Novel 1, 2-diaminobenzimidazole derivatives

Abstract

Provided herein is a novel compound having an inhibitory effect on the activation of the STING pathway. The provided compound is a 1, 2-diaminobenzimidazole derivative represented by the compound formula (I) or a pharmaceutically acceptable salt thereof: # imgabs0 # wherein A1, A2, R1, R2, R3, R4 and R5 are defined in the specification.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority from Japanese Application No. 2021-120698, filed on Jul. 21, 2021, which is hereby incorporated by reference herein in its entirety. Technical Field

[0003] The present invention relates to a drug, and in particular to a novel 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof having an inhibitory effect on STING pathway activation. Background Art

[0004] STING (stimulator of interferon genes) plays an important role in biological defense mechanisms as a molecule that induces innate immune responses to various RNA and DNA virus infections. STING binds to ligands such as cyclic GMP-AMP (cGAMP), a cyclic dinucleotide produced by cyclic GMP-AMP synthase (cGAS), to activate TANK binding kinase 1 (TBK1) and induce type I IFN production via transcription factor IRF3 (Non-patent Document 1).

[0005] Recently, it has been reported that STING is also activated by tumor-derived self-DNA and mitochondrial DNA, etc., and induces a proinflammatory response, and is attracting increasing attention as a drug target for cancer and autoimmune diseases (Non-Patent Document 2).

[0006] Human STING is encoded by the gene Tmem173, and an autoinflammatory disease called STING-associated vasculopathy (SAVI) of infancy has been reported as a genetic disease caused by Tmem173 mutations. SAVI patients have mutations that constitutively activate STING, and excessive inflammation causes abnormal antibody production and tissue damage to the skin and lungs (Non-patent Document 3). It has also been reported that even patients with autoinflammatory genetic diseases such as familial pernio-like lupus and familial lupus-like syndrome have activating mutations in STING (Non-patent Document 4).

[0007] In addition, it is known that accumulation of self-DNA in cells due to insufficient DNA degradation leads to constitutive activation of the STING pathway, thereby causing autoimmune diseases. Aicardi-Goutieres syndrome (AGS) is considered to be one of such diseases, and it has been reported that the lack of STING in model mice of this disease suppresses symptoms (Non-patent Document 5).

[0008] In systemic lupus erythematosus (SLE), nucleic acid antibodies, which are autoantibodies, and in particular, excessive production of anti-DNA antibodies are considered to be the cause of excessive immune responses. However, in recent years, it has been revealed that activation of the STING pathway induces the production of interferon, which is important in the pathological state of SLE. That is, cGAMP contained in the patient's peripheral blood is correlated with the pathological score, and it has also been reported that interferon induction of cGAMP in patient serum is inhibited in STING-deficient cells (non-patent literature 6 and 7).

[0009] Since STING is involved in various immune responses in the body, it has also been reported that STING is involved in many diseases. For example, in a study of sepsis in which systemic inflammation caused by pathogen infection leads to organ damage, it has been reported that the lack of STING in sepsis model mice alleviates symptoms (Non-patent Documents 8 and 9). In addition, studies using model mice have also revealed that STING is involved in inflammatory diseases such as non-alcoholic steatohepatitis (NASH), liver fibrosis, acute pancreatitis, and polyarthritis (Non-patent Documents 10, 11, 12, and 13). In addition, it has been revealed that in patients with Parkinson's disease (a neurodegenerative disease), inflammatory cytokines increase due to the destruction of mitochondrial homeostasis, and it has been reported that the lack of STING in model mice improves these abnormalities (Non-patent Documents 14 and 15).

[0010] Therefore, inhibitors of STING pathway activation may be useful in treating various inflammatory and immune diseases in which the STING pathway is involved. Summary of the invention

[0011] One object of the present invention is to provide a drug, and in particular a novel 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, which has an inhibitory effect on STING pathway activation (eg, by inhibiting STING or cGAS).

[0012] The present invention is achieved by the following (1) to (6):

[0013] (1) A 1,2-diaminobenzimidazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0014]

[0015] Among them A 1 Represents nitrogen atom or CR 6 , A 2 Represents nitrogen atom or CR 7 , R 1 represents a halogen atom or an alkyl group, R 2 , R 3 , R 4 , R 6and R 7 Each of R independently represents a hydrogen atom or a fluorine atom, and R 5 represents a hydrogen atom or an optionally substituted alkyl group.

[0016] (2) A 1,2-diaminobenzimidazole derivative of formula (I) according to (1) or a pharmaceutically acceptable salt thereof, wherein A 1 and A 2 CR 6 and CR 7 express.

[0017] (3) A 1,2-diaminobenzimidazole derivative of formula (I) according to (1) or a pharmaceutically acceptable salt thereof, wherein A 1 and A 2 The nitrogen atom and CR 7 express.

[0018] (4) A 1,2-diaminobenzimidazole derivative of formula (I) according to (1) or a pharmaceutically acceptable salt thereof, wherein A 1 and A 2 CR 6 and nitrogen atoms.

[0019] (5) A 1,2-diaminobenzimidazole derivative of formula (I) according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R 1 Represented by halogen atoms.

[0020] (6) The compounds of Examples 1 to 29 described later or pharmaceutically acceptable salts thereof.

[0021] As a result of various studies to solve the above problems, the inventors found that the novel 1,2-diaminobenzimidazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof exhibits excellent inhibitory effects on the activation of the STING pathway, and completed the present invention. The compounds provided by the present invention can be used as preventive or therapeutic drugs (pharmaceutical compositions) for diseases known to be associated with STING-mediated cellular responses, such as inflammatory diseases, autoimmune diseases, or cancer. When combined with therapeutic agents for other inflammatory diseases, autoimmune diseases, and cancer, the compound is expected to have an effect on the immune response, and therefore can also be used as a therapeutic drug (pharmaceutical composition). As a STING inhibitor, it can be further used as a reagent for experiments and studies. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The representative compounds of the Examples were shown to have inhibitory effects on IL-6 production in a mouse model stimulated by a STING agonist (Test Example 3).

[0023] Figure 2 The representative compounds of the Examples were shown to have inhibitory effects on IFN-β production in a mouse model stimulated by a STING agonist (Test Example 3). DETAILED DESCRIPTION

[0024] 1. General Description of Certain Embodiments of the Invention:

[0025] Hereinafter, the present invention will be described in detail. The novel 1,2-diaminobenzimidazole derivative of the present invention is represented by the following formula (I):

[0026]

[0027] And it is a compound having a basic structure, in which the bicyclic nitrogen-containing heteroaryl ring is substituted with the 2-amino group of the 1,2-diaminobenzimidazole ring.

[0028] More specifically, in formula (I), A 1 Represents nitrogen atom or CR 6 ; A 2 Represents nitrogen atom or CR 7 ; R 1 represents a halogen atom or an alkyl group; R 2 , R 3 , R 4 , R 6 and R 7 each independently represents a hydrogen atom or a fluorine atom; and R 5 represents a hydrogen atom or an optionally substituted alkyl group.

[0029] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (I), A 1 and A 2 Each by CR 6 and CR 7 express.

[0030] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (I), A 1 represented by nitrogen atoms; and A 2 By CR 7 express.

[0031] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (I), A 1 By CR 6 indicates; and A 2 Represented by nitrogen atoms.

[0032] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (I), A 1 and A 2 Each is CR 6 and CR 7 indicates; and R 1 Represented by halogen atoms.

[0033] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes compounds described in formula (I) and subsequently in Examples 1-29 and pharmaceutically acceptable salts thereof.

[0034] In another aspect, the novel 1,2-diaminobenzimidazole derivative of the present invention is represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof:

[0035]

[0036] Among them A 1 Represents nitrogen atom or CR 6 ; A 2 Represents nitrogen atom or CR 7 ; R 1 represents a halogen atom or an alkyl group; and R 2 , R 3 , R 6 and R 7 Each of independently represents a hydrogen atom or a fluorine atom.

[0037] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 and A 2 Each by CR 6 and CR 7 express.

[0038] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 represented by nitrogen atoms; and A 2 By CR 7 express.

[0039] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 By CR 6 indicates; and A2 Represented by nitrogen atoms.

[0040] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 and A 2 Each by CR 6 and CR 7 indicates; and R 1 Represented by halogen atoms.

[0041] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 and A 2 Each by CR 6 and CR 7 indicates; and R 6 and R 7 Each is represented by hydrogen.

[0042] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 and A 2 Each by CR 6 and CR 7 Represents; R 6 and R 7 Each is represented by hydrogen; and R 1 Represented by halogen atoms.

[0043] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 and A 2 Each by CR 6 and CR 7 Represents; R 2 , R 6 and R 7 Each is represented by hydrogen; and R 1 Represented by halogen atoms.

[0044] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 and A 2 Each by CR 6 and CR 7 Represents; R3 , R 6 and R 7 Each is represented by hydrogen; and R 1 Represented by halogen atoms.

[0045] One aspect of the 1,2-diaminobenzimidazole derivatives of the present invention includes a 1,2-diaminobenzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein in formula (Ia), A 1 and A 2 Each by CR 6 and CR 7 Represents; R 2 , R 3 , R 6 and R 7 Each is represented by hydrogen; and R 1 Represented by halogen atoms.

[0046] The terms used in this specification are described below.

[0047] 2. Compounds and Definitions

[0048] Reference to a compound of formula (I) (eg, a 1,2-diaminobenzimidazole derivative) includes reference to any subgenus and / or species described herein, including reference to a compound of formula (Ia).

[0049] Unless otherwise specified, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0050] Unless otherwise specified, alkyl means a linear or branched saturated hydrocarbon group (C 1-4 alkyl), and specific examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.

[0051] Substituents used for the terms are then described.

[0052] Examples of the substituent of the substitutable alkyl group include halogen atoms, and one or more of the same or different halogen atoms may be substituted at any position.

[0053] Examples of other substituents of the substitutable alkyl group include hydroxy, methoxy, dimethylamino, cyclopropyl, dimethylcarbamoyl, cyano, morpholino and the like, and one or more identical or different substituents including a halogen atom may be substituted at any position of the alkyl group.

[0054] The compounds of formula (I) of the present invention may have isomers, for example, depending on the type of substituents. Although only one form of chemical structure may be described in this article among those isomers, the present invention not only contains all isomers (geometric isomers, optical isomers, tautomers, etc.) that can be produced due to the structure, but also contains individual isomers or their mixtures.

[0055] In the present invention, "hydrogen atom" includes 1 H and 2 H(D), and includes not only any one or more of the compounds represented by formula (I) 1 H is converted to 2 The deuterium conversion product of H(D) includes compounds represented by formula (I). For example, in the case of a compound having a methyl group -CH3, a compound having a -CD3 group, a -CD2H group or a -CDH2 group is also included.

[0056] Pharmaceutically acceptable salts of the compound of formula (I) of the present invention include inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid, etc.; and organic acid salts with formic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. In addition to alkali metal salts with sodium, potassium, etc.; alkaline earth metal salts with magnesium, calcium, etc.; organic amine salts with lower alkylamines, lower alcoholamines, etc.; and basic amino acid salts with lysine, arginine, ornithine, etc., ammonium salts are also included in the present invention.

[0057] The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes both an intermolecular salt and a solvate such as a hydrate thereof.

[0058] Formula (I) compound of the present invention or its pharmaceutically acceptable salt can be produced, for example, by the following method.Please note that in the production method shown below, if the defined group changes under the method conditions of implementation or is not suitable for the implementation method, then the commonly used method in organic synthesis chemistry such as protection and deprotection of functional groups (TWGreene, "Protective Groups in Organic Synthesis 3rd Edition", John Wiley & Sons, Inc., 1999) is implemented, so that it is easier to produce them.If necessary, the order of reaction steps such as substituent introduction can be changed.

[0059] The synthesis of 1,2-diaminobenzimidazole derivatives disclosed in the present invention is described in detail below using a general reaction scheme. The compounds of the present invention of formula (I) disclosed herein can be produced by the methods described in the following schemes 1-7. As listed in the examples, the compounds can be produced by general synthetic methods and starting materials of commercial products or by starting materials synthesized from commercial compounds by known methods or methods analogous thereto or by varying methods well known to those skilled in the art.

[0060] Each variable moiety shown in the following schemes applies to all functional groups detailed in the compounds provided in the present invention.Tautomers and solvates (eg, hydrates) of the compounds of formula (I) are also included in the present invention.

[0061] The meanings of abbreviations and symbols used in the following description are as follows.

[0062] EDCI-HC1: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0063] DMF: N,N-dimethylformamide

[0064] THF: Tetrahydrofuran

[0065] NMP: N-methylpyrrolidone

[0066] DIPEA: N,N-diisopropylethylamine

[0067] Boc2O: di-tert-butyl dicarbonate

[0068] Boc: tert-Butyloxycarbonyl

[0069] 3. Methods for producing compounds of the present invention

[0070] The compound represented by formula (I) of the present invention can be produced by Scheme 1, for example.

[0071] Solution 1.

[0072]

[0073] Among them A 1 , A 2 , R 1 , R 2 , R 3 , R 4 and R 5 Each has the same meaning as defined above, and PG represents a protecting group.

[0074] The compound of formula (I) of the present invention can be produced by deprotecting compound (II), which is obtained by cyclizing thiourea obtained by coupling reaction of isothiocyanate (III) and aniline (IV). That is, the corresponding thiourea can be obtained by reacting isothiocyanate (III) with 0.5-1.5 molar equivalents of aniline (IV) in a solvent.

[0075] Any solvent inert to the reaction can be used, such as chloroform, THF, DMF and NMP, and DMF can be preferably used. The reaction can be carried out for several minutes to several days in the range of 0°C-100°C, and preferably for 10 minutes to 24 hours at room temperature to 80°C. The reaction can obtain a mixture of thiourea reacted with the NH2 of aniline and thiourea reacted with the NH of hydrazine, and these mixtures can be used for the next reaction without purification, but can be purified. Then, under the condensation conditions commonly used in organic synthetic chemistry, for example, using a condensing agent such as 1-3 molar equivalents of EDCI-HCl, the resulting thiourea is subjected to cyclization in a solvent to obtain compound (II).

[0076] Any solvent inert to the reaction can be used, and there is no particular limitation. For example, DMF, THF and NMP can be used, and DMF can be preferably used. The reaction can be carried out in the range of 0°C-100°C for several minutes to several days, and preferably at room temperature to 80°C for 0.5 hour to 24 hours. The compound of formula (I) of the present invention can be obtained by removing the protective group PG of the obtained composition (II) by deprotection under conditions commonly used in organic chemistry.

[0077] Isothiocyanate (III) used as a starting material in Scheme 1 can be produced from compound (V), for example, as shown in Scheme 2.

[0078] Solution 2.

[0079]

[0080] Among them A 1 , A 2 , R 1 and R 2 Each has the same meaning as defined above.

[0081] Isothiocyanate (III) can be produced by converting the amino group of compound (V) into an isothiocyanate group. That is, isothiocyanate (III) can be obtained by reacting compound (V) with 1-3 molar equivalents of an isothiocyanate reagent such as thiophosgene in a solvent in the presence of a base such as 1-3 molar equivalents of DIPEA. Any solvent inert to the reaction can be used, such as chloroform or THF, and THF can be preferably used. The reaction can be carried out in the range of -20°C to 50°C for several minutes to several days, and preferably at 0°C to room temperature for 10 minutes to 24 hours.

[0082] Compound (V) used as a starting material in Scheme 2 can be produced from compound (VI), for example, as shown in Scheme 3.

[0083] Solution 3.

[0084]

[0085] Among them A 1 , A 2 , R 1 and R 2 Each has the same meaning as defined above.

[0086] Compound (V) can be produced by reducing the nitro group of compound (VI). That is, compound (V) can be obtained by reducing the nitro group of compound (VI) in a solvent by a reduction method commonly used in organic synthetic chemistry, such as catalytic reduction using palladium-carbon, and metal reduction using tin, zinc, iron, etc.

[0087] In the reduction reaction, for the purpose of improving the yield, the amino group of compound (V) is carried out by a compound protected by a Boc group. That is, a compound wherein the amino group of compound (V) is protected by a Boc group by reacting compound (VI) with Boc2O in a solvent in the presence of a metal such as ammonium chloride and zinc. The Boc group can be removed by deprotection under conditions commonly used in organic chemistry, such as using hydrochloric acid.

[0088] Compound (VI) used as a starting material in Scheme 3 can be obtained commercially or produced from compound (VII), for example as shown in Scheme 4.

[0089] Solution 4.

[0090]

[0091] Among them A 1 , A 2 , R 1 and R 2 Each has the same meaning as defined above.

[0092] Compound (VI) can be produced by nitration of compound (VII). That is, compound (VI) can be obtained by reacting compound (VII) with nitration reaction conditions commonly used in organic chemistry, such as fuming nitric acid or a mixed acid of concentrated sulfuric acid and nitric acid. The nitrating agent is not particularly limited, and for example, 1-5 molar equivalents of potassium nitrate can be used in the presence of concentrated sulfuric acid. The reaction can be carried out in the range of -20°C to 50°C for several minutes to several days, and preferably at 0°C to room temperature for 10 minutes to 1 hour.

[0093] Compound (VI) can also be produced by known methods (see, for example, Bioorg.Med.Chem.2007,15,3248-3265 or Tetrahedron Letters 2012,53,4841-4842) or methods similar thereto. That is, compound (VI) is obtained by reacting compound (VII) with 1-5 molar equivalents of a nitrating agent and 1-5 molar equivalents of an acyl chloride in a solvent. Any solvent inert to the reaction can be used, and there is no particular limitation. For example, acetonitrile can be used as a reaction solvent, 1-5 molar equivalents of silver nitrate can be used as a nitrating agent, and 1-5 molar equivalents of benzoyl chloride can be used as an acyl chloride. The reaction can be carried out for several minutes to several days in the range of -10 ° C to 50 ° C, and preferably for 1 hour to 24 hours at 0 ° C to room temperature.

[0094] Compound (VII) used as a starting material in Scheme 4 is commercially available or produced by a known method or a method analogous thereto.

[0095] Compound (V) used as a starting material in Scheme 2 can also be produced by Scheme 5, for example.

[0096] Solution 5.

[0097]

[0098] Among them A 1 , A 2 , R 1 and R 2 Each has the same meaning as defined above, and PG represents a protecting group.

[0099] Compound (V) can be produced by deprotecting compound (VIII), which is obtained by Fischer indole synthesis using compound (IX) and compound (X). That is, compound (IX) is reacted with 0.5-1.5 molar equivalents of compound (X) in a solvent under the conditions of Fischer indole synthesis to obtain compound (VIII). Any solvent inert to the reaction can be used, such as chloroform, 1,2-dichloroethane, THF and toluene, and a mixed solvent of 1,2-dichloroethane / toluene can be preferably used.

[0100] The reaction can be carried out within the range of 0°C to 100°C for several minutes to several days, and preferably at room temperature to 100°C for 30 minutes to 24 hours. Compound (V) can be obtained by treating the protecting group of the obtained compound (VIII) under deprotection conditions commonly used in synthetic organic chemistry.

[0101] Compound (IX) and compound (X) used as starting materials in Scheme 5 are commercially available or produced by a known method or a method analogous thereto.

[0102] Aniline (IV) used as a starting material in Scheme 1 can be produced from compound (XI), for example, as shown in Scheme 6.

[0103] Solution 6.

[0104]

[0105] Where R 3 , R 4 and R 5 Each has the same meaning as defined above, and PG represents a protecting group.

[0106] Aniline (IV) can be produced by reducing the nitro group of compound (XI). That is, aniline (IV) can be obtained by reducing the nitro group of compound (XI) in a solvent by a reduction method commonly used in organic synthetic chemistry, such as catalytic reduction using palladium-carbon, metal reduction using tin, zinc, iron, etc.

[0107] Compound (XI) used as a starting material in Scheme 6 can be produced, for example, by the method shown in Scheme 7.

[0108] Solution 7.

[0109]

[0110] Where R 3 , R 4 and R 5 Each has the meaning as defined above, X represents a halogen atom, and PG represents a protecting group.

[0111] Compound (XI) can be produced by a nucleophilic substitution reaction using compound (XII) and compound (XIII). That is, compound (XI) can be obtained by reacting compound (XII) with 0.5-2 molar equivalents of compound (XIII) in a solvent. Any solvent inert to the reaction can be used, and there is no particular limitation, but NMP can be preferably used. The reaction can be carried out in the range of 0°C-180°C for several minutes to several days, and preferably at room temperature to 120°C for 30 minutes to 24 hours.

[0112] In addition, compound (XII) and compound (XIII) used as starting materials in Scheme 7 can be commercially obtained or produced by a known method or a method analogous thereto.

[0113] The above methods can be appropriately combined, and methods commonly used in organic synthetic chemistry (e.g., nucleophilic substitution reaction of an amino group, alkylation reaction of an amino group, Mitsunobu reaction, reaction of converting a carboxyl group into a substituted or unsubstituted carboxamide group, cross-coupling reaction such as Suzuki-Miyaura reaction, and carbon-carbon double bond reduction by hydrogenation reaction) can be performed to obtain a compound of formula (I) of the present invention having a desired functional group at a desired position.

[0114] 4. Uses of the compounds of the present invention

[0115] The compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be prepared in the form of a conventional pharmaceutical preparation (pharmaceutical composition) suitable for oral, parenteral or topical administration.

[0116] Preparations for oral administration include solid preparations, such as tablets, granules, powders and capsules, and liquid preparations, such as syrups. Preparations can be prepared by conventional methods. Solid dosage forms can be prepared by using conventional pharmaceutical carriers, such as lactose, starch (such as corn starch), crystalline cellulose (such as microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium), talcum and magnesium stearate. Capsules can be prepared by encapsulating granules or powders prepared in this way. Syrups can be prepared by dissolving or suspending the compound of formula (I) of the present invention or its pharmaceutically acceptable salt in an aqueous solution containing sucrose, carboxymethyl cellulose, etc.

[0117] Preparations for parenteral administration include injections, such as intravenous infusions. Infusion preparations can also be prepared by conventional methods, and isotonic agents (e.g., mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose and mannose), stabilizers (e.g., sodium sulfite and albumin), preservatives (e.g., benzyl alcohol and methyl paraben) can be appropriately incorporated.

[0118] The dosage of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt may vary depending on the severity of the disease, the age and weight of the patient, the dosage form, etc. However, in adults, it can be normally administered in the range of 1 mg to 1,000 mg per day, orally or parenterally, in a single dose or in two or three divided doses.

[0119] In addition, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be used as a STING inhibitor and as a reagent for experiments or researches.

[0120] The compounds of formula (I) of the present invention which are radiolabeled can also be used as molecular probes for PET.

[0121] In some embodiments, the present invention provides a method of inhibiting STING pathway activation in a patient or a biological sample (e.g., by inhibiting STING or cGAS), comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or contacting the biological sample with a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0122] In some embodiments, the present invention provides a method for treating a disease associated with a STING-mediated cellular response in a patient (e.g., by inhibiting STING or cGAS), comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0123] In some embodiments, the disease associated with a STING-mediated cellular response is selected from an inflammatory disease, an autoimmune disease, a cardiovascular disease, a pulmonary disease, a metabolic disease, a neurodegenerative disease, a viral infection, an ophthalmic disease, and cancer.

[0124] In some embodiments, the present invention provides a method of treating an inflammatory disease in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0125] In some embodiments, the present invention provides a method of treating an autoimmune disease in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0126] In some embodiments, the present invention provides a method of treating cardiovascular disease in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0127] In some embodiments, the present invention provides a method of treating a pulmonary disease in a patient, comprising administering to said patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0128] In some embodiments, the present invention provides a method of treating a metabolic disease in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0129] In some embodiments, the present invention provides a method of treating a neurodegenerative disease in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0130] In some embodiments, the present invention provides a method of treating a viral infection in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0131] In some embodiments, the present invention provides a method of treating an ophthalmic disease in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0132] In some embodiments, the present invention provides a method of treating cancer in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0133] In some embodiments, the disease associated with STING-mediated cellular responses (e.g., STING or cGAS-associated diseases) is STING-associated vasculopathy of infancy (SAVI), familial lupus-like syndrome, Aicardi-Guterres syndrome (AGS), systemic lupus erythematosus (SLE) (e.g., lupus nephritis, familial lupus pernio), sepsis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), pancreatitis (e.g., acute), dermatomyositis, macular degeneration (e.g., dry age-related macular degeneration), psoriasis, Sjögren's syndrome, Niemann-Pick disease (e.g., type C ), interferonopathy (e.g., rare type 1 interferonopathy), infarction (e.g., myocardial infarction), heart failure, cardiomyopathy, intestinal inflammation (e.g., inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), irritable bowel syndrome (IBS)), cellular senescence, aging, COPA syndrome, acute kidney injury (AKI), fibrosis (e.g., kidney, lung, liver), acne, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), kidney disease (e.g., chronic kidney disease), obesity, arthritis (e.g., polyarthritis, rheumatoid arthritis), viral hepatitis, and COVID-19 (e.g., see non-patent document 16).

[0134] In some embodiments, the present invention provides a method of treating STING-associated vasculopathy of infancy (SAVI) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0135] In some embodiments, the present invention provides a method of treating familial lupus-like syndrome in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0136] In some embodiments, the present invention provides a method of treating Acardi-Guterres syndrome (AGS) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0137] In some embodiments, the present invention provides a method for treating systemic lupus erythematosus (SLE) (e.g., lupus nephritis, familial lupus pernio) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0138] In some embodiments, the present invention provides a method of treating sepsis in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0139] In some embodiments, the present invention provides a method of treating alcoholic liver disease (ALD) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0140] In some embodiments, the present invention provides a method of treating non-alcoholic fatty liver disease (NAFLD) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0141] In some embodiments, the present invention provides a method of treating non-alcoholic steatohepatitis (NASH) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0142] In some embodiments, the present invention provides a method of treating pancreatitis (eg, acute) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0143] In some embodiments, the present invention provides a method of treating dermatomyositis in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0144] In some embodiments, the present invention provides a method of treating macular degeneration (eg, dry age-related macular degeneration) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0145] In some embodiments, the present invention provides a method of treating psoriasis in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0146] In some embodiments, the present invention provides a method of treating Sjögren's syndrome in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0147] In some embodiments, the present invention provides a method of treating Niemann-Pick disease (eg, type C) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0148] In some embodiments, the present invention provides a method for treating interferonopathy (eg, rare type 1 interferonopathy) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0149] In some embodiments, the present invention provides a method of treating infarction (eg, myocardial infarction) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0150] In some embodiments, the present invention provides a method of treating heart failure in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0151] In some embodiments, the present invention provides a method of treating cardiomyopathy in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0152] In some embodiments, the present invention provides a method for treating intestinal inflammation (e.g., inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), irritable bowel syndrome (IBS)) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0153] In some embodiments, the present invention provides a method of treating cellular senescence in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0154] In some embodiments, the present invention provides a method of treating aging in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0155] In some embodiments, the present invention provides a method of treating COPA syndrome in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0156] In some embodiments, the present invention provides a method of treating acute kidney injury (AKI) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0157] In some embodiments, the present invention provides a method of treating fibrosis (eg, kidney, lung, liver) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0158] In some embodiments, the present invention provides a method of treating acne in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0159] In some embodiments, the present invention provides a method of treating amyotrophic lateral sclerosis (ALS) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0160] In some embodiments, the present invention provides a method of treating Parkinson's disease (PD) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0161] In some embodiments, the present invention provides a method of treating Alzheimer's disease (AD) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0162] In some embodiments, the present invention provides a method of treating kidney disease (eg, chronic kidney disease) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0163] In some embodiments, the present invention provides a method of treating obesity in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0164] In some embodiments, the present invention provides a method of treating arthritis (eg, polyarthritis, rheumatoid arthritis) in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0165] In some embodiments, the present invention provides a method of treating viral hepatitis in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0166] In some embodiments, the present invention provides a method of treating COVID-19 in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0167] In some embodiments, the present invention provides a method of inhibiting STING from promoting cytokine production in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof inhibits the production of IFN-β and IL-6 in a patient.

[0168] In some embodiments, the present invention provides a method of inhibiting wild-type STING activation in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0169] In some embodiments, the present invention provides a method of inhibiting mutant STING activation in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0170] In some embodiments, the present invention provides a method of inhibiting elevated cGAS levels in a patient, comprising administering to the patient a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0171] In some embodiments, methods of inhibiting wild-type or mutant STING activation, or elevated cGAS levels in a patient can be determined by measuring clinical biomarkers in the patient.

[0172] Combination therapy

[0173] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with one or more additional therapeutic agents and / or regimens. For example, the methods provided herein for treating diseases associated with STING-mediated cellular responses (e.g., STING or cGAS-related diseases) may further include administering one or more (e.g., two, three, four, five, six or more) additional therapeutic agents.

[0174] Additional therapeutic agents of the invention may include, but are not limited to, small molecules or recombinant biologics (e.g., acetaminophen), nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac, and celecoxib), colchicine Corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), probenecid, allopurinol, febuxostat Sulfasalazine Antimalarial drugs (such as hydroxychloroquine and chloroquine ), methotrexate Gold salts (such as thioglucosinolate gold gold thiomalate Auranofin )、D-Penicillamine( or ), Azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and “anti-TNF” agents (such as etanercept Infliximab Golimumab Becelimumab Adalimumab ), "anti-IL-1" agents (such as anakinra Rinascept ), Canakinumab Anti-Jak inhibitors (such as tofacitinib), antibodies (such as rituximab ), "anti-T cell" agents (such as abatacept ), "anti-IL-6" agents (such as tocilizumab ), diclofenac, cortisone, hyaluronic acid ( or ), monoclonal antibodies (such as tanizumab), anticoagulants (such as heparin ( or ) and warfarin ), antidiarrheal drugs (such as diphenoxylate and loperamide ), bile acid binders (such as cholestyramine), alosetron Lubiprostone Laxatives (such as milk of magnesia, polyethylene glycol and ), anticholinergics or anticonvulsants (such as dicyclomine ), β2 agonists (such as salbutamol ( HFA, HFA), levosalbutamol Metaproterenol Pirbuterol acetate Terbutaline sulfate Salmeterol xinafoate and formoterol ), anticholinergics (such as ipratropium bromide and tiotropium ), inhaled corticosteroids (such as beclomethasone dipropionate ( and ), triamcinolone acetonide acetate Mometasone Budesonide Flunisolide ), Sodium cromoglycate Methylxanthines (such as theophylline ) and aminophylline), IgE antibodies (such as omalizumab ), nucleoside reverse transcriptase inhibitors (such as zidovudine Abacavir Abacavir / Lamivudine Abacavir / Lamivudine / Zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine ), non-nucleoside reverse transcriptase inhibitors (such as delavirdine Efavirenz Nevirapine and etravirine ), nucleoside reverse transcriptase inhibitors (such as tenofovir ), protease inhibitors (such as amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir ( or ) and tipranavir ), entry inhibitors (such as enfuvirtide and Maravero ), integrase inhibitors (such as raltegravir Doxorubicin Vincristine Bortezomib and / or dexamethasone Lenalidomide combination) or any combination thereof.

[0175] In some embodiments, the present invention provides a method of treating an inflammatory or autoimmune disease, comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from but not limited to the following: gamma globulin, immunomodulatory and immunosuppressive compounds (e.g., cyclosporine, ), TNF antagonists (e.g. etanercept, infliximab), IL-1 inhibitors (e.g., anakinra, canakinumab, rimarcept), phosphodiesterase inhibitors (e.g., apremilast), JAK / STAT inhibitors (e.g., tofacitinib, baricitinib, GLPG0634), IRAK4 inhibitors, leflunomide, cyclophosphamide, rituximab, belimumab, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone), cyclophosphamide, azathioprine, sulfasalazine, acetaminophen, and / or nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine).

[0176] In some embodiments, the present invention provides a method of treating STING-associated vasculopathy of infancy (SAVI), comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from the group consisting of JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0177] In some embodiments, the present invention provides a method of treating Icardi-Guterres syndrome (AGS), comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents and / or regimens selected from the group consisting of physical therapy, treatment of respiratory complications, anticonvulsant therapy for epileptic seizures, tube feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., ), tenofovir (e.g. ), emtricitabine / tenofovir (e.g. ), zidovudine, lamivudine, and abacavir) and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0178] In some embodiments, the present invention provides a method of treating familial lupus-like syndrome or systemic lupus erythematosus (SLE) (e.g., lupus nephritis, familial pernio lupus), comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from the group consisting of steroids, topical immunomodulators (e.g., tacrolimus ointment, and pimecrolimus cream ), Thalidomide Nonsteroidal anti-inflammatory drugs (NSAIDs; for example, ibuprofen and naproxen), antimalarials (for example, hydroxychloroquine (Plaquenil)), corticosteroids (for example, prednisone), and immunomodulators (for example, evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine Cyclophosphamide and cyclosporine (Neoral, ) and mycophenolate mofetil, baricitinib, iguratimod, filgotinib, GS-9876, rapamycin, and PF-06650833), and biologics (e.g., belimumab

[0179] anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin Dapirolizumab, edratide, IFN-α-kinoid, OMS721, RC18, RSLY-132, theralizumab, XmAb5871, and ustekinumab For example, non-limiting treatments for systemic lupus erythematosus include nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarials (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone), and immunomodulators (e.g., iberdomide, voclosporin, azathioprine, Cyclophosphamide and cyclosporine (Neoral, ) and mycophenolate mofetil, baricitinib, filgotinib, and PF-06650833), and biologics (e.g., belimumab anifrolumab, prezalumab, MEDI0700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin Dapirolizumab, edretinoin, IFN-α-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab ).

[0180] In some embodiments, the present invention provides a method of treating arthritis (e.g., rheumatoid arthritis) comprising administering to a patient in need thereof a compound of formula (I) and one or more additional therapeutic agents selected from, but not limited to, nonsteroidal anti-inflammatory drugs (NSAIDS) (such as, but not limited to, aspirin, ibuprofen, naproxen, etodolac, and celecoxib), corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), sulfasalazine Antimalarial drugs (such as hydroxychloroquine and chloroquine ), methotrexate Gold salts (such as gold thioglucosinolate gold thiomalate Auranofin )、D-Penicillamine( or ), Azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and “anti-TNF” agents (such as etanercept Infliximab Golimumab Becelimumab Adalimumab ), "anti-IL-1" agents (such as anakinra Rinascept ), antibodies (such as rituximab ), "anti-T cell" agents (such as abatacept ) and / or “anti-IL-6” agents (such as tocilizumab ).

[0181] In some embodiments, the present invention provides a method of treating inflammatory bowel disease (IBD) comprising administering to a patient in need thereof a compound of formula (I) and one or more additional therapeutic agents selected from, but not limited to, 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI 655066, BMS-936557, becelimumab Cobitomod, corticosteroids (e.g., prednisone, methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, edrema, fecal microbiota transplantation, figlotinib, fmgolimod, SB-683699 (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK 1399686, HMPL-004 (Andrographis paniculata) paniculata extract), I1V1U-838, infliximab, interleukin-2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, migizone (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peftinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, teloizumab (MK 3222), TJ301, Tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.

[0182] In some embodiments, the present invention provides a method of treating Crohn's disease (CD), comprising administering to a patient in need thereof a compound of formula (I) and one or more additional therapeutic agents selected from, but not limited to, adalimumab, autologous CD34-selected peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, becelimumab Corticosteroids (e.g., prednisone), edrelizumab, E6011, fecal microbiota transplantation, figlotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.

[0183] In some embodiments, the present invention provides a method of treating ulcerative colitis (UC), comprising administering to a patient in need thereof a compound of formula (I) and one or more additional therapeutic agents selected from but not limited to the following: AbGn-168H, ABT-494, ABX464, Apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitomod, pecilizumab CP-690,550, corticosteroids (e.g., multimaxbudesonide, methylprednisolone), cyclosporine, E6007, etrasimod, edrema, fecal microbiota transplantation, figlotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI6555066), SHP647, sulfasalazine, TD-1473, TJ301, tirazumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

[0184] In some embodiments, the present invention provides a method of treating irritable bowel syndrome (IBS) comprising administering to a patient in need thereof a compound of formula (I) and one or more additional therapeutic agents selected from, but not limited to, alosetron, bile acid sequestrants (e.g., cholestyramine, celestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, farnesoid X receptor agonists (e.g., obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin, guanylate cyclase C agonists (e.g., linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium bromide, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tanpanor.

[0185] In some embodiments, the present invention provides a method of treating psoriasis comprising administering to a patient in need thereof a compound of formula (I) and one or more additional therapeutic agents selected from, but not limited to, topical corticosteroids, topical crisaborole / AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafmib, topical IDP-118, topical M518101, topical calcipotriene, and betamethasone dipropionate (e.g., MC2-01 cream and ), local P-3073, local LEO 90100 Betamethasone dipropionate topical Halobetasol Propionate Vitamin D analogs (eg, calcipotriene Calcitriol ), anthralin (e.g. and ), topical retinoids (e.g. tazarotene (e.g. and )), calcineurin inhibitors (e.g. tacrolimus and pimecrolimus ), salicylic acid, coal tar, moisturizers, light therapy (such as exposure to sunlight, UVB light therapy, narrow-band UVB light therapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (such as etretinate ), methotrexate Apo805Kl, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (pilinosen), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), aprmilast, tofacitinib, cyclosporine Biological (eg, etanercept Etanercept-szzs Infliximab Adalimumab Adalimumab-adbm Ustekinumab Golimumab

[0186] Apremilast Secukinumab Becelimumab, secukinumab, tirazumab-asmn, infliximab-dyyb, abatacept, icamizumab ABP 710, BCD-057, BI695501, bimegilide (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB 11022, mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brocitumab), namerucizumab (MT203, tildrakizumab (MK-3222), and icamizumab ), thioguanine, and hydroxyurea (e.g. and ).

[0187] Exemplary Immuno-Oncology Agents

[0188] In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to a substance that effectively enhances, stimulates, and / or upregulates an immune response in a subject. In some embodiments, the immuno-oncology agent is administered together with the compounds of the invention to have a synergistic effect in treating diseases associated with STING-mediated cellular responses (e.g., STING or cGAS-related diseases).

[0189] The immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biological or small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human.

[0190] In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in amplification of antigen-specific T cell responses.

[0191] Some stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF molecule family that binds to homologous TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANK L, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR 3. EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0192] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation for stimulating an immune response.

[0193] In some embodiments, the combination of the compound of the present invention and an immuno-oncology agent can stimulate T cell response. In some embodiments, an immuno-oncology agent is: (i) an antagonist (e.g., immune checkpoint inhibitor) of a protein that inhibits T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0194] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirelumab.

[0195] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies, including imituzumab (RG7155).

[0196] In some embodiments, the immuno-oncology agent is selected from agonists that bind positive co-stimulatory receptors, blockers that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by in vitro anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or exhaustion), and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0197] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonist CTLA-4 antibody. In some embodiments, the antagonist CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0198] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonist PD-1 antibody. In some embodiments, the antagonist PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) or MEDI-0680 (AMP-514). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.

[0199] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonist PD-L1 antibody. In some embodiments, the PD-L1 antibody is atezolizumab (RG7446), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and avelumab (MSB0010718C).

[0200] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonist LAG-3 antibody. In some embodiments, the LAG3 antibody is relalizumab (BMS-986016), or IMP-731 or eftilagimod alpha (IMP-321).

[0201] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is Urecitabine or Utolumab (PF-05082566).

[0202] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO2006 / 105021, WO2009 / 009116) or MK-4166 (WO2011 / 028683).

[0203] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from icaridostat (INCB024360, Incyte); indomod (NLG-8189, NewLink Genetics Corporation); capacitinib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO2009 / 073620, WO2009 / 115665, WO2011 / 056652, WO2012 / 142237).

[0204] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0205] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonist OX40 antibody. In some embodiments, the OX40L antagonist is pegalizumab (RG-7888).

[0206] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0207] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0208] In some embodiments, the immuno-oncology agent is enoximab (MGA271) (directed against B7H3).

[0209] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0210] In some embodiments, the immuno-oncology agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in a growing number of tumor histologies, including some tumor types that are not conventionally considered to be sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab ( Bristol-Myers Squibb (also known as ONO-4538, MDX1106, and BMS-936558), shows potential in improving overall survival in patients with RCC who have experienced disease progression during or after prior anti-angiogenic therapy.

[0211] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include: pomalidomide ( Celgene; Lenalidomide ( Celgene; Ingenol Methyl Butyrate ( LEO Pharma).

[0212] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from: Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (( BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodular lesions in melanoma. In some embodiments, the immuno-oncology agent is selected from oncolytic virus therapies such as pexastimogenedevacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-) deficient vaccinia virus engineered to express GM-CSF for use in hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( Oncolytics Biotech, a reovirus variant that is unable to replicate in non-RAS-activated cells in many cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic cancer (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors, such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS), respectively, in peritoneal carcinoma (NCT01443260); fallopian tube and ovarian cancer (NCT02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).

[0213] In some embodiments, the immuno-oncology agent is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutics targeting difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated as: Ad5 / 3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (Vira Therapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express a protein designed to enhance antigen-specific CD8+ Antigens to which T cells respond.

[0214] In some embodiments, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor (or CAR). T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

[0215] CARs have been constructed that consist of binding domains derived from the following: natural ligands, single-chain variable fragments (scFv) derived from monoclonal antibodies specific for cell surface antigens, fused to an internal domain that is the functional end of the T cell receptor (TCR), such as the CD3-ζ signaling domain from the TCR, which is capable of generating activation signals in T lymphocytes. Upon antigen binding, this CAR connects to endogenous signaling pathways in effector cells and generates activation signals similar to those triggered by the TCR complex.

[0216] For example, in some embodiments, the CAR-T cell is one of those described in U.S. Pat. No. 8,906,682 (June; hereby incorporated by reference in its entirety), which discloses that the CAR-T cell design is modified to include an extracellular domain with an antigen binding domain (such as a domain that binds to CD19), fused to an intracellular signaling domain of a T cell antigen receptor complex ζ chain (such as CD3ζ). When expressed in T cells, the CAR is able to redirect antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, hundreds of clinical trials using CAR-T are underway in a wide range of indications [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&p g=1].

[0217] In some embodiments, the immunostimulator is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells and the differentiation of innate immune cell subsets expressing IL-17, such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0218] In some embodiments, the immunostimulator is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being studied for B cells, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in the present invention include Motomod (VTX-2337, VentiRx Pharmaceuticals), which is being studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0219] Other immuno-oncology agents that can be used in the present invention include: usulerumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varirizumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirelumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; and andreximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0220] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mivastatin, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0221] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been clinically tested as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to a soluble IL-15 binding protein IL-15 receptor α chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0222] In some embodiments, the immuno-oncology agent is selected from those described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 by Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from those listed in Table 2 by Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule selected from those listed in Table 2 by Jerry L. Adams et al.

[0223] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent targeting a pathway as described by Peter L. Toogood.

[0224] In some embodiments, the immuno-oncology agent is selected from Sandra L. Ross et al., "Bispecific T cell engager Antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T cell engager Antibody Constructs. In some embodiments, the bispecific T cell engager The antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager The antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager Antibody constructs activate T cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, which release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on neighboring cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, resulting in induced bystander cell lysis. In some embodiments, the bystander cells are in a solid tumor. In some embodiments, the lysed bystander cells are near Activated T cells. In some embodiments, the adjacent cells include tumor-associated antigen (TAA) negative cancer cells. In some embodiments, the adjacent cells include EGFR negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the immuno-oncology agent is a tumor-infiltrating T cell amplified ex vivo. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly connects T cells to tumor-associated surface antigens (TAA).

[0225] 5. Further implementation plans

[0226] Further embodiments of the present invention are described below. These embodiments are illustrative and should not be construed as limiting the scope of the claimed invention.

[0227] Embodiment 1. A 1,2-diaminobenzimidazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0228]

[0229] in:

[0230] A l Represents nitrogen atom or CR 6 ;

[0231] A 2 Represents nitrogen atom or CR 7 ;

[0232] R 1 represents a halogen atom or an alkyl group;

[0233] R 2 , R 3 , R 4 , R 6 and R 7 each of which independently represents a hydrogen atom or a fluorine atom, and

[0234] R 5 represents a hydrogen atom or an optionally substituted alkyl group.

[0235] Embodiment 2. A compound described in any one of Embodiments 1-29 or a pharmaceutically acceptable salt thereof.

[0236] Example

[0237] The present invention is described in more detail below, including examples and test examples, but the present invention is not limited to these examples.

[0238] The compounds were characterized by H NMR spectroscopy ( 1 H-NMR) and mass spectrometry (MS). Unless otherwise specified, 1 H-NMR is measured at 400MHz, and exchangeable hydrogen may not be clearly observed depending on the compound and measurement conditions. Please note that br means a broad range signal (broad). HPLC preparative chromatography was performed using a commercially available ODS column with a gradient mode of water / acetonitrile (containing formic acid) or water / methanol (containing formic acid) as eluent.

[0239] Reference Example 1. Production of 5-chloro-3-isothiocyanato-1H-indole

[0240]

[0241] (Step 1) Production of N-(5-chloro-1H-indol-3-yl)-2,2,2-trifluoroacetamide

[0242]

[0243] Trifluoroacetic anhydride (51.87 g, 247 mmol) was added dropwise to a THF solution (210 mL) of 2,2-diethoxyethane-1-amine (30 g, 225 mmol) and DIPEA (34.92 g, 270 mmol), and the residual reagent was added dropwise to a dropping funnel by adding THF (30 mL). After stirring at room temperature for 1 hour, the reaction mixture was washed twice with a mixture of water (88 mL), concentrated hydrochloric acid (8 mL) and sodium chloride (4.8 g), and the organic layer was evaporated under reduced pressure. The resulting residue (34.9 g) was dissolved in a mixed solvent of 1,2-dichloroethane / toluene (1:1, 240 mL), and 4-chlorophenylhydrazine hydrochloride (36.41 g, 203 mmol) was added to the solution and stirred at 50°C for 1 hour. After the reaction mixture was cooled to room temperature, water (60 mL) was added. After cooling to 0°C, the precipitated solid was filtered off. The solid was washed with water and then with a mixed solvent of 1,2-dichloroethane / toluene (1:1, 30 mL). To the obtained solid was added a 2-propanol aqueous solution (20%, 250 mL) and cooled to 0°C, and then the solid was filtered off and dried to obtain the title compound (28.07 g). 1 H NMR (DMSO-d6) δ11.39(s,1H),11.28(s,1H),7.93-7.87(m,1H),7.82(d,J=2.6Hz,1H),7.42(d,J=8.7Hz,1H),7.14(dd,J=8.7,2.1Hz,1H);

[0244] LCMS (m / z) 261.0 [MH] - .

[0245] (Step 2) Production of 5-chloro-1H-indol-3-amine hydrochloride

[0246]

[0247] A mixture of N-(5-chloro-1H-indol-3-yl)-2,2,2-trifluoroacetamide (7.1 g, 27 mmol) and 2N hydrochloric acid / ethanol solution (70 mL) was stirred overnight at 80° C. The solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the solid was filtered off and dried to obtain the title compound (4.96 g). 1 H NMR(DMSO-d6)δ11.63(s,1H),10.35(brs,3H),7.72(d,J=2.0Hz,1H),7.58(d,J=2. 8Hz,1H),7.47(d,J=8.7Hz,1H),7.19(dd,J=8.7,2.1Hz,1H); LCMS(m / z)167.0[M+H] + .

[0248] (Step 3) Production of 5-chloro-3-isothiocyanato-1H-indole. To a THF solution (100 mL) of 5-chloro-1H-indole-3-amine hydrochloride (4.96 g, 24.43 mmol) were added thiophosgene (3.09 g, 26.9 mmol) and DIPEA (6.31 g, 48.9 mmol), and the mixture was stirred at room temperature for 50 minutes. Ethyl acetate was added to the reaction mixture and washed with dilute hydrochloric acid and saturated brine in sequence, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title mixture (5.04 g). 1 H NMR(DMSO-d6)δ11.76(s,1H),7.84(d,J=2.9Hz,1H),7.63-7.55(m,1H),7.48(dd,J=8.7Hz,0.7Hz,1H),7.24(dd,J=8.7,2.0Hz,1H); LCMS(m / z)207.1[MH] - .

[0249] Reference Example 2. Production of tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]hydrazine-1-carboxylate

[0250]

[0251] (Step 1) Production of tert-butyl 2-[2-nitro-4-(trifluoromethyl)phenyl]hydrazine-l-carboxylate

[0252]

[0253]

[0254] To a solution (50 mL) of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (10 g, 47.8 mmol) in NMP was added tert-butyl carbazate (9.48 g, 71.7 mmol) and stirred at 80°C overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give the title compound (15.36 g). 1 H NMR (CHLOROFORM-d) δ9.15 (s, 1H), 8.50-8.45 (m, 1H), 7.72 (dd, J=9.0, 2.1 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 6.44 (s, 1H), 1.49 (s, 9H).

[0255] (Step 2) Production of tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]hydrazine-l-carboxylate. tert-butyl 2-[2-nitro-4-(trifluoromethyl)phenyl]hydrazine-l-carboxylate (15.36 g, 47.8 mmol) was dissolved in a mixed solvent (1:1:1, 300 mL) of methanol / THF / saturated aqueous ammonium chloride solution, and zinc powder (15.63 g, 239 mmol) was added thereto at 0°C and stirred at 0°C for 20 minutes. The reaction mixture was filtered through celite to remove insoluble materials. The organic layer was concentrated under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate. Then, it was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (12.49 g). 1 H NMR (DMSO-d6) δ8.89 (s, 1H), 7.15 (d, J = 2.1 Hz, 1H), 6.85-6.77 (m, 2H), 6.59 (d, J = 8.2 Hz, 1H), 5.02 (s, 2H), 1.42 (s, 9H).

[0256] Reference Example 3. Production of 5,6-difluoro-3-isothiocyanato-1H-indole

[0257]

[0258] (Step 1) Production of 5,6-difluoro-3-nitro-1H-indole

[0259]

[0260] A solution of fuming nitric acid (1.296 g, 20.57 mmol) in acetic acid (9 mL) was added dropwise to a solution of 5,6-difluoro-1H-indole (3 g, 19.59 mmol) and acetic anhydride (4.32 g, 42.3 mmol) in acetic acid (15 mL) at 0°C and stirred at room temperature for 4 hours. Water (30 mL) was added to the reaction mixture to terminate the reaction, and acetic acid (4 mL) was added thereto. After cooling to 0°C, the precipitated solid was filtered out. The solid was purified by amine-modified silica gel chromatography (hexane: ethyl acetate = 1:0-0:1) to give the title compound (1.94 g). 1 H NMR(DMSO-d6)δ12.81(s,1H),8.71(s,1H),7.97(dd,J=10.8Hz,7.9Hz,1H),7.66(dd,J=10.4,6.8Hz,1H); LCMS(m / z)197.1[MH] - .

[0261] (Step 2) Production of tert-butyl (5,6-difluoro-1H-indol-3-yl)carbamate

[0262]

[0263] 5,6-difluoro-3-nitro-1H-indole (1.9 g, 9.59 mmol) was added to a mixed solvent of methanol / THF / saturated aqueous ammonium chloride solution (1:1:1, 60 mL). Zinc powder (6.27 g, 96 mmol) was added to the suspension at 0°C and stirred at 0°C for 5 minutes, followed by Boc2O (2.512 g, 11.51 mmol) and stirred at 0°C for 30 minutes, and then stirred at room temperature for 1 hour. To complete the reaction, zinc powder (2.7 g, 41.3 mmol) was placed therein and further stirred at room temperature for 3 hours. The reaction mixture was filtered through diatomaceous earth to remove insoluble materials. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1:0-7:3) to obtain the title compound (1.16 g). 1 H NMR(DMSO-d6)δ10.87(s,1H),9.18(s,1H),7.73(dd,J=11.6,8.2Hz,1H),7.47(s,1H),7.29(dd,J=11.3,7.0Hz,1H),1.49(s,9H); LCMS(m / z)267.1[MH] - .

[0264] (Step 3) Production of 5,6-difluoro-1H-indol-3-amine hydrochloride

[0265]

[0266] A mixture of tert-butyl (5,6-difluoro-1H-indol-3-yl)carbamate (1.16 g, 4.32 mmol) and 4N hydrochloric acid / ethyl acetate solution (10 mL) was stirred at room temperature for 1 hour. The precipitated solid was filtered off and dried to give the title compound (650 mg). 1 H NMR(DMSO-d6)δ11.59-11.54(m,1H),10.14(brs,3H),7.61(dd,J=11.1,7.9Hz, 1H),7.57(d,J=2.8Hz,1H),7.49(dd,J=11.1,7.0Hz,1H); LCMS(m / z)169.1[M+H] + .

[0267] (Step 4) Production of 5,6-difluoro-3-isothiocyanato-1H-indole. To a THF solution (15 mL) of 5,6-difluoro-1H-indole-3-amine hydrochloride (650 mg, 3.18 mmol) were added thiophosgene (402 mg, 3.49 mmol) and DIPEA (821 mg, 6.35 mmol) and stirred at room temperature for 2 hours. To complete the reaction, thiophosgene (402 mg, 3.49 mmol) and DIPEA (821 mg, 6.35 mmol) were placed therein and further stirred at room temperature for 1.5 hours. Ethyl acetate and saturated brine were added to the reaction mixture and the reaction mixture was filtered through celite to remove insoluble materials. The filtrate was washed with water and saturated brine in sequence. The obtained organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain the title compound (668 mg). 1 H NMR(DMSO-d6)δ11.72(s,1H),7.85(d,J=2.9Hz,1H),7.63-7.56(m,1H),7.51(dd,J=10.9,6.8Hz,1H); LCMS(m / z)209.1[MH] - .

[0268] Reference Example 4. Production of 4,5-difluoro-3-isothiocyanato-1H-indole

[0269]

[0270] (Step 1) Production of 4,5-difluoro-3-nitro-1H-indole

[0271]

[0272] Fuming nitric acid (1.059 g, 16.8 mmol) in acetic acid (9 mL) was added dropwise to 4,5-difluoro-1H-indole (2.45 g, 16 mmol) and acetic anhydride (3.528 g, 34.6 mmol) in acetic acid (15 mL) at 0 ° C and stirred at room temperature for 1.5 hours. Water (30 mL) was added to the reaction mixture and cooled to 0 ° C, and then the precipitated solid was filtered out. The solid was purified by amine-modified silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1, then ethyl acetate: methanol = 9: 1) to give the title compound (2.04 g). 1 H NMR(DMSO-d6)δ12.94(s,1H),8.73(s,1H),7.44-7.35(m,2H); LCMS(m / z)197.1[MH] - .

[0273] (Step 2) Production of tert-butyl (4,5-difluoro-1H-indol-3-yl)carbamate

[0274]

[0275] 4,5-difluoro-3-nitro-1H-indole (2.04 g, 10.3 mmol) was added to a mixed solvent of methanol / THF / saturated aqueous ammonium chloride solution (1:1:1, 75 mL). Zinc powder (3.366 g, 51.5 mmol) was added to the suspension at 0°C and stirred for 5 minutes, followed by addition of Boc2O (2.472 g, 11.33 mmol) and stirring at room temperature for 45 minutes. The reaction mixture was filtered through celite to remove insoluble materials. The filtrate was concentrated under reduced pressure, and the residue was purified by amine-modified silica gel chromatography (hexane: ethyl acetate = 1:0-1:1) to obtain the title compound (2.22 g). 1 H NMR(DMSO-d6)δ11.20(s,1H),8.40(s,1H),7.30(s,1H),7.16-7.01(m,2H),1.45(s,9H); LCMS(m / z)267.1[MH] - .

[0276] (Step 3) Production of 4,5-difluoro-1H-indol-3-amine hydrochloride

[0277]

[0278] A mixture of tert-butyl (4,5-difluoro-1H-indol-3-yl)carbamate (2.22 g, 8.28 mmol) and 4N hydrochloric acid / ethyl acetate solution (10 mL) was stirred at room temperature for 30 minutes. The precipitated solid was filtered off and dried to give the title compound (1.35 g). 1 H NMR(DMSO-d6)δ11.73(s,1H),10.20(brs,3H),7.59(d,J=2.7Hz,1H),7.35-7.20(m,2H); LCMS(m / z)169.1[M+H] + .

[0279] (Step 4) Production of 4,5-difluoro-3-isothiocyanato-1H-indole. To a THF solution (30 mL) of 4,5-difluoro-1H-indole-3-amine hydrochloride (1,348 mg, 6.59 mmol) was added thiophosgene (833 mg, 7.25 mmol) and DIPEA (1,703 mg, 13.18 mmol) and stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture and washed with water and saturated brine in that order. The obtained organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain the title compound (1,352 mg). 1H NMR (chloroform-d) δ8.08 (brs, 1H), 7.22 (d, J=2.8 Hz, 1H), 7.15-7.01 (m, 2H); LCMS (m / z) 209.1 [MH] - .

[0280] Reference Example 5. Production of tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]-1-methylhydrazine-1-carboxylate

[0281]

[0282] Production of tert-butyl 1-methyl-2-[2-nitro-4-(trifluoromethyl)phenyl]hydrazine-l-carboxylate

[0283]

[0284] To a DMF solution (100 mL) of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (10 g, 47.8 mmol) was added tert-butyl 1-methylhydrazine-1-carboxylate (7.69 g, 52.6 mmol) and triethylamine (7.26 g, 71.7 mmol) and stirred at 100°C for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (16.3 g). 1 H NMR(chloroform-d)δ9.31(s,1H),8.49(d,J=1.1Hz,1H),7.71(ddd,J=8.9,1.5,0.6Hz,1 H),7.08(dd,J=9.1,0.9Hz,1H),3.26(s,3H),1.42(s,9H); LCMS(m / z)334.2[MH] - .

[0285] (Step 2) Production of tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]-1-methylhydrazine-1-carboxylate. tert-Butyl 1-methyl-2-[2-nitro-4-(trifluoromethyl)phenyl]hydrazine-1-carboxylate (13.1 g, 38.3 mmol) was dissolved in a mixed solvent of methanol / THF / saturated aqueous ammonium chloride solution (5:5:4, 280 mL), and zinc powder (12.52 g, 191 mmol) was added thereto at 0°C and stirred at 0°C for 30 minutes. The reaction mixture was filtered through celite to remove insoluble materials. The organic layer was concentrated under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate, then washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (10.57 g). 1H NMR (chloroform-d) δ7.06 (d, J = 8.4Hz, 1H), 6.95 (d, J = 1.9Hz, 1H), 6.73 (d, J = 8.2Hz, 1H), 6.04 (s, 1H), 3.53 (brs, 2H), 3.19 (brs, 3H), 1.42 (brs, 9H).

[0286] Reference Example 6. Production of 5,7-difluoro-3-isothiocyanato-1H-indole

[0287]

[0288] (Step 1) Production of N-(5,7-difluoro-1H-indol-3-yl)-2,2,2-trifluoroacetamide

[0289]

[0290] Trifluoroacetic anhydride (7.98 g, 38 mmol) was added dropwise to a THF solution (35 mL) of 2,2-diethoxyethane-1-amine (4.6 g, 34.5 mmol) and DIPEA (5.36 g, 41.4 mmol), and the residual reagent was added dropwise to the dropping funnel by placing THF (5 mL). After stirring at room temperature for 40 minutes, the reaction mixture was washed twice with a mixed solution of saturated brine (15 mL) and concentrated hydrochloric acid (1.15 mL), and the organic layer was evaporated under reduced pressure. The obtained residue (5.36 g) was dissolved in a mixed solvent of 1,2-dichloroethane / toluene (1:1, 40 mL), and (2,4-difluorophenyl)hydrazine hydrochloride (5.2 g, 28.8 mmol) was added to the solution and stirred at 50°C for 1.5 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by amine-modified silica gel chromatography (hexane:ethyl acetate=1:0-7:3) to obtain the title compound (3.5 g). LCMS (m / z) 263.0 [MH] - .

[0291] (Step 2) Production of 5,7-difluoro-1H-indol-3-amine hydrochloride

[0292]

[0293]

[0294] A mixture of N-(5,7-difluoro-1H-indol-3-yl)-2,2,2-trifluoroacetamide (3.5 g, 13.25 mmol) and 2N hydrochloric acid / ethanol solution (30 mL) was stirred at 80°C overnight. The solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, and the solid was filtered off and dried to obtain the title compound (2.3 g). LCMS (m / z) 169.1 [M+H] + .

[0295] (Step 3) Production of 5,7-difluoro-3-isothiocyanato-1H-indole. To a THF solution (50 mL) of 5,7-difluoro-1H-indole-3-amine hydrochloride (2.3 g, 11.24 mmol) was added thiophosgene (1.42 g, 12.37 mmol) and DIPEA (2.91 g, 22.48 mmol) and stirred at room temperature for 30 minutes. The residue obtained by distilling off the solvent under reduced pressure was roughly purified by silica gel chromatography (chloroform: methanol = 1: 0-4: 1). The obtained crude product was dissolved in ethyl acetate and washed with dilute hydrochloric acid and saturated brine in sequence, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2 g). LCMS (m / z) 209.1 [MH] - .

[0296] Reference Example 7. Production of tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]-1-ethylhydrazine-1-carboxylate

[0297]

[0298] Production of tert-butyl 1-ethyl-2-[2-nitro-4-(trifluoromethyl)phenyl]hydrazine-1-carboxylate

[0299]

[0300] To a solution (30 mL) of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (5.12 g, 24.49 mmol) in NMP was added tert-butyl 1-ethylhydrazine-1-carboxylate (5.1 g, 31.8 mmol) and stirred at 80°C overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (8.5 g). LCMS (m / z) 348.3 [MH] - .

[0301] (Step 2) Production of tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]-1-ethylhydrazine-1-carboxylate. tert-butyl 1-ethyl-2-[2-nitro-4-(trifluoromethyl)phenyl]hydrazine-1-carboxylate (8.5 g, 24.33 mmol) was dissolved in a mixed solvent (1:1:1, 180 mL) of methanol / THF / saturated aqueous ammonium chloride solution, and zinc powder (7.95 g, 122 mmol) was added thereto at 0°C and stirred at 0°C for 25 minutes. The reaction mixture was filtered through celite to remove insoluble materials. The organic layer was concentrated under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate, then washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by amine-modified silica gel chromatography (hexane:ethyl acetate=1:0-7:3) to give the title compound (7.0 g). 1 H NMR(DMSO-d6)δ7.53(s,1H),6.86-6.84(m,1H),6.82-6.76(m,1H),6.50(d,J=8. 2Hz, 1H), 5.04 (s, 2H), 3.47-3.36 (m, 2H), 1.35 (brs, 9H), 1.12 (t, J = 7.1Hz, 3H).

[0302] Example 1. Generation of N2-(5-chloro-1H-indol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine hydrochloride

[0303]

[0304] (Step 1) Production of tert-butyl {2-[(5-chloro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl}carbamate

[0305]

[0306] To a DMF solution (50 mL) of 5-chloro-3-isothiocyanato-1H-indole (Reference Example 1, 1.5 g, 7.19 mmol) was added tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]hydrazine-1-carboxylate (Reference Example 2, 2.3 g, 7.91 mmol) and stirred at 50°C overnight. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water and saturated brine in sequence. The obtained organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was roughly purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-19: 1) to obtain thiourea (2.06 g). The obtained thiourea (2.06 g, 4.12 mmol) was dissolved in DMF (20 mL). EDCI-HCl (1.19 g, 6.18 mmol) was added to the solution and stirred at 50°C for 2.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water and saturated brine in sequence. The obtained organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1) to obtain the title compound (1.89 g). LCMS (m / z) 466.2 [M + H] + .

[0307] (Step 2) Generation of N2-(5-chloro-1H-indol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine hydrochloride. A mixture of tert-butyl {2-[(5-chloro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl}carbamate (1.89 g, 4.06 mmol) and 4N hydrochloric acid / ethyl acetate solution (25 mL) was stirred at room temperature for 2 hours. The precipitated solid was filtered off and dried to give the title compound (1.35 g). 1 H NMR (methanol-d4) δ7.72-7.66 (m, 2H), 7.62 (s, 1H), 7.57-7.54 (m, 2H), 7.50-7.47 (m, 1H), 7.22 (dd, J = 8.8, 2.0 Hz, 1H); LCMS (m / z) 366.1 [M+H] + .

[0308] Example 2. Production of N2-(5,6-difluoro-1H-indol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine formate

[0309]

[0310] (Step 1) Production of tert-butyl {2-[(5,6-difluoro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1-benzo[d]imidazol-1-yl}carbamate

[0311]

[0312] To a DMF solution (5 mL) of 5,6-difluoro-3-isothiocyanato-1H-indole (Reference Example 3, 150 mg, 0.714 mmol) was added tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]hydrazine-1-carboxylate (Reference Example 2, 270 mg, 0.928 mmol) and stirred at 50°C overnight. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water and saturated brine in sequence. The organic layer was evaporated under reduced pressure, and the resulting residue was roughly purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-19: 1) to give thiourea (110 mg). The resulting thiourea (110 mg, 0.219 mmol) was dissolved in DMF (2 mL). EDCI-HCl (63.1 mg, 0.329 mmol) was added to the solution and stirred at 50°C for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water and saturated brine in sequence. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0-1:1) to give the title compound (55 mg). LCMS (m / z) 468.1 [M+H] + .

[0313] (Step 2) Production of N2-(5,6-difluoro-1H-indol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine formate. A mixture of tert-butyl {2-[(5,6-difluoro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazole-1-yl}carboxylate (55 mg, 0.118 mmol) and 4N hydrochloric acid / ethyl acetate solution (1 mL) was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified using HPLC preparative chromatography to give the title compound. 1 HNMR(DMSO-d6)δ11.03-10.98(m,1H),8.77(s,1H),8.25(s,1H),7.89(d,J=2.5Hz,1H),7.80(dd ,J=11.7,8.1Hz),7.52(d,J=1.5Hz,1H),7.41-7.31(m,3H),5.91(s,2H); LCMS(m / z)368.1[M+H] + .

[0314] Example 3. Generation of N2-(4,5-difluoro-1H-indol-3-yl)-N1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine hydrochloride

[0315]

[0316] (Step 1) Production of tert-butyl {2-[(4,5-difluoro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl}(methyl)carbamate

[0317]

[0318] To a DMF solution (15 mL) of 4,5-difluoro-3-isothiocyanato-1H-indole (Reference Example 4, 1.35 g, 6.42 mmol) was added tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]-1-methylhydrazine-1-carboxylate (Reference Example 5, 2.55 g, 8.35 mmol) and stirred at 60° C. for 5 hours. After the reaction mixture was cooled to room temperature, it was diluted with water and extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was roughly purified by amine-modified silica gel chromatography (hexane:ethyl acetate=1:0-0:1, then ethyl acetate:methanol=1:0-3:7) to give thiourea (2.52 g). The obtained thiourea (2.517 g, 4.88 mmol) was dissolved in DMF (20 mL). To the solution was added EDCI-HCl (1.872 g, 9.77 mmol) and pyridine (0.772 g, 9.77 mmol) and stirred at 50°C for 30 minutes. After the reaction mixture was cooled to room temperature, it was diluted with water and extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl = 1: 0-0: 1) to give the title compound (1.596 g). 1 HNMR (chloroform-d) δ8.81 (s, 1H), 7.82-7.79 (m, 1H), 7.78-7.74 (m, 1H), 7.43-7.38 (m, 1H), 7.15-7.08 (m, 1H), 7.01-6.89 (m, 2H), 6.80-6.75 (m, 1H), 3.47 (s, 3H), 1.42 (s, 9H); LCMS (m / z) 482.2 [M+H] + .

[0319] (Step 2) Generation of N2-(4,5-difluoro-1H-indol-3-yl)-N1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine hydrochloride. A mixture of tert-butyl {2-[(4,5-difluoro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl}(methyl)carbamate (1.595 g, 3.31 mmol) and 4N hydrochloric acid / ethyl acetate solution (10 mL) was stirred at room temperature for 2 hours. The precipitated solid was filtered off and dried to give the title compound (1.172 g). 1 H NMR(methanol-d4)δ7.74(d,J=8.5Hz,1H),7.68(d,J=8.4Hz,1H),7.63(s,1H),7.60-7.57 (m,1H),7.29-7.24(m,1H),7.19-7.08(m,1H),3.02(s,3H); LCMS(m / z)382.2[M+H] + .

[0320] Example 4. Preparation and Production of N2-(5,6-difluoro-1H-indol-3-yl)-N1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine

[0321]

[0322] (Step 1) Production of tert-butyl {2-[(5,6-difluoro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl}(methyl)carbamate

[0323]

[0324] To a DMF solution (1 mL) of 5,6-difluoro-3-isothiocyanato-1H-indole (Reference Example 3, 103 mg, 0.491 mmol) was added tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]-1-methylhydrazine-1-carboxylate (Reference Example 5, 125 mg, 0.409 mmol) and stirred at 50° C. for 1 hour, and then at 70° C. for 2 hours. To complete the reaction, 5,6-difluoro-3-isothiocyanato-1H-indole (20 mg, 0.095 mmol) was placed therein and further stirred at 70° C. for 30 minutes. After the reaction mixture was cooled to room temperature, it was diluted with water and extracted twice with ethyl acetate. The resulting organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was roughly purified by amine-modified silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1, followed by ethyl acetate: methanol = 1: 0-3: 7) to give thiourea (45 mg). The obtained thiourea (43 mg, 0.083 mmol) was dissolved in DMF (1 mL). EDCI-HCl (32 mg, 0.167 mmol) and pyridine (13.2 mg, 0.167 mmol) were added to the solution and stirred at 50 ° C for 1.5 hours. After the reaction mixture was cooled to room temperature, it was diluted with water and extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1) to give the title compound (21.6 mg). 1 H NMR(chloroform-d)δ8.28(brs,1H),7.74(s,1H),7.69(d,J=2.6Hz,1H),7.41-7.37(m,1H),7.25-7.22(m,1H),7.15( dd,J=10.3,6.5Hz,1H),7.10(d,J=8.2Hz,1H),6.26(s,1H),3.47(s,3H),1.41(s,9H); LCMS(m / z)482.2[M+H] + .

[0325] (Step 2) Production of N2-(5,6-difluoro-1H-indol-3-yl)-N1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine. A mixture of tert-butyl {2-[(5,6-difluoro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazole-1-yl}(methyl)carbamate (20.9 mg, 0.043 mmol) and 4N hydrochloric acid / ethyl acetate solution (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was neutralized by adding saturated sodium bicarbonate and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=1:0-0:1, then ethyl acetate:methanol=1:0-9:1) to give the title compound (13.2 mg). 1 H NMR(DMSO-d6)δ11.05-11.00(m,1H),8.77(s,1H),7.87(d,J=2.5Hz,1H),7.78(dd,J=11.7,8.1Hz,1H),7.55-7.53 (m,1H),7.44(d,J=8.2Hz,1H),7.42-7.31(m,2H),6.60-6.51(m,1H),2.81(d,J=5.5Hz,3H); LCMS(m / z)382.1[M+H] + .

[0326] Example 5. Generation of N2-(5,7-difluoro-1H-indol-3-yl)-N1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine

[0327]

[0328] (Step 1) Production of tert-butyl {2-[(5,7-difluoro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl}(methyl)carbamate

[0329]

[0330] To a DMF solution (2 mL) of 5,7-difluoro-3-isothiocyanato-1H-indole (Reference Example 6, 49.2 mg, 0.234 mmol) was added tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]-1-methylhydrazine-1-carboxylate (Reference Example 5, 55 mg, 0.18 mmol) and stirred at 50°C overnight. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water and saturated brine in that order. The organic layer was dried over anhydrous sodium sulfate, and then the residue obtained by distilling off the solvent under reduced pressure was roughly purified by amine-modified silica gel chromatography (chloroform: methanol = 1:0-1:1) to give thiourea (34 mg). The obtained thiourea (34 mg, 0.066 mmol) was dissolved in DMF (0.7 mL). EDCI-HCl (18.97 mg, 0.099 mmol) was added to the solution and stirred at 50°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water and saturated brine in sequence. The organic layer was dried over anhydrous sodium sulfate, and then the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-1: 1) to give the title compound (18.7 mg). LCMS (m / z) 482.2 [M + H] + .

[0331] (Step 2) Production of N2-(5,7-difluoro-1H-indol-3-yl)-N1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine. A mixture of tert-butyl {2-[(5,7-difluoro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazole-1-yl}(methyl)carbamate (18.7 mg, 0.039 mmol) and 4N hydrochloric acid / ethyl acetate solution (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was neutralized by adding saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=1:0-0:1) to give the title compound (10.3 mg). 1 H NMR(DMSO-d6)δ11.52-11.48(m,1H),8.80(s,1H),7.93(d,J=2.6Hz,1H),7.58-7.54(m,1H),7.48-7.40(m, 2H),7.37-7.32(m,1H),7.05-6.95(m,1H),6.60-6.53(m,1H),2.81(d,J=5.5Hz,3H); LCMS(m / z)382.1[M+H] + .

[0332] Example 6. Generation of N2-(5-chloro-1H-indol-3-yl)-N1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazole-1,2-diamine hydrochloride

[0333]

[0334] (Step 1) Production of tert-butyl {2-[(5-chloro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl}(ethyl)carbamate

[0335]

[0336] To a DMF solution (30 mL) of 5-chloro-3-isothiocyanato-1H-indole (Reference Example 1, 1.2 g, 5.75 mmol) was added tert-butyl 2-[2-amino-4-(trifluoromethyl)phenyl]-1-ethylhydrazine-1-carboxylate (Reference Example 7, 2.02 g, 6.33 mmol) and stirred at 50°C overnight. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water and saturated brine in that order. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was roughly purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-97: 3) to give thiourea (1.7 g). The obtained thiourea (1.7 g, 3.22 mmol) was dissolved in DMF (20 mL). EDCI-HCl (0.926 g, 4.83 mmol) was added to the solution and stirred at 55°C for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water and saturated brine in sequence. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=1:0-7:3) to give the title compound (1.38 g). LCMS (m / z) 494.2 [M+H] + .

[0337] (Step 2) Production of N2-(5-chloro-1H-indol-3-yl)-N1-ethyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-1,2-diamine hydrochloride. A mixture of tert-butyl {2-[(5-chloro-1H-indol-3-yl)amino]-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl}(ethyl)carbamate (1.38 g, 2.79 mmol) and 4N hydrochloric acid / ethyl acetate solution (20 mL) was stirred at 55° C. for 45 minutes. The precipitated solid was filtered off and dried to give the title compound (677 mg). 1H NMR (methanol-d4) δ7.74 (d, J = 8.4Hz, 1H), 7.70-7.66 (m, 1H), 7.63 (s, 1H), 7.58-7.55 (m, 1H), 7.53-7.51 (m, 1H), 7.50 -7.47(m,1H),7.23(dd,J=8.7,2.0Hz,1H),3.40(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H); LCMS(m / z)394.1[M+H] + .

[0338] Example 7-29.

[0339] According to the methods described in the above examples, the following example compounds Table 1 were produced by using corresponding starting materials (commercial products or compounds derived from commercial compounds by known methods or methods analogous thereto) and, if necessary, by appropriately combining methods generally used in synthetic organic chemistry. The physicochemical data of each compound are shown in Table 2.

[0340] Table 1.

[0341]

[0342]

[0343]

[0344]

[0345]

[0346] Table 2.

[0347]

[0348]

[0349]

[0350] Test Example 1. Inhibition test of the human STING (hSTING) pathway in cells using reporter cells

[0351] Since STING activates the transcription factor IRF3 through ligand stimulation, the activity of STING can be assessed by a reporter gene assay using secreted alkaline phosphatase (SEAP reporter gene) incorporated downstream of the IRF inducible promoter. TMISG cells (manufactured by Invivogen, #hkb-isg-1) were used to evaluate the hSTING inhibitory activity of the test compound. hSTING activation was performed by stimulation with the small molecule ligand compound 3 as described in the literature (Ramanjulu, JM et al., Nature. 2018, 564(7736), 439-443).

[0352] HEK-Blue TM ISG cells were seeded in a 96-well plate and cultured overnight in a 5% CO2 incubator at 37°C. To each well of the cell culture plate, a test compound solution adjusted to a final concentration of 0.1-10 μM was added and cultured in a CO2 incubator for 1 hour, and then compound 3 (final concentration of 10 nM) was added thereto and further cultured in a CO2 incubator for 21 hours. After collecting the culture supernatant from each well, the reporter gene activity was measured by a luminescent reaction with alkaline phosphatase.

[0353] Method for evaluating inhibitory activity. The reporter gene activity of the group without adding the test compound and adding compound 3 was set to 100%, and the reporter gene activity of the group without adding the test compound and adding compound 3 was set to 0%, IC 50 Values ​​were determined by regression analysis of the inhibition ratios calculated from the reporter gene activity at each compound concentration and the test compound concentration (logarithmic).

[0354] Evaluation results. Table 3 shows the inhibitory activity of representative compounds of the present invention on hSTING. The inhibitory effect on hSTING is indicated as follows: IC < 0.1 μM 50 Values ​​are marked as ***, ≥0.1 μM and <1 μM are marked as **, ≥1 μM and <10 μM are marked as *, and ≥10 μM is marked as “-”.

[0355] Table 3.

[0356]

[0357]

[0358] This result indicates that the compound of formula (I) of the present invention has a strong inhibitory activity on the STING pathway. Test Example 2. Inhibition test of human IFN-β production stimulated by cGAMP

[0359] The inhibitory activity of the test compounds on STING activation was evaluated by measuring the amount of IFN-β produced when stimulated with the endogenous ligand cGAMP using THP-1 cells, a human monocytic cell line.

[0360] After THP-1 cells (manufactured by ATCC) were inoculated in 96-well plates, PMA (manufactured by Santa Cruz Biotechnology, Inc.) was adjusted to a concentration after adding 100 nM and cultured overnight at 37 ° C in a 5% CO2 incubator (RPMI 1640 medium containing 10% FBS, 50U / mL penicillin / 50μg / mL streptomycin). Add a test compound solution adjusted to a final concentration of 0.001-1 μM of the test compound and culture in a CO2 incubator for 1 hour (DMSO final concentration of 0.1%). 0.12 μg / well of 2'3'-cGAMP (manufactured by ChemieTek, #CT-CGAMP) was introduced into the cells by the transfection method using Lipofectamine 2000 (manufactured by Invitrogen) and cultured in a CO2 incubator for another 18 hours. After the culture supernatant was collected from each well, the amount of human IFN-β produced in the culture supernatant was measured by an ELISA method using R&D Human IFN-β Duoset (manufactured by R&D systems).

[0361] Method for evaluating inhibitory activity. The amount of human IFN-β produced in the group without adding the test compound and adding cGAMP was set to 100%, and the amount of human IFN-β produced in the group without adding the test compound and adding cGAMP was set to 0%, IC 50 The values ​​were determined by regression analysis of the inhibition ratios calculated from the amount of human IFN-β production at each compound concentration and the test compound concentration (logarithmic).

[0362] Evaluation results. Table 4 shows the inhibitory activity of representative compounds of the present invention on IFN-β production. The inhibitory effect on IFN-β production is indicated as follows: IC<0.01 μM 50 Values ​​are marked as ***, ≥0.01 μM and <0.1 μM are marked as **, ≥0.1 μM and <1 μM are marked as *, and ≥1 μM is marked as “-”, and NT is marked as not measured.

[0363] Table 4.

[0364]

[0365] This result indicates that the compound of formula (I) of the present invention has a strong inhibitory effect on IFN-β production induced by STING activation in cells.

[0366] Test Example 3. Cytokine production inhibition test using a mouse model stimulated by a STING agonist

[0367] A mouse STING agonist CMA (10-carboxymethyl-9-acridone) was administered to mice to stimulate the STING pathway, and then the inhibitory effect of the compound of formula (I) of the present invention on the production amount of cytokines (IFN-β and IL-6) released into the blood was evaluated.

[0368] Adjustment of test compound solution. DMSO, polyethylene glycol #400 and 30% (w / v) hydroxypropyl-β-cyclodextrin were sequentially added to the test compound and mixed thoroughly (5:20:75 solvent composition) to adjust the test compound solution. For the solvent administration group, a solution with similar solvent composition characteristics but without the test compound was used.

[0369] CMA stimulates the reaction. The test compound solution adjusted to the solvent or test dose was orally administered to C57BL / 6N mice (female, 7-8 weeks old) (4 mice per group). One hour after administration, CMA (manufactured by Tokyo Chemical Industry Co., Ltd) suspended in 0.5% methylcellulose solution was intraperitoneally administered to mice at a dose of 224 mg / kg. After CMA was administered for 2 hours, blood samples were collected from each mouse, and the concentrations of IFN-β and IL-6 in plasma were measured using Duoset ELISA kits (manufactured by R&D Systems).

[0370] Evaluation results. Figure 1 and 2 As shown. Figure 1 and 2 As shown, compared with the solvent group, the representative compounds of the present invention significantly inhibited or tended to inhibit the production of cytokines stimulated by STING. These results indicate that the compounds of formula (I) of the present invention have an inhibitory effect on the production of IFN-β and IL-6 induced by STING activation in mice.

[0371] The compounds provided by the present invention can be used as preventive or therapeutic drugs (pharmaceutical compositions) for diseases known to be associated with STING-mediated cellular responses, such as inflammatory diseases, autoimmune diseases, or cancer. When combined with therapeutic agents for other inflammatory diseases, autoimmune diseases, and cancer, the compounds are expected to have an effect on immune responses and are therefore also useful as therapeutic drugs (pharmaceutical compositions). As STING inhibitors, they can further be used as reagents for experiments and research.

[0372] Although we have described many embodiments of the present invention, it is apparent that our basic examples can be altered to provide other embodiments utilizing the compounds and methods of the present invention. Accordingly, the scope of the present invention will be defined by the appended claims rather than by the specific embodiments that have been presented by way of example.

[0373] Reference List

[0374] [Non-patent document 1] Paludan, SR and Bowie, AG, Immunity, 2013, 38(5), 870-880

[0375] [Non-patent document 2] Motwani M., et al., Nat. Rev. Genet., 2019, 20(11), 657-674

[0376] [Non-patent document 3] Liu, Y. et al., N. Engl. J. Med., 2014, 371(6), 507-518

[0377] [Non-patent document 4] Jeremiah, N., et al., J. Clin. Invest., 2014, 124(12), 5516-5520

[0378] [Non-patent document 5] Mackenzie, KJ, et al., ENBO J., 2016, 35(8), 831-844

[0379] [Non-patent document 6] An, J., et al., Arthritis Rheumatol., 2017, 69(4), 800-807

[0380] [Non-patent document 7] Kato, Y., et al., Ann. Rheum. Dis., 2018, 77(10), 1507-1515

[0381] [Non-patent document 8] Zeng, L., et al., Sci. Transl. Med., 2017, 9(412)

[0382] [Non-patent document 9] Hu, Q., et al., EBioMedicine, 2019, 41, 497-508

[0383] [Non-patent document 10] Yu, Y., et al., J. Clin. Invest., 2019, 129(2), 546-555

[0384] [Non-patent document 11] Iracheta-Vellve, A., et al., J. Biol. Chem., 2016, 291(52), 26794-26805

[0385] [Non-patent document 12] Maekawa, H., et al., Cell Rep., 2019, 29(5), 1261-1273.e6

[0386] [Non-patent document 13] Ahn, J., et al., Proc. Natl. Acad. Sci. USA 2012, 109(47), 19386-19391

[0387] [Non-patent document 14] Andrea, A. and Chen, ZJ, Science, 2019, 363(6431)

[0388] [Non-patent document 15] Sliter, DA, et al., Nature, 2018, 561(7722), 258-262

[0389] [Non-patent document 16] Skopelja-Gardner S., et al., Nat. Rev. Nephrol., 2022 Jun 22: 1-5

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: A 1 Represents nitrogen atom or CR 6 ; A 2 Represents nitrogen atom or CR 7 ; R 1 represents a halogen atom or an alkyl group; R 2 , R 3 , R 4 , R 6 and R 7 each of which independently represents a hydrogen atom or a fluorine atom, and R 5 represents a hydrogen atom or an optionally substituted alkyl group.

2. The compound according to claim 1, wherein A 1 and A 2 By CR 6 and CR 7 express.

3. A compound according to claim 1, wherein A 1 and A 2 Composed of nitrogen atoms and CR 7 express.

4. A compound according to claim 1, wherein A 1 and A 2 By CR 6 and nitrogen atoms.

5. The compound according to claim 1, wherein R 1 Represented by halogen atoms.

6. The compound according to claim 1, wherein the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: in: A 1 Represents nitrogen atom or CR 6 ; A 2 Represents nitrogen atom or CR 7 ; R 1 represents a halogen atom or an alkyl group; and R 2 , R 3 , R 6 and R 7 Each of independently represents a hydrogen atom or a fluorine atom.

7. A compound according to claim 6, wherein A 1 and A 2 By CR 6 and CR 7 express.

8. A compound according to claim 6, wherein A 1 represented by nitrogen atoms; and A 2 By CR 7 express.

9. A compound according to claim 6, wherein A 1 By CR 6 indicates; and A 2 Represented by nitrogen atoms.

10. The compound according to claim 6, wherein A 1 and A 2 Each is CR 6 and CR 7 indicates; and R 1 Represented by halogen atoms.

11. The compound according to claim 6, wherein A 1 and A 2 Each is CR 6 and CR 7 indicates; and R 6 and R 7 Each is represented by hydrogen.

12. A compound according to claim 6, wherein A 1 and A 2 Each is CR 6 and CR 7 Represents; R 6 and R 7 Each is represented by hydrogen; and R 1 Represented by halogen atoms.

13. A compound according to claim 6, wherein A 1 and A 2 Each is CR 6 and CR 7 Represents; R 2 , R 6 and R 7 Each is represented by hydrogen; and R 1 Represented by halogen atoms.

14. A compound according to claim 6, wherein A 1 and A 2 Each is CR 6 and CR 7 Represents; R 3 , R 6 and R 7 Each is represented by hydrogen; and R 1 Represented by halogen atoms.

15. A compound according to claim 6, wherein A 1 and A 2 Each is CR 6 and CR 7 Represents; R 2 , R 3 , R 6 and R 7 Each is represented by hydrogen; and R 1 Represented by halogen atoms.

16. The compound according to any one of claims 1-15, wherein the compound is selected from any one of the compounds depicted in Examples 1-29 or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier, isotonicity agent, stabilizer or preservative.

18. A method for inhibiting STING pathway activation in a patient or a biological sample, comprising administering to the patient a compound or a pharmaceutical composition thereof according to any one of claims 1 to 16, or contacting the biological sample with a compound or a pharmaceutical composition thereof according to any one of claims 1 to 16.

19. A method for treating a disease associated with a STING-mediated cellular response in a patient, comprising administering to the patient a compound of any one of claims 1-16 or a pharmaceutical composition thereof.

20. The method according to claim 19, wherein the disease associated with STING-mediated cellular response is selected from inflammatory diseases, autoimmune diseases, cardiovascular diseases, pulmonary diseases, metabolic diseases, neurodegenerative diseases, viral infections, ophthalmic diseases and cancer.

21. The method according to claim 19, wherein the disease associated with STING-mediated cellular responses is STING-associated vasculopathy of infancy (SAVI), familial lupus-like syndrome, Aicardi-Guterres syndrome (AGS), systemic lupus erythematosus (SLE), sepsis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), pancreatitis, dermatomyositis, macular degeneration, psoriasis, Sjögren's syndrome, Niemann-Pick disease, interferon pathology, infarction, heart failure, cardiomyopathy, intestinal inflammation, cellular senescence, aging, COPA syndrome, acute kidney injury (AKI), fibrosis, acne, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease (AD), kidney disease, obesity, arthritis, viral hepatitis and COVID-19.

Images