental section). In some cases, the order of reaction steps may be varied. Variations of reaction methods known to those skilled in the art but not described in detail herein may also be used.

[0193] The general process for preparing compounds according to the present invention will become apparent to those skilled in the art who study the following procedures. Starting materials can be prepared by methods described in the literature or herein, or in a similar or analogous manner. Known protecting groups can be used to protect any functional groups in the starting materials or intermediates. These protecting groups can be further cleaved at appropriate stages within the reaction sequence using methods familiar to those skilled in the art.

[0194] For preparative ( One method of one of the compounds is illustrated in process I: indazole [B] Can be derived from o-methylaniline derivatives [A] Synthesis. Subsequent iodination produces 3-iodo-indazole. [C]. Intermediate [D] can be obtained, for example, via Chan-Lam coupling using (6-fluoropyridin-3-yl)boronic acid. Conversion to the intermediate can be achieved, for example, via Suzuki coupling. [E]. Finally, for example, compounds are synthesized through nucleophilic aromatic substitution. [F]. The product is separated by conventional means and preferably purified by chromatography. Process I:

[0195] [Preparation of intermediates] [B]

[0196] [B1 7-] [methyl] [-6-] [Nitro] [-1H-] [Indazole] [ ]

[0197] A mixture of 2,6-dimethyl-3-nitroaniline (2.0 g, 12 mmol) and acetic acid (177 ml) was cooled to 5 °C. Water (4 ml) containing sodium nitrite (1.08 g, 15.6 mmol) was added dropwise. The mixture was stirred for 24 h and concentrated under vacuum. The title compound was obtained by recrystallization from methanol. Yield: 0.7 g (34%). HPLC-MS: M+H = 178; tR = 1.85 min (Method 4)

[0198] [B2] [7-] [methyl] [-1H-] [Indazole] [-6-] Methyl formate

[0199] A concentrated HCl aqueous solution (7 ml) was added to a mixture of methyl 3-amino-2,4-dimethylbenzoate (5.0 g, 27.9 mmol) in water (15 ml) at 0 °C, followed by the addition of NaNO₂ (2.3 g, 33.5 mmol in 4 ml water) and sodium tetrafluoroborate (4.0 g, 36.3 mmol in 4 ml water). The mixture was stirred for 45 min. The solid was collected by filtration, washed with ether, dried, and dissolved in chloroform (40 ml). Potassium acetate (2.2 g, 22.3 mmol) and 18-crown-6 (synonyms: 1,4,7,10,13,16-hexaoxane; 0.22 g, 0.84 mmol) were added with stirring, and stirring was continued at room temperature for 2 h. Water (70 ml) was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO₄, concentrated under vacuum, and washed with pentane. Yield: 3.5 g (66%). HPLC-MS: M+H = 191; tR = 1.85 min (Method 5)

[0200] [B3] [ (7-) [methyl] [-1H-] [Indazole] [-6-] [base] [)] [Methanol]

[0201] At 0°C, methyl 7-methyl-1H-indazole-6-carboxylate was added to... [B2] Lithium aluminum hydride (1.05 g, 27.6 mmol) was added to THF (40 ml) at a concentration of 3.5 g (18.4 mmol). After stirring at room temperature for 5 min, 4N NaOH aqueous solution (1 ml) was added. The mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under vacuum. Yield of crude product: 3.0 g (99%). HPLC-MS: M+H = 163; tR = 1.47 min (Method 5)

[0202] [Preparation of intermediates] [C]

[0203] [C1 (3-)] [iodine] [-7-] [methyl] [-1H-] [Indazole] [-6-] [base] [)] [Methanol] [ ] [ ]

[0204] To (7-methyl-1H-indazole-6-yl)-methanol at 0℃ Iodine (298 mg, 4.32 mmol) and K₂CO₃ (895 mg, 6.47 mmol) were added to DMF (6 ml) containing 0.35 g (2.16 mmol). After stirring at room temperature for 2 h, EtOAc (100 ml) was added, and the mixture was extracted with water, 10% Na₂S₂O₃ aqueous solution, and brine. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. Yield of crude product: 0.3 g (48%). HPLC-MS: M+H = 289; tR = 1.75 min (Method 5)

[0205] From intermediate [B] Similarly, the following intermediates were prepared: [serial number] [structure] [IUPAC] [name] tR [min] [M+H] AM [C2] 3-Iodo-7-methyl-6-nitro-1H-indazole 2.12 304 Method 5 [C3] methyl 3-iodo-7-methyl-1H-indazole-6-carboxylate 2.13 317 Method 5 [C4] 3-Iodo-7-methoxy-1H-indazole 0.53 275 Method 7 [C5] 7-Chloro-3-iodo-1H-indazole 0.919 279 Method 1

[0206] [C6 6-{[(] [Tributyldimethylsilyl] [)] [Oxygen group] []] [methyl] [}-3-] [iodine] [-7-] [methyl] [-1H-] [Indazole] [ ]

[0207] At 0°C, (3-iodo-7-methyl-1H-indazol-6-yl)-methanol [C1] (100 mg, 347 µmol) was added to a stirred solution of DMF (2 ml) containing imidazole (35 mg, 521 µmol) and TBDMS chloride (63 mg, 417 µmol). The mixture was stirred at room temperature for 16 h and then partitioned between EtOAc and ice water. The organic layer was dried over MgSO4, concentrated under vacuum, and purified by NP chromatography. Yield: 70 mg (50%). HPLC-MS: M+H = 403; tR = 2.85 min (Method 5)

[0208] [Preparation of intermediates] [D]

[0209] [ ] [D1 1-(6-] [Fluoropyridine] [-3-] [base] [)-3-] [iodine] [-7-] [methyl] [-1H-] [Indazole] [ ]

[0210] A mixture of 3-iodo-7-methyl-1H-indazole (17 g, 65.9 mmol), (6-fluoropyridin-3-yl)boronic acid (15.8 g, 112 mmol), copper(II) acetate (17.9 g, 98.8 mmol), and pyridine (10.4 g, 132 mmol) in DCM (340 ml) was stirred at room temperature for 16 h under air exposure. The solid was filtered off, the mixture was concentrated under vacuum, and the product was purified by RP chromatography. Yield: 14 g (60%). HPLC-MS: M+H = 354; tR = 1.50 min (Method 2).

[0211] Self-corresponding 3-iodo-indazole (intermediate) [C]), similarly prepare the following intermediates: serial number [structure] [IUPAC] [name] tR [min] [M+H] AM [D2] 1-(6-Fluoropyridin-3-yl)-3-iodo-7-methyl-6-nitro-1H-indazole 2.42 399 Method 5 [D3] methyl 1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole-6-carboxylate 2.24 421 Method 6 [D4] 7-Chloro-1-(6-Fluoropyridin-3-yl)-3-iodo-1H-indazole 1.074 374 Method 1 [D5] 7-Bromo-1-(6-Fluoropyridin-3-yl)-3-iodo-1H-indazole 1.06 418 / 420 Method 1 [D6] 7-Ethyl-1-(6-Fluoropyridin-3-yl)-3-iodo-1H-indazole 1.06 368 Method 1 [D7] 1-(6-Fluoropyridin-3-yl)-3-iodo-7-(trifluoromethyl)-1H-indazole 1.05 408 Method 1 [D8] 1-(6-Fluoropyridin-3-yl)-3-iodo-5,7-dimethyl-1H-indazole - - - [D9] 6-{[(tri-butyldimethylsilyl)oxy]methyl}-1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole 3.06 498 Method 5

[0212] [D10 [1-(6-)] [Fluoropyridine] [-3-] [base] [)-3-] [iodine] [-7-] [methyl] [-1H-] [Indazole] [-6-] [base] []] [Methanol] [ ]

[0213] To 6-{[(tri-butyldimethylsilyl)oxy]methyl}-1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole [D9] 50 mg (101 µmol) of THF (2 ml) was mixed with tetrabutylammonium fluoride (1 mol / L in THF, 202 µL, 202 µmol). The mixture was stirred at room temperature for 16 h. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, concentrated under vacuum, and the product was purified by RP chromatography. Yield: 26 mg (68%). HPLC-MS: M+H = 384; tR = 1.82 min (Method 6)

[0214] [Preparation of intermediates] [E]

[0215] [ ] [E1 1-(6-] [Fluoropyridine] [-3-] [base] [)-2',7-] [Dimethyl] [-1H,2'H-3,4'-] [Bitinazole] [ ]

[0216] 1-(6-fluoropyridin-3-yl)-3-iodo-7-methyl-1H-indazole was stirred at 110°C under an argon atmosphere. [D1] (1.0 g, 2.8 mmol), 2-methyl-4-(tetramethyl-1,3,2-dioxaborphane-2-yl)-2H-indazole (1.1 g, 4.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.21 g, 0.28 mmol), and Na2CO3 (0.9 g, 8.5 mmol) were mixed in dimethyl ether (20 ml) and water (5 ml) for 2 h. Water (100 ml) was added at room temperature, and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated under vacuum, and the product was purified by RP HPLC. Yield: 0.8 g (79%). HPLC-MS: M+H = 358; tR = 0.997 min (Method 1).

[0217] From intermediate [D], Using the corresponding boric acid derivative, the following intermediates were similarly prepared: serial number [structure] [IUPAC] [name] tR [min] [M+H] AM [E2] 1-(6-Fluoropyridin-3-yl)-2',7-Dimethyl-6-nitro-1H,2'H-3,4'-Biindazole 2.27 403 Method 5 [E3] methyl 1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-[3,4'-biinazole]-6-carboxylate 0.96 416 Method 1 [E4] 7-Chloro-1-(6-Fluoropyridin-3-yl)-2'-methyl-1H,2'H-3,4'-Biindazole 1.027 378 Method 1 [E5] 7-Bromo-1-(6-Fluoropyridin-3-yl)-2'-methyl-1H,2'H-3,4'-Biindazole 1.04 422 / 424 Method 1 [E6] 7-Ethyl-1-(6-Fluoropyridin-3-yl)-2'-methyl-1H,2'H-3,4'-Biindazole 1.48 372 Method 2 [E7] 1-(6-Fluoropyridin-3-yl)-2'-methyl-7-(trifluoromethyl)-1H,2'H-3,4'-biinazole 1.46 412 Method 2 [E8] 1-(6-Fluoropyridin-3-yl)-2',5,7-trimethyl-1H,2'H-3,4'-biinazole 1.02 372 Method 1 [E9] [1-(6-Fluoropyridin-3-yl)-2',7-Dimethyl-1H,2'H-[3,4'-Biindazole]-6-yl]methanol 0.83 388 Method 1

[0218] Synthesize additional intermediates as follows [E]:

[0219] [E10 1-(6-)] [Fluoropyridine] [-3-] [base] [)-2',7-] [Dimethyl] [-1H,2'H-[3,4'-] [Bitinazole] []-6-] [amine] [ ]

[0220] To contain 1-(6-fluoropyridin-3-yl)-7,2'-dimethyl-6-nitro-1H,2'H-[3,4']biinazole [E2] (0.5 g, 1.2 mmol) was added to methanol (5 ml) and THF (5 ml) with palladium / carbon (41 mg, 0.39 mmol). The mixture was hydrogenated at room temperature (50 psi) for 16 h. The reaction mixture was filtered through diatomaceous earth and washed with methanol (50 ml). The filtrate was concentrated under vacuum, and the crude product was used without further purification. Yield: 0.35 g (76%). HPLC-MS: M+H = 373; tR = 1.96 min (Method 5)

[0221] [E11 1-(6-)] [Fluoropyridine] [-3-] [base] [)-6-] [iodine] [-2',7-] [Dimethyl] [-1H,2'H-3,4'-] [Bitinazole] [ ]

[0222] At 0 °C, an agent containing 1-(6-fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-[3,4'-biindazole]-6-amine was subjected to treatment. [E10] (0.1 g, 270 µmol) of water (1 ml) was mixed with 1 ml of concentrated HCl solution, followed by 1 ml of water containing sodium nitrite (20 mg; 295 µmol). The reaction mixture was stirred at room temperature for 1 h. Sodium tetrafluoroborate (43 mg, 394 µmol) was added and stirring was continued for 10 min. The mixture was filtered, and the solid was washed with 10% NaBF4 solution and ether, and dried under vacuum. This solid was added together with 1 ml of DMSO to a mixture of DMSO (2 ml) containing iodine (68 mg, 270 µmol) and potassium iodide (70 mg, 414 µmol). The mixture was stirred at room temperature for 1 h, followed by stirring at 45 °C for 30 min, then FeSO4*7H2O (90 mg, 324 µmol) was added and stirred for another 30 min. The mixture was poured into an aqueous sodium thiosulfate solution and extracted with EtOAc. The combined organic layers were washed with an aqueous solution of sodium thiosulfate and water, dried over Na₂SO₄, and concentrated under vacuum. Yield of crude product: 50 mg (39%). HPLC-MS: M+H = 484; tR = 2.59 min (Method 5)

[0223] [E12 1-(6-)] [Fluoropyridine] [-3-] [base] [)-2',7-] [Dimethyl] [-6-(1-)] [methyl] [-1H-] [Pyrazole] [-4-] [base] [)-1H,2'H-3,4'-] [Bitinazole] [ ]

[0224] 1-(6-fluoropyridin-3-yl)-6-iodo-2',7-dimethyl-1H,2'H-3,4'-biinazole was stirred at 80°C under an argon atmosphere. A mixture of [E11] (100 mg, 200 µmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (52 mg, 240 µmol), ({[1,1'-biphenyl]-2-yl}amino)palladiumylium dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphonosulfonate (8 mg, 10 µmol), K3PO4 (87 mg, 400 µmol), dimethyl ether (1 ml), and water (0.5 ml) was prepared for 16 h. Water (30 ml) was added at room temperature, and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give 50 mg (56%) crude [E11]. [E12] was used in the next step without further purification.

[0225] By following the alternative order of the synthesis steps shown in process 1, it is possible to achieve this through intermediates. [S] Obtain additional intermediate items [E]:

[0226] [S1 7-] [Methoxy] [-2'-] [methyl] [-1H,2'H-3,4'-] [Bitinazole] [ ] 3-Iodo-7-methoxy-1H-indazole was stirred at 80°C under an argon atmosphere. A mixture of [C4] (500 mg, 1.62 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2H-indazole (512 mg, 1.94 mmol), ({[1,1'-biphenyl]-2-yl}amino)palladium-onium dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphonium methanesulfonate (126 mg, 162 µmol), K3PO4 (695 mg, 3.24 mmol), dimethyl ether (5 ml), and water (1 ml) was prepared for 16 h. The mixture was diluted with DCM and extracted with water at room temperature. The organic layer was dried over Na2SO4, concentrated under vacuum, and the intermediate 7-methoxy-2'-methyl-1H,2'H-3,4'-biindazole was purified by NP chromatography. Yield: 256 mg (57%). HPLC-MS: M+H = 279; tR = 0.55 min (Method 7)

[0227] Similar to [S1], synthesize the following intermediates [S2]: [serial number] [structure] [IUPAC] [name] tR [min] [M+H] AM [S2] 2',7-Dimethyl-1H,2'H-3,4'-Biindazole 1.16 263 Method 1

[0228] [E13 1-(6-)] [Fluoropyridine] [-3-] [base] [)-7-] [Methoxy] [-2'-] [methyl] [-1H,2'H-3,4'-] [Bitinazole] [ ] 7-Methoxy-2'-methyl-1H,2'H-3,4'-biinazole [S1] (256 mg, 920 µmol) was added to DCM (5 ml) and DMF (2.25 ml) containing (6-fluoropyridin-3-yl)boronic acid (259 mg, 1.84 mmol), copper(II) acetate (167 mg, 920 µmol), and pyridine (218 µl, 2.8 mmol). The mixture was stirred at room temperature for 60 h under exposure to air. The solid was filtered off, the filtrate was concentrated under vacuum, and the product was purified by NP chromatography. Yield: 185 mg (54%). HPLC-MS: M+H = 374; tR = 0.70 min (Method 7).

[0229] In addition, intermediate products [D] can be boronized into an intermediate. [T] is used for Suzuki coupling with, for example, heteroaryl bromides to obtain other intermediates. [E]:

[0230] [T1 3-(5,5-] [Dimethyl] [-1,3,2-] [Dioxaboronhexacyclohexane] [-2-] [base] [)-1-(6-] [Fluoropyridine] [-3-] [base] [)-7-] [methyl] [-1H-] [Indazole] [ ]

[0231] Under an argon atmosphere, 1-(6-fluoro-pyridin-3-yl)-3-iodo-7-methyl-1H-indazole was introduced into the atmosphere. [D1] (17 g, 48.1 mmol) of diammonium ether (170 ml) was mixed with dipentyldiol diborane (16.3 g, 72.2 mmol), potassium acetate (14.2 g, 144 mmol), and dichlorobis(triphenylphosphine)palladium(II) (3.38 g, 4.8 mmol) and stirred at 100 °C for 16 h. EtOAc and water were added at room temperature, and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated under vacuum and washed with petroleum ether. The crude product was used in the next step without further purification. Yield of crude product: 4 g (25%).

[0232] [E14 1-(6-)] [Fluoropyridine] [-3-] [base] [)-7-] [methyl] [-3-{] [Pyrazolo] [[1,5-a]] [Pyridine] [-4-] [base] [}-1H-] [Indazole] [ ]

[0233] 3-(5,5-dimethyl-1,3,2-dioxaboranecyclohex-2-yl)-1-(6-fluoropyridin-3-yl)-7-methyl-1H-indazole was stirred at 110°C under an argon atmosphere. A mixture of [T1] (50 mg, 147 µmol), 4-bromopyrazolo[1,5-a]pyridine (44 mg, 223 µmol), 1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (11 mg, 15 µmol), and Na2CO3 (47 mg, 443 µmol) in dimethyl ether (1 ml) and water (250 µl) was prepared for 1 h. Water (20 ml) was added at room temperature, and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4, concentrated under vacuum, and the product was purified by RP HPLC. Yield: 35 mg (69%). HPLC-MS: M+H = 344; tR = 0.993 min (Method 1).

[0234] From intermediate [T1], by coupling with the corresponding heteroaryl bromide, the following intermediates were similarly prepared. Using... [U2] and [U3] Preparation [E15] and [E18] serial number [structure] [IUPAC] [name] tR [min] [M+H] AM [E15] 1-(6-Fluoropyridin-3-yl)-7-methyl-3-(2-methylpyrazolo[1,5-a]pyridin-4-yl)-1H-indazole 1.062 358 Method 1 [E16] 5-(1-(6-fluoropyridin-3-yl)-7-methyl-1H-indazol-3-yl)-3-methylisoquinoline 1.001 369 Method 1 [E17] 5-[1-(6-Fluoropyridin-3-yl)-7-methyl-1H-indazol-3-yl]isoquinoline NA NA NA: [E18] 5-(1-(6-fluoropyridin-3-yl)-7-methyl-1H-indazol-3-yl)-N,N-dimethylisoquinoline-3-amine 1.138 398 Method 1 [E19] 3-(benzo[d][1,3]dioxol-4-yl)-1-(6-fluoropyridin-3-yl)-7-methyl-1H-indazole 0.772 348 Method 8

[0235] [U1 3-] [bromine] [-2-(] [C] [-1-] [Alkyne] [-1-] [base] [)] [Pyridine] [ ]

[0236] DMF (100 ml) was purged with propyne for 10 min at room temperature under an argon atmosphere. 3-Bromo-2-iodopyridine (10 g, 35.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (2.47 g, 3.52 mmol), and copper iodide(I) (669 mg, 3.52 mmol) were added, and the mixture was stirred for 4 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The product was purified by NP chromatography. Yield: 4.0 g (58%). HPLC-MS: M+H = 196; tR = 1.94 min (Method 5).

[0237] [U2 4-] [bromine] [-2-] [Methylpyrazolo] [[1,5-a]] [Pyridine] [ ]

[0238] At 0°C, 3-bromo-2-prop-1-ynylpyridine [U1] (6.0 g; 30.6 mmol) was added to a stirred mixture in DCM (55 ml) containing O-(tris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(m- ...

[0239] [ ] [U3) 5-] [bromine] [-N,N-] [Dimethylisoquinoline] [-3-] [amine] [ ]

[0240] A mixture of 5-bromo-3-chloroisoquinoline (100 mg, 412 µmol), dimethylamine hydrochloride (2.45 g, 30 mmol), NMP (3 ml), and DIPEA (5.1 ml, 30 mmol) was heated to 200 °C for 15 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under vacuum. The product was purified by RP chromatography. Yield: 69 mg (67%). HPLC-MS: M+H = 251 / 253; tR = 1.045 min (Method 1).

[0241] [ ] Example

[0242] Preparation Examples [#1] to [#45] and intermediates [F]: [ ]

[0243] [ ] [#1) 3-(5-(2',7-] [Dimethyl] [-1H,2'H-[3,4'-] [Bitinazole] []-1-] [base] [)] [Pyridine] [-2-] [base] [)-3-] [Nitrogen-based bicyclic] [[3.1.0]] [Hexane] [-6-] Methyl formate [ ]

[0244] 1-(6-Fluoropyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biinazole was stirred at 80°C. A mixture of [E1] (20 mg, 56 µmol), methyl 3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (10 mg, 56 µmol), and DIPEA (50 µl, 0.29 mmol) in DMSO (0.1 ml) for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under vacuum. The product was purified by RP chromatography. Yield: 13 mg (48%). HPLC-MS: M+H = 479; tR = 1.47 min (Method 2).

[0245] From intermediate [E], using the corresponding amine, the following examples are prepared similarly. In the case of amine salts (e.g., hydrochloride salts), an additional equivalent amount of base is used. serial number [structure] [IUPAC] [name] tR [min] [M+H] AM [#2] 8-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-1,8-diazaspiro[4.5]dec-2-one 1.32 492 Method 2 [#3] 2',7-Dimethyl-1-(6-{2-oxa-6-azaspiro[3.3]heptane-6-yl}pyridin-3-yl)-1H,2'H-3,4'-biinazole 1.31 437 Method 2 [#4] 2-(5-{2',7-dimethyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)-7λ6-thia-2-azaspiro[3.5]nonane-7,7-dione 1.30 513 Method 2 [#5] 4-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-1λ6-thioline-1,1-dione 1.37 473 Method 2 [#6] N-[1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)pyrrolidin-3-yl]-N-methylacetamide 1.32 480 Method 2 [#7] 4-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)piperazine-1-methylamine 1.23 467 Method 2 [#8] 7-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-hexahydro-1H-[1,3]azolo[3,4-a]pyridine-3-one 1.32 480 Method 2 [#9] 8-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-1,3-dimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione 1.41 535 Method 2 [#10] 7-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-2,7-diazaspiro[3,5]nonane-1-one 1.29 478 Method 2 [#11] 2',7-Dimethyl-1-(6-{2-oxa-5-azabicyclo[2.2.1]heptane-5-yl}pyridin-3-yl)-1H,2'H-3,4'-biinazole 1.37 437 Method 2 [#12] 1-(6-{5H,6H,7H,8H-imidazo[1,5-a]pyridin-7-yl}pyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biinazole 1.33 461 Method 2 [#13] 4-[(5-{2',7-dimethyl-1H,2'H-[3,4'-biinzol]-1-yl}pyridin-2-yl)amino]pyrrolidin-2-one 1.19 438 Method 2 [#14] 5-{2',7-dimethyl-1H,2'H-[3,4'-biinazole]-1-yl}-N-(2-methoxyethyl)pyridine-2-amine 1.35 413 Method 2 [#15] 1-[4-(5-{2',7-dimethyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)piperazine-1-yl]acetoone 1.31 466 Method 2 [#16] 1-[6-(4-methoxypiperidin-1-yl)pyridin-3-yl]-2',7-dimethyl-1H,2'H-3,4'-biinazole 1.52 453 Method 2 [#17] 2',7-Dimethyl-1-[6-(olylin-4-yl)pyridin-3-yl]-1H,2'H-3,4'-biinazole 1.42 425 Method 2 [#18] 1-[6-(4-methanesulfonylpiperidin-1-yl)pyridin-3-yl]-2',7-dimethyl-1H,2'H-3,4'-biinazole 1.34 501 Method 2 [#19] 2',7-Dimethyl-1-{6-[4-(2H-1,2,3,4-tetrazol-5-yl)piperidin-1-yl]pyridin-3-yl}-1H,2'H-3,4'-biinazole 1.11 491 Method 2 [#20] 2',7-Dimethyl-1-{6-[4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]pyridin-3-yl}-1H,2'H-3,4'-biinazole 1.49 503 Method 2 [#twenty one] 1-[1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)piperidin-4-yl]pyrrolidin-2-one 1.31 506 Method 2 [#twenty two] 1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)piperidine-4-sulfonamide 1.30 502 Method 2 [#twenty three] 1-[1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)piperidin-4-yl]acetoone 1.52 465 Method 2 [#twenty four] 5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}-N-[(pyrimidin-5-yl)methyl]pyridine-2-amine 1.26 447 Method 2 [#25] 1-[6-(4-methanesulfonylpiperidin-1-yl)pyridin-3-yl]-2',7-dimethyl-1H,2'H-[3,4'-biinazole]-6-carboxylic acid methyl ester 1.32 559 Method 2 [#75] {1-[6-(4-methanesulfonylpiperidin-1-yl)pyridin-3-yl]-2',7-dimethyl-1H,2'H-[3,4'-biindazole]-6-yl}methanol 1.09 531 Method 2 [#26] 3-(5-{7-chloro-2'-methyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1.08 485 Method 2 [#27] 1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)-4-methylpiperidin-4-carboxylic acid 1.10 481 Method 2 [#28] 3-{5-[2',7-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)-1H,2'H-[3,4'-biinzol]-1-yl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 0.99 545 Method 2 [#29] 3-(5-{7-methoxy-2'-methyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1.08 481 Method 2 [#30] 3-{5-[3-(2H-1,3-benzodioxacyclopenten-4-yl)-7-methyl-1H-indazol-1-yl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1.10 455 Method 2 [#31] 1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)piperidine-4-carboxylic acid ethyl ester 1.58 495 Method 2 [#32] 2-[4-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-2-sideoxypiperazine-1-yl]methyl acetate 0.59 510 Method 3 [#33] 1-[5-(7-methyl-3-{pyrazolo[1,5-a]pyridin-4-yl}-1H-indazol-1-yl)pyridin-2-yl]piperidin-4-carboxylic acid ethyl ester 1.136 481 Method 1 [#34] 1-{5-[7-methyl-3-(3-methylisoquinoline-5-yl)-1H-indazol-1-yl]pyridin-2-yl}piperidine-4-carboxylic acid ethyl ester 1.139 506 Method 1 [#35] 1-{5-[3-(isoquinolin-5-yl)-7-methyl-1H-indazol-1-yl]pyridin-2-yl}piperidine-4-carboxylic acid ethyl ester 1.109 492 Method 1 [#36] 1-(5-{3-[3-(dimethylamino)isoquinoline-5-yl]-7-methyl-1H-indazol-1-yl}pyridin-2-yl)piperidine-4-carboxylic acid ethyl ester 1.221 535 Method 1 [#37] 3-(5-{7-bromo-2'-methyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid methyl ester 1.089 543 / 545 Method 1 [#38] 3-(5-{7-ethyl-2'-methyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid methyl ester 1.06 493 Method 1 [#39] 1-(5-{7-ethyl-2'-methyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)piperidine-4-carboxylic acid ethyl ester 1.13 509 Method 1 [#40] 1-{5-[2'-methyl-7-(trifluoromethyl)-1H,2'H-[3,4'-biinazole]-1-yl]pyridin-2-yl}piperidine-4-carboxylic acid ethyl ester 1.63 549 Method 2 [#41] 3-[5-(7-methyl-3-{2-methylpyrazolo[1,5-a]pyridin-4-yl}-1H-indazol-1-yl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid methyl ester 1.54 479 Method 2 [#42] 3-(5-{2',5,7-trimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid methyl ester 1.54 493 Method 2 [#43] 1-(5-{2',5,7-trimethyl-1H,2'H-[3,4'-biinzol]-1-yl}pyridin-2-yl)piperidine-4-carboxylic acid methyl ester 1.66 509 Method 2 [#44] 3-{5-[6-(hydroxymethyl)-2',7-dimethyl-1H,2'H-[3,4'-biinazole]-1-yl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid methyl ester 1.22 509 Method 2

[0246] Similar to synthesis #1, prepare the following intermediate products. [F]: serial number [structure] [IUPAC] [name] tR [min] [M+H] AM [F1] 4-(5-(2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl)pyridin-2-yl)-1,4-diaza-1-carboxylic acid tributyl ester 1.66 538 Method 2 [F2] 4-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)teryl piperidine-1-carboxylic acid NA NA - [F3] N-[3-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]aminocarbamate tributyl ester 0.76 536 Method 3 [F4] 2-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-2,6-diazaspiro[3,4]octane-6-carboxylic acid tributyl ester 1.54 550 Method 2 [F5] 6-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tributyl ester 1.56 536 Method 2 [F6] N-[1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)piperidin-4-yl]aminocarbamate tributyl ester 0.89 538 Method 7

[0247] Preparation Examples [#45] to [#49]:

[0248] [#45 1-(6-(1,4-] [Dazon] [𠰢] [-1-] [base] [)] [Pyridine] [-3-] [base] [)-2',7-] [Dimethyl] [-1H,2'H-3,4'-] [Lindazole] [ ]

[0249] At room temperature, 4-(5-(2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl)pyridin-2-yl)-1,4-diaza-1-carboxylic acid tributyl ester [F1] (42 mg, 78 µmol) was stirred in 2 ml of DCM containing 400 µl of TFA for 2 h. Toluene (10 ml) was added, the mixture was concentrated under vacuum, and the product was purified by RP chromatography. Yield: 12 mg (35%). HPLC-MS: M+H = 438; tR = 1.36 min (Method 2)

[0250] From each [F2-F6], similarly prepare the following examples: Number [Structure] [IUPAC] [Name] tR [min] [M+H] AM [#46] 2',7-Dimethyl-1-(6-(piperazine-1-yl)pyridin-3-yl)-1H,2'H-3,4'-biinazole 1.30 424 Method 2 [#47] 3-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexyl-6-amine 1.29 436 Method 2 [#48] 1-(6-{2,6-diazaspiro[3.4]oct-2-yl}pyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biinazole 1.48 450 Method 2 [#49] 1-(6-{2,6-diazaspiro[3.3]heptane-2-yl}pyridin-3-yl)-2',7-dimethyl-1H,2'H-3,4'-biinazole 1.31 436 Method 2 [#50] 1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)piperidin-4-amine 1.31 438 Method 2

[0251] Preparation Examples [#51] to [#54]:

[0252] [#51 4-(5-(2',7-] [Dimethyl] [-1H,2'H-[3,4'-] [Bitinazole] []-1-] [base] [)] [Pyridine] [-2-] [base] [)] [Pipeline] [𠯤] [-1-] [formaldehyde] [ ]

[0253] A mixture of formic acid (2 µl; 53 µmol) and N-methylthioline (6 µl; 57 µmol) in DCM (200 µl) was cooled to 0 °C. Isobutyl chloroformate (7 µl; 54 µmol) was added, and the reaction mixture was stirred at 20 °C for 2 h. 2',7-Dimethyl-1-[6-(piperazine-1-yl)pyridin-3-yl]-1H,2'H-3,4'-biinazole was added. [#46] (10 mg, 24 µmol), and continue stirring at room temperature for 16 h.

[0254] The mixture was concentrated under vacuum, and the product was purified by RP chromatography. Yield: 7 mg (66%). HPLC-MS: M+H = 452; tR = 1.31 min (Method 2)

[0255] The following examples were similarly prepared from #45, #48, and #49 respectively: Number [Structure] [IUPAC] [Name] tR [min] [M+H] AM [#52] 4-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-1,4-diaza-1-carboxaldehyde 1.30 466 Method 2 [#53] 2-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-2,6-diazaspiro[3,4]octane-6-carboxaldehyde 1.26 478 Method 2 [#54] 6-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxaldehyde 1.23 464 Method 2

[0256] [#55 N-[3-(5-{2',7-] [Dimethyl] [-1H,2'H-[3,4'-] [Bitinazole] []-1-] [base] [}] [Pyridine] [-2-] [base] [)-3-] [Nitrogen-based bicyclic] [[3.1.0]] [Self] [-6-] [base] []] [Acetamide] [ ]

[0257] At room temperature, 3-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexyl-6-amine [#47] DIPEA (103 µl, 636 µmol) and acetyl chloride (10 µl, 139 µmol) were added to DCM (200 µl) and NMP (200 µl) at a concentration of 46 mg, 106 µmol. The mixture was stirred for 40 min, concentrated under vacuum, and the product was purified by RP HPLC. Yield: 18 mg (36%). HPLC-MS: M+H = 478; tR = 1.26 min (Method 2).

[0258] [#56 N-[1-(5-{2',7-] [Dimethyl] [-1H,2'H-[3,4'-] [Bitinazole] []-1-] [base] [}] [Pyridine] [-2-] [base] [)] [piperidine] [-4-] [base] []] [Methylsulfonylurea] [ ]

[0259] 1-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)piperidin-4-amine was stirred at room temperature. A mixture of [#50] (45 mg, 103 µmol), triethylamine (250 µl, 1.8 mmol), NMP (750 µl), and methanesulfonyl chloride (18 µl, 235 µmol) was prepared for 1 h. The mixture was concentrated under vacuum, and the product was purified by RP HPLC. Yield: 23 mg (43%). HPLC-MS: M+H = 516; tR = 1.36 min (Method 2).

[0260] Preparation Examples [#57] to [#71]:

[0261] [#57] [1-(5-(2',7-] [Dimethyl] [-1H,2'H-[3,4'-] [Bitinazole] []-1-] [base] [)] [Pyridine] [-2-] [base] [)] [piperidine] [-4-] [Formic acid]

[0262] Ethyl 1-(5-(2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl)pyridin-2-yl)piperidin-4-carboxylate [#31] THF (1 ml), MeOH (800 µl), water (200 µl), and LiOH (19 mg; 793 µmol) were added to a mixture of 40 mg (81 µmol). The mixture was stirred at room temperature for 2 h. After neutralization with 1 N HCl aqueous solution, the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated under vacuum, and the product was purified by RP HPLC. Yield: 35 mg (93%). HPLC-MS: M+H = 467; tR = 1.03 min (Method 2).

[0263] The following examples were prepared similarly, from #32, #1, #33 to #44 respectively: serial number [structure] [IUPAC] [name] tR [min] [M+H] AM [#58] 2-[4-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-2-sideoxypiperazine-1-yl]acetic acid 1.04 496 Method 2 [#59] 3-(5-{2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1.07 465 Method 2 [#60] 1-[5-(7-methyl-3-{pyrazolo[1,5-a]pyridin-4-yl}-1H-indazol-1-yl)pyridin-2-yl]piperidin-4-carboxylic acid 1.03 453 Method 2 [#61] 1-{5-[7-methyl-3-(3-methylisoquinoline-5-yl)-1H-indazol-1-yl]pyridin-2-yl}piperidin-4-carboxylic acid 1.09 478 Method 2 [#62] 1-{5-[3-(isoquinolin-5-yl)-7-methyl-1H-indazol-1-yl]pyridin-2-yl}piperidine-4-carboxylic acid 0.91 464 Method 2 [#63] 1-(5-{3-[3-(dimethylamino)isoquinoline-5-yl]-7-methyl-1H-indazol-1-yl}pyridin-2-yl)piperidin-4-carboxylic acid 1.19 507 Method 2 [#64] 3-(5-{7-bromo-2'-methyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1.09 529 Method 2 [#65] 3-(5-{7-ethyl-2'-methyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1.11 479 Method 2 [#66] 1-(5-{7-ethyl-2'-methyl-1H,2'H-[3,4'-biinazole]-1-yl}pyridin-2-yl)piperidin-4-carboxylic acid 1.14 481 Method 2 [#67] 1-{5-[2'-methyl-7-(trifluoromethyl)-1H,2'H-[3,4'-biinazole]-1-yl]pyridin-2-yl}piperidine-4-carboxylic acid 1.63 521 Method 2 [#68] 3-[5-(7-methyl-3-{2-methylpyrazolo[1,5-a]pyridin-4-yl}-1H-indazol-1-yl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1.05 465 Method 2 [#69] 3-(5-{2',5,7-trimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 2.09 479 Method 2 [#70] 1-(5-{2',5,7-trimethyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)piperidin-4-carboxylic acid 1.08 481 Method 2 [#71] 3-{5-[6-(hydroxymethyl)-2',7-dimethyl-1H,2'H-[3,4'-biindazole]-1-yl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 0.88 495 Method 2

[0264] Other examples can be obtained through other chemical transformations:

[0265] [#72 3-(5-{2',7-] [Dimethyl] [-1H,2'H-[3,4'-] [Bitinazole] []-1-] [base] [}] [Pyridine] [-2-] [base] [)-3-] [Nitrogen-based bicyclic] [[3.1.0]] [Hexane] [-6-] [Methionine] [ ]

[0266] To 3-(5-{2',7-dimethyl-1H,2'H-[3,4'-biinzol]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid [#1] HATU (25 mg, 66 µmol) was added to a mixture of DIPEA (22 µl, 129 µmol) and NMP (500 µl), and the mixture was stirred at room temperature for 10 min.

[0267] Ammonium chloride (10 mg, 187 µmol) was added, and stirring was continued for 16 h. The mixture was concentrated under vacuum, and the product was purified by RP chromatography. Yield: 11 mg (55%). HPLC-MS: M+H = 464; tR = 1.28 min (Method 2).

[0268] With intermediate goods [S2] begins, using constructing blocks [V] Synthesis Example [#73]:

[0269] [V1] [5-] [bromine] [-2-(4-)] [Methylsulfonylurea] [)] [Pyridine] [ ]

[0270] A mixture of 2,5-dibromopyridine (50 mg, 211 µmol), (4-methanesulfonylphenyl)boronic acid (42 mg, 211 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 21 µmol), dimethyl ether (1 ml), and an aqueous sodium carbonate solution (2 mol / L, 264 µL, 528 µmol) was stirred at 80 °C for 2 h under an argon atmosphere. Water (100 ml) was added at room temperature, and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated under vacuum, and the product was purified by RP HPLC. Yield: 43 mg (65%). HPLC-MS: M+H = 312 / 314; tR = 0.57 min (Method 8).

[0271] [V2] [[6-(4-] [Methylsulfonylurea] [)] [Pyridine] [-3-] [base] []] [Boric acid] [ ]

[0272] 5-Bromo-2-(4-methanesulfonylphenyl)pyridine was stirred at 80°C under an argon atmosphere. [V1] (450 mg, 1.44 mmol), double ( A mixture of diboron (732 mg, 2.88 mmol), 1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (121 mg, 144 µmol), and potassium acetate (707 mg, 7.2 mmol) in dimethyl ether (9 ml) was prepared for 1 h. The solid was filtered off, the filtrate was concentrated under vacuum, and the product was purified by RP chromatography. Yield: 245 mg (61%). HPLC-MS: M+H = 278; tR = 0.24 min (Method 2).

[0273] [#73] [1-[6-(4-)] [Methylsulfonylurea] [)] [Pyridine] [-3-] [base] []-2',7-] [Dimethyl] [-1H,2'H-3,4'-] [Bitinazole] [ ]

[0274] To 2',7-dimethyl-1H,2'H-3,4'-biinazole [S2] (26 mg, 99 µmol) was added to a mixture of ACN (1 ml) and DCM (1 ml) containing pyridine (24 µl, 300 µmol) and [6-(4-methanesulfonylphenyl)pyridin-3-yl]boronic acid. [V2] (87 mg, 303 µmol) and copper(II) acetate (27 mg, 149 µmol). The mixture was stirred at 80 °C for 3 days. The solid was filtered off, the filtrate was concentrated under vacuum, and the product was purified by RP chromatography. Yield: 4.3 mg (9%). HPLC-MS: M+H = 494; tR = 0.74 min (Method 8).

[0275] via [W1] Synthesis Example [#74]:

[0276] [W1 3-(5-{2'-] [methyl] [-7-[2-(] [Trimethylsilyl] [)] [Ethyne group] []-1H,2'H-[3,4'-] [Bitinazole] []-1-] [base] [}] [Pyridine] [-2-] [base] [)-3-] [Nitrogen-based bicyclic] [[3.1.0]] [Hexane] [-6-] Methyl formate [ ]

[0277] Under an argon atmosphere and at room temperature, dichlorobis(triphenylphosphine)palladium(II) (13 mg, 19 µmol) was added to methyl 3-(5-{7-bromo-2'-methyl-1H,2'H-[3,4'-biindazole]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate. [#37] A mixture of 100 mg (184 µmol), ethynyltrimethylsilane (181 mg, 1.8 mmol), copper iodide (I) (4 mg, 21 µmol), DIPEA (94 µl, 550 µmol), and NMP (2 ml) was stirred at 50 °C for 4 h. The mixture was concentrated under vacuum and the product was purified by RP HPLC. Yield: 24 mg (23%). HPLC-MS: M+H = 561; tR = 1.214 min (Method 1).

[0278] [#74 3-(5-{7-] [Ethyne group] [-2'-] [methyl] [-1H,2'H-[3,4'-] [Bitinazole] []-1-] [base] [}] [Pyridine] [-2-] [base] [)-3-] [Nitrogen-based bicyclic] [[3.1.0]] [Hexane] [-6-] [Formic acid] [ ]

[0279] Methyl 3-(5-{2'-methyl-7-[2-(trimethylsilyl)ethynyl]-1H,2'H-[3,4'-biinzol]-1-yl}pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate THF (1 ml), MeOH (800 µl), water (200 µl), and LiOH (10 mg, 412 µmol) were added to [W1] (24 mg; 43 µmol). The mixture was stirred at room temperature for 2 h, concentrated under vacuum, and the product was purified by RP HPLC. Yield: 2 mg (10%). HPLC-MS: M+H = 475; tR = 0.777 min (Method 1).

[0280] For Examples #1, 26, 28, 29, 30, 37, 38, 41, 42, 44, 47, 55, 59, 64, 65, 68, 69, 71, 72, and 74, the values ​​reported below indicate that the isomer contains either (1R,5S,6R)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid or the (1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-amine moiety. In the case of Example #6, data for the (R) isomer are shown.

[0281] Pharmacological activity

[0282] [ ] [and] [hSTING] [Of] [interaction] [,] [Such as using differential scanning fluorometry] [(differential scanning fluorimetry] [;] [DSF] [Measured] [ ] In DSF, the temperature at which a protein unfolds (also known as the melting temperature Tm) is measured by the fluorescence change of a dye bound to the hydrophobic portion of the protein. After small molecule binding, the Tm shift is related to the binding affinity of that small molecule. Human STING (hSTING, residues 155-341, MW: 21578.4 Da; protein stock solution: c = 1302 µM, in a stock solution of 20 mM Tris, 100 mM NaCl, and 2 mM TCEP pH 8.8) was used as the target protein. If necessary, 20 mM Tris and 150 mM NaCl pH 7.5 were added as the analysis buffer.

[0283] Final concentrations of components in the analysis: 100 µM test compound, 5 µM target protein, and "5×" SYPR orange (from SYPRO orange stock solution in DMSO (Invitrogen catalog number S6650-500 μl), concentration "5000×").

[0284] Analysis procedure: 1) Prepare a dilution buffer (10 mM in DMSO) for the compound stock solution in analytical buffer (20 mM Tris, 150 mM NaCl; pH 7.5). 2) Mix 5 µl of fluorescent dye stock solution (5000× DMSO containing SYPRO Orange) with 19 µl of target protein (1302 µM) and 976 µl of analysis buffer. 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 in step 1. The final volume is 10 µl. 4) For every 20 compounds, two negative controls were measured. 5) The preparation tray was used for repeated measurements and centrifuged at 1000g for 2 min. 6) For this measurement, the CFX384 real-time system (Bio-Rad) was used. The run consisted of the following: 140 cycles at 0.5°C / cycle (temperature gradient change of 15s / cycle, 25°C to 95°C).

[0285] Data Analysis: The melting curve was processed in the Bio-Rad CFX Manager. The peak type was set to "negative". The average of two replicates of the TM (melting temperature) measurement was calculated, and the standard deviation was also calculated.

[0286] The changes in TM (“thermal offset”) are shown in Table 1. Table 1: Interaction with hSTING as determined by DSF Example #1 #2 #3 #4 #6 #7 TM [K] twenty one twenty two 20 20 twenty two twenty two Example #8 #9 #10 #11 #12 #14 TM [K] twenty one twenty three 20 twenty one twenty one 18 Example #15 #17 #18 #19 #20 #twenty one TM [K] twenty one 16 twenty two twenty one 20 20 Example #twenty two #25 #27 #28 #29 #30 TM [K] twenty three 25 twenty two 27 twenty two 20 Example #45 #51 #52 #53 #54 #55 TM [K] 19 15 twenty one 20 twenty one 20 Example #56 #56 #58 #59 #61 #62 TM [K] 20 17 twenty three twenty one 16 20 Example #63 #65 #66 #67 #68 #71 TM [K] 19 twenty one 16 twenty three twenty four 29 Example #72 #74 #75 TM [K] 18 16 26

[0287] [In vitro cytokine induction measured by activation of reporter genes induced by interferon regulators] [ ] The cytokine-inducible activity of the compounds according to the present invention has been confirmed using the THP1 reporter cell line, thereby generating 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 by the stable integration of the interferon regulatory factor (IRF)-inducible secreted embryonic alkaline phosphatase (SEAP) gene reporter construct. SEAP activity can be detected and quantified using Invivogen's THP1-Blue™ ISG colorimetric assay and a suitable optical density (OD) reader. This technique can be used to characterize pharmacological modifications of the STING pathway.

[0288] Several single nucleotide polymorphisms (SNPs) have been identified in the human STING gene. To determine the activity of the compounds described above, THP1-Blue™ ISG reporter cell lines expressing different human STING variants were generated. For this purpose, endogenous human STING was first induced using a CRISPR / CAS9 system: THP1-Blue ISG cells were electroporated using an integrated CRISPR plasmid targeting the STING gene (purchased from Sigma, encoding gRNA with GFP as the successfully transduced reporter gene). GFP-positive cells were then sorted 24 h after transfection and expansion. Cells were then dispersed in semi-solid methylcellulose medium to isolate single-cell lineages. Quanti-Blue was then used... [, TM The report analyzed cGAMP-responsive screening strains. Subsequently, non-responsive strains were analyzed for STING loss using Western ink spot assay and STING locus sequencing.

[0289] For overexpression of human STING variants, THP1-Blue was transduced with individual retroviral plasmids (MSCV-ires-GFP-Blasti) encoding alleles of hSTING (WT (H232R), HAQ, R232H, AQ, and R293Q). [™] ISG hSTING KO strain. Transduced cells were sorted for different GFP fluorescence levels, and STING allele expression was analyzed using Western blotting. Populations expressing ectopic STING proteins (WT, HAQ, R232H, AQ, and R293Q) at levels comparable to the endogenous STING levels of the unmodified parental THP1-Blue ISG cell line were selected for compound characterization.

[0290] THP1-Blue exhibits stable performance in different human STING isoforms and IRF-induced SEAP reported constructs. SEAP activity was measured in [™ ]ISG cells. Cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, 50 µg / ml penicillin-streptomycin, 100 µg / ml zeocin, and 100 µg / ml normocin in an incubator at 37°C, 95% humidity, and 5% CO2.

[0291] For the preparation used in the analysis, cells were distributed into the analytical dish at a density of 10,000 cells / 15 µL / well. The compound was prepared by an 8-point serial dilution in 50% DMSO aqueous solution and a final dilution in the culture medium to ensure a final DMSO concentration of 0.5% for the analysis. 5 µL of the diluted compound was added to the dish, and the mixture was then incubated at 37°C for 24 hours.

[0292] On the day of analysis, 75 µl of Quanti-Blue was applied to each well. [, TM The reagent was added to all wells of the dish, and the dish was incubated at 37°C for another 30 minutes. The OD was measured at 620 nm using an EnVision reader (PerkinElmer).

[0293] The EC50 value and Hill slope are derived from an 8-point four-parameter nonlinear curve fitting using Megalab software (Boehringer Ingelheim) at 620 nM.

[0294] Data on EC50 values ​​can be found in Tables 2a-2e.

[0295] Data on EC50 values ​​for the STING HAQ variant are available in Table 2a. The data shown below are derived from the parent THP1-Blue. [™] ISG cell lines (which endogenously express HAQ) or THP1-Blue derived from genetically engineered cells that, as described above, have had the first STING knocked out and have been re-introduced with an HAQ-specific STING isoform. [™ ]ISG cell line. Table 2a: Example #1 #2 #3 #4 #5 #6 EC50 [µM] 0.7 0.6 3.0 1.1 1.4 3.1 Example #7 #8 #9 #10 #11 #12 EC50 [µM] 0.8 1.2 1.0 2.1 3.2 1.9 Example #14 #15 #17 #18 #19 #20 EC50 [µM] 6.9 1.0 6.8 0.7 6.5 2.2 Example #twenty one #twenty two #twenty four #25 #26 #27 EC50 [µM] 4.7 0.7 2.7 0.2 0.9 5.2 Example #28 #29 #30 #31 #45 #51 EC50 [µM] 0.08 0.8 6.1 5.4 1.9 0.3 Example #52 #53 #54 #55 #56 #57 EC50 [µM] 1.9 1.7 2.1 2.3 3.0 0.7 Example #58 #59 #60 #61 #62 #63 EC50 [µM] 6.8 0.2 6.6 3.0 3.1 4.9 Example #64 #65 #66 #67 #68 #69 EC50 [µM] 0.7 0.2 1.6 2.2 1.6 1.4 Example #70 #71 #72 #73 #74 #75 EC50 [µM] 16.1 0.6 1.8 4.4 4.3 0.1

[0296] Data on EC50 values ​​for the STING H232R variant can be found in Table 2b: Example #1 #2 #5 #7 #9 #10 EC50 [µM] 0.2 0.09 0.5 0.2 0.1 0.4 Example #12 #15 #17 #18 #twenty two #twenty four EC50 [µM] 0.4 0.2 2.1 0.2 0.1 2.0 Example #26 #29 #51 #53 #54 #55 EC50 [µM] 0.2 0.2 0.05 0.7 0.3 0.8 Example #56 #57 #59 #61 #64 #65 EC50 [µM] 0.4 0.2 0.1 2.9 0.2 0.1 Example #66 #67 #68 #69 #72 #75 EC50 [µM] 0.3 0.7 0.7 0.3 0.6 0.03

[0297] Data on EC50 values ​​for the STING R232H variant can be found in Table 2c: Example #1 #2 #5 #7 #9 #10 EC50 [µM] 0.2 0.05 1.0 0.2 0.2 0.5 Example #12 #15 #17 #18 #twenty two #twenty four EC50 [µM] 0.6 0.2 2.0 0.2 0.2 2.3 Example #26 #29 #51 #53 #55 #56 EC50 [µM] 0.2 0.6 0.05 0.7 0.7 0.8 Example #57 #59 #61 #64 #65 #66 EC50 [µM] 0.2 0.1 2.9 0.6 0.1 0.2 Example #67 #68 #69 #72 #75 EC50 [µM] 0.8 0.7 0.3 0.3 0.05

[0298] Data on EC50 values ​​for the STING R293Q variant can be found in Table 2d: Example #1 #2 #5 #7 #9 #10 EC50 [µM] 0.4 0.4 1.2 0.7 0.6 2.1 Example #12 #15 #17 #18 #twenty two #twenty four EC50 [µM] 2.1 0.7 6.1 0.7 0.7 2.2 Example #26 #29 #51 #53 #55 #56 EC50 [µM] 0.6 0.6 0.3 1.6 1.7 2.2 Example #57 #59 #61 #64 #65 #66 EC50 [µM] 0.6 0.2 2.2 0.5 0.1 0.7 Example #67 #68 #69 #72 #75 EC50 [µM] 2.1 0.8 0.7 0.7 0.1

[0299] Data on EC50 values ​​for the STING AQ variant can be found in Table 2e: Example #1 #2 #7 #9 #10 #12 EC50 [µM] 0.2 0.2 0.6 0.7 2.2 1.5 Example #15 #17 #18 #twenty two #26 #29 EC50 [µM] 0.7 5.7 0.6 0.7 0.7 0.7 Example #51 #53 #54 #55 #56 #57 EC50 [µM] 0.2 1.9 5.3 1.2 2.1 0.3 Example #59 #61 #65 #66 #67 #68 EC50 [µM] 0.1 3.0 0.1 0.8 2.3 0.8 Example #69 #72 #75 EC50 [µM] 0.7 0.8 0.1

[0300] [Cell permeability measurement] [ ] The Caco-2 cell line was obtained from the Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany) and cultured in Durbecco's modified Eagle medium (DMEM) containing (final concentration) 10% fetal calf serum (FCS), 1% non-essential amino acid (NEAA), 2 mM glutamic acid, 100 U / mL penicillin, and 100 µg / mL streptomycin. Caco-2 cells were seeded at a density of 160,000 cells / cm² onto 24-well Transwell inserts (Corning, #3379) for two-dimensional permeability analysis and cultured for 3 weeks, with the medium changed every other day.

[0301] For two-way permeability analysis, a 10 mM DMSO stock solution was diluted in a transport buffer containing 0.25% bovine serum albumin (final concentration: 128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4, 0.41 mM NaH2PO4, 15 mM 2-[4-(2-hydroxyethyl)piperazine-1-yl]ethanesulfonic acid (HEPES), 20 mM glucose, pH 7.4) to a final concentration of 10 µM of the test compound; this was then added to either the top-side or bottom-side compartment. Cells were incubated with the compound for up to 2 h. Samples were collected from the relative compartments at different time points.

[0302] The concentration of compounds in the compartment was quantified using a RapidFire-based high-throughput HPLC / MS / MS system (BioCius) customized to a fully automated and flexible platform (referred to as RIAS). In this modified apparatus, the sample was aspirated into a 10 µL sample loop for 250 ms using a vacuum pump and flushed onto a C4 column (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). An internal standard solution was added to the sample prior to bioanalysis, and the sample was diluted with acetonitrile (ACN) for protein precipitation. Measurements were performed in multiple reaction monitoring (MRM) mode. Quantification was performed using an external calibration. A solid-phase extraction step retained the analyte for 3000 ms while removing interfering matrices (e.g., buffer components). Using a simple step gradient, the analyte was back-dissolved from the column for 3,000 ms using an organic mobile phase (99.9% acetonitrile / methanol [1:1, v:v], 0.09% formic acid, and 0.01% TFA), and then washed into the mass spectrometer at a flow rate of 1.25 mL / min. The column was then reequilibrated with an aqueous mobile phase for 500 ms (flow rate 1.5 mL / min). RapidFire software and customized control software were obtained from BioCius. QuickQuan 2.3, Xcalibur 2.0.7, and XDK 2.1.0.25 were used to operate 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 RIAS Master software system is internally programmed using LabVIEW (version 8.6.1; National Instruments, Austin, TX). Data analysis is performed in AssayExplorer 3.2 (Symyx, Sunnyvale, CA), and correlation plots are observed in Spotfire version 2.2.0 (TIBCO, Palo Alto, CA).

[0303] The apparent permeability and efflux rate are calculated as follows in the direction from top to bottom (Papp, AB) and from bottom to top (Papp, BA): Papp,AB = QAB / (C0 ∙ s ∙ t) Papp,BA = QBA / (C0 ∙ s ∙ t) Excretion rate = Papp,BA / Papp,AB Where Q represents the amount of compound recovered in the acceptor compartment after incubation time t, C0 represents the initial concentration of the compound given to the donor compartment, and s represents the surface area of ​​the Transwell insert. As a quality control, each analytical dish included a reference P-gp acceptor (apafant) and a low-permeability compound (BI internal reference, Papp ~ 3 ∙ 10⁻⁷ cm / s, no effluent). Additionally, the transepithelial resistance (TEER) value of each dish was measured prior to permeability analysis, and the total recovery of each compound in the donor and acceptor compartments was determined. The results are shown in Tables 3a and 3b. Table 3a: Cell permeability measurement - Papp, AB: Example #2 #6 #7 #9 #10 #11 Caco A→B [10⁻⁶ cm / s] 20 39 28 twenty three 26 27 Example #12 #14 #15 #17 #18 #twenty one Caco A→B [10⁻⁶ cm / s] 11 39 26 26 36 twenty three Example #twenty two #27 #30 #53 #54 #55 Caco A→B [10⁻⁶ cm / s] 10 32 14 50 38 twenty one Example #56 #57 #59 #62 #63 #60 Caco A→B [10⁻⁶ cm / s] twenty one 15 11 11 19 19 Example #61 #67 #68 #69 #70 #75 Caco A→B [10⁻⁶ cm / s] 10 16 16 14 18 9

[0304] Cell permeability measurement - Efflux rate: Example #1 #2 #3 #6 #7 #9 External discharge rate 0.4 0.6 0.6 0.4 0.6 0.3 Example #11 #12 #14 #15 #17 #18 External discharge rate 0.3 0.4 0.3 0.5 0.3 0.3 Example #20 #twenty one #twenty two #27 #30 #31 External discharge rate 0.8 0.3 1.6 0.5 0.9 0.6 Example #52 #53 #54 #55 #56 #57 External discharge rate 0.4 0.2 0.8 1.0 0.6 1.2 Example #59 #60 #61 #62 #63 #67 External discharge rate 2.5 0.9 1.1 1.2 0.6 1.2 Example #68 #69 #70 #73 #75 External discharge rate 1.0 1 1.2 0.5 4.8

[0305] [Solubility Measurement] [ ] Water solubility was determined using a 10 mM stock solution of the compound in DMSO, diluted to a final concentration of 250 µM with McIlvaine aqueous buffer (pH 6.8) or with acetonitrile / water (1:1) as a reference. Samples were shaken for 24 h at room temperature in a 96-well plate (Whatman Uniplate® 96-well, 750 µL, polypropylene, round bottom). The plate was then centrifuged at 3,000 rpm for 2 min. 250 µL of each sample was transferred to a Millipore MultiScreenHTS filter plate with a polycarbonate membrane and 0.45 μm pore size. The filtrate was collected by centrifugation at 3,000 rpm for 2 min. Solubility was determined by UPLC / UV (ultra-high performance liquid chromatography / ultraviolet) using a short gradient (5 to 95% B, with a total cycle time of 1.7 min) on a Waters ACQUITY UPLC® SQD system equipped with a Waters ACQUITY UPLC® BEH 2.1x50 mm C18 column and a particle size of 1.7 µm. Compound signals were measured using a photodiode array UV detector operating at 254 nm. Solubility was determined by comparing peak areas relative to reference standards using Waters Empower software, with single-point calibration. The results are shown in Table 4. Table 4: Solubility of HTS at pH 6.8 Example #19 #26 #28 #29 #30 Solubility [µg / ml] 51 60 87 63 42 Example #57 #58 #59 #62 #63 Solubility [µg / ml] 80 84 66 49 75 Example #67 #69 #70 #71 Solubility [µg / ml] 82 70 74 67

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or hydrate thereof for the manufacture of a medicament for treating cancer, wherein the medicament is administered in a sterile, injectable formulation, wherein A is N or C, and B is a group selected from the group consisting of: a 5-7 member monocyclic heterocyclic group containing 1 or 2 N atoms; a 6 member bicyclic heterocyclic group containing 1 N atom; a 7-11 member bicyclic heterocyclic group containing 2 N atoms; a 7 member bicyclic heterocyclic group containing 1 N atom and 1 O atom; a 6 member monocyclic heterocyclic group containing 1 N atom and 1 heteroatom selected from the group consisting of O and S; a 9 member bicyclic heterocyclic group containing 3 heteroatoms, wherein 2 heteroatoms are N and the other is O; or a 9 member bicyclic heterocyclic group containing 1 N atom and 1 S atom. The group consists of a 10-membered bicyclic heterocyclic group containing 3 nitrogen atoms, of which 2 nitrogen atoms are substituted with C1-6 alkyl groups, phenyl groups, and a 9-membered bicyclic heteroaryl group containing 3 nitrogen atoms; D is a group selected from the following groups: a 9-membered bicyclic heteroaryl group containing 2 nitrogen atoms, a 10-membered bicyclic heteroaryl group containing 1 nitrogen atom, and benzo[a]dioxane; R1 is a group selected from the following groups: -H, -C1-6 alkyl, -CF3, -C2-6 ynyl, -O-C1-6 alkyl, and halogens; R2 is a group selected from the following groups: -H, -C1-6 alkyl, -C1-6 alkyl-OH, -C(O)OH, -C(O)O-C1-6 alkyl, and -pyrazolyl-C1-6 alkyl; R3 is -H or -C1-6 alkyl. R4 is selected from the group consisting of: -H, -C1-3 alkyl, -NH2, -NHC1-3 alkyl, and N(C1-3 alkyl)2; R5 is absent or selected from the group consisting of: -H, -C1-6 alkyl, -S(O2)-C1-6 alkyl, -NH-S(O2)-C1-6 alkyl, =O, -C(O)-C1-6 alkyl, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)O-C1-6 alkyl, -NR5.1R5.2, -C1-6 alkyl-C(O)OH, -S(O2)-NH2, -pyrrolidin-2-one-1-yl, -tetrazolyl, and R5.3 substituted 5-membered heteroaryl groups having one or two heteroatoms selected from the groups consisting of N and O; R5.1 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl, and -C1-6 enylalkyl-O-C1-6 alkyl; R5.2 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl, -C1-6 enylalkyl-O-C1-6 alkyl, and -C1-6 enylalkyl-R5.3; R5.The 3 group is selected from the following groups: -H, -C1-6 alkyl, and 6-membered heteroaryl groups having one or two heteroatoms selected from the groups of N and O; R6 is absent or selected from the following groups: -H, -C1-6 alkyl, =O, and -C(O)OH.

2. As claimed in claim 1, wherein R1 is selected from the group consisting of: -C1-6 alkyl, -CF3, -O-C1-6 alkyl and halogen; and R4 is -H or -C1-3 alkyl.

3. For any of the uses of claims 1 to 2, wherein the D series is selected from the group consisting of: ; the R1 series is selected from the group consisting of: -C1-6 alkyl, -CF3, -O-C1-6 alkyl, -Br and -Cl; R2 is -H; R3 is -H.

4. As requested in any of items 1 to 2, where D is selected from the group consisting of: .

5. As requested in any of items 1 to 2, where D is selected from the group consisting of: .

6. For any of the uses of claims 1 to 2, wherein R5 is selected from the group consisting of: -H, -C1-6 alkyl, -S(O2)-C1-6 alkyl, =O, -C(O)H, -C(O)NH2, -C(O)OH, -C(O)O-C1-6 alkyl, -NR5.1R5.2, and a 5-membered heteroaryl group substituted with R5.3 having one or two heteroatoms selected from the group consisting of N and O; R5.1 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl and -C1-6 alkyl-O-C1-6 alkyl; R5.2 is selected from the group consisting of: -H, -C1-6 alkyl, -C(O)-C1-6 alkyl, -C1-6 alkyl-O-C1-6 alkyl and -C1-6 alkyl-R5.3; R5.3 is -H or -C1-6 alkyl.

7. As requested in any of items 1 to 2, wherein B is selected from the group consisting of: .

8. For the purpose of any of the requests 1 to 2, wherein B is selected from the group consisting of: .

9. As requested in any of items 1 to 2, wherein B is selected from the group consisting of: .

10. The use of any of claims 1 to 2, wherein the compound is selected from the group consisting of: ; or a pharmaceutically acceptable salt, isomer or hydrate thereof.