Novel benzimidazole derivatives

Abstract

A benzimidazole derivative represented by formula (I) (wherein A 1 To A 3 and R 1 to R 6 As described in the specification) or a pharmaceutically acceptable salt thereof, which inhibits the activation of the STING pathway, and thus can be used as a preventive or therapeutic drug for inflammatory diseases, autoimmune diseases, cancer, etc. #imgabs0#

Description

Technical Field

[0001] The present invention relates to pharmaceutical agents, in particular to novel benzimidazole derivatives or pharmaceutically acceptable salts thereof having an inhibitory effect on STING pathway activation. Background Art

[0002] The stimulator of interferon genes (STING) 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); activates TANK binding kinase 1 (TBK1); and induces type I IFN production via the transcription factor IRF3 (Non-patent Document 1).

[0003] In recent years, it has been reported that STING is also activated by tumor-derived self-DNA, mitochondrial DNA, etc., and induces a proinflammatory response, and is attracting increasing attention as a target for drug discovery for cancer and autoimmune diseases (Non-Patent Document 2).

[0004] Human STING is encoded by a gene called Tmem173, and an autoinflammatory disease called infantile-onset STING-associated vasculitis (SAVI: STING-associated vasculopathy in infancy) has been reported as a genetic disease caused by mutations in this Tmem173. In SAVI patients, STING is constantly activated due to mutations, and excessive inflammation causes abnormal antibody production and skin and lung tissue damage (Non-patent Document 3). It has also been reported that activating mutations in STING occur in patients with autoinflammatory genetic diseases such as familial lupus pernio and familial lupus-like syndrome (Non-patent Document 4).

[0005] In addition, it is known that when self-DNA accumulates in cells due to defective DNA degradation, the STING pathway is continuously activated, causing autoimmune diseases. Aicardi-Goutieres syndrome (AGS) is also considered to be one of them, and it has been reported that when STING is lacking in this disease model mouse, the symptoms are suppressed (Non-patent Document 5).

[0006] In systemic lupus erythematosus (SLE), autoantibodies called antinuclear antibodies, especially anti-DNA antibodies, are overproduced, which are thought to cause excessive immune responses. However, it has recently become clear that activation of the STING pathway induces interferon production, which is important in the pathology of SLE. That is, it has been reported that cGAMP contained in the peripheral blood of patients is associated with pathological symptom scores, and interferon induction of cGAMP in patient serum is inhibited in cells lacking STING (Non-patent Documents 6 and 7).

[0007] 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 organ damage is caused by systemic inflammation due to pathogen infection, it has been reported that the symptoms are alleviated when STING is lacking in sepsis model mice. (Non-patent documents 8 and 9) 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, patients with Parkinson's disease, a neurodegenerative disease, have been shown to have increased levels of inflammatory cytokines due to disruption of mitochondrial homeostasis, and it has been reported that these abnormalities are improved by the lack of STING in model mice (Non-patent documents 14 and 15).

[0008] Therefore, inhibitors of STING pathway activation may be useful in treating various inflammatory and immune diseases involving the STING pathway.

[0009] Reference List

[0010] Non-patent literature

[0011] Non-patent document 1: Paludan, SR and Bowie, AG, Immunity, 2013, 38(5), 870-880

[0012] Non-patent document 2: Motwani M. et al., Nature Reviews Genetics (Nat. Rev. Genet.), 2019, 20(11), 657-674

[0013] Non-patent document 3: Liu, Y. et al., New England Journal of Medicine (N. Engl. J. Med.), 2014, 371(6), 507-518

[0014] Non-patent document 4: Jeremiah, N. et al., Journal of Clinical Research (J. Clin. Invest.), 2014, 124 (12), 5516-5520

[0015] Non-patent document 5: Mackenzie, KJ et al., ENBO J., 2016, 35(8), 831-844

[0016] Non-patent document 6: An, J. et al., Arthritis Rheumatol., 2017, 69(4), 800-807

[0017] Non-patent document 7: Kato, Y. et al., Ann. Rheum. Dis., 2018, 77(10), 1507-1515

[0018] Non-patent document 8: Zeng, L. et al., Sci. Transl. Med., 2017, 9(412)

[0019] Non-patent document 9: Hu, Q. et al., EBio Medicine, 2019, 41, 497-508

[0020] Non-patent literature 10: Yu, Y. et al., Journal of Clinical Research, 2019, 129(2), 546-555

[0021] Non-patent document 11: Iracheta-Vellve, A. et al., Journal of Biological Chemistry (J. Biol. Chem.), 2016, 291(52), 26794-26805

[0022] Non-patent document 12: Maekawa, H. et al., Cell Rep., 2019, 29(5), 1261-1273.e6

[0023] Non-patent document 13: Ahn, J. et al., Proc. Natl. Acad. Sci. USA, 2012, 109(47), 19386-19391

[0024] Non-patent document 14: Andrea, A. and Chen, ZJ, Science, 2019, 363(6431)

[0025] Non-patent document 15: Sliter, DA et al., Nature, 2018, 561(7722), 258-262 Summary of the invention

[0026] Problems to be solved by the present invention

[0027] The object of the present invention is to provide a pharmaceutical agent, in particular a novel benzimidazole derivative or a pharmaceutically acceptable salt thereof, which has an active inhibitory effect on STING pathway activation.

[0028] Ways to solve the problem

[0029] The objectives of the present invention are achieved by the following (1) to (9):

[0030] A benzimidazole derivative or a pharmaceutically acceptable salt thereof, which is represented by:

[0031] (1) Formula (I):

[0032] [Chemical formula 1]

[0033]

[0034] (A 1 Represents nitrogen atom or CR 7 , A 2 Represents nitrogen atom or CR 8 , A 3 Represents nitrogen atom or CR 9 ,

[0035] R 1 is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted carbamoyl group, a 4-morpholinecarbonyl group, a cyano group, a carboxyl group or an alkoxycarbonyl group,

[0036] R 2 , R 3 , R 4 and R 5 each independently and optionally selected from the group consisting of a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted cycloalkyloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted heterocyclicoxy group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted aminosulfonyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, and a nitro group, wherein R 2 and R3 or R 3 and R 4 or R 4 and R 5 can bond to each other to form a ring,

[0037] R 6 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclyl group or a substituted or unsubstituted amino group,

[0038] R 7 , R 8 and R 9 Each is independently and optionally selected from the group consisting of a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxyl group, a substituted or unsubstituted amino group, and a substituted or unsubstituted carbamoyl group.)

[0039] (2) The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to (1) above, wherein in formula (I), 1) A 1 Yes CR 7 , A 2 Yes CR 8 , A 3 Yes CR 9 ; 2) A 1 is a nitrogen atom, A 2 Yes CR 8 , A 3 Yes CR 9 ; 3) A 1 Yes CR 7 , A 2 is a nitrogen atom, A 3 Yes CR 9 ; 4) A 1 Yes CR 7 , A 2 Yes CR 8 , A 3 is a nitrogen atom, or 5) A 1 and A 3 Both represent nitrogen atoms and A 2 Represents CR 8 .

[0040] (3) The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to (1) or (2) above, wherein in formula (I), A 2 Represents CR8 , 1) A 1 Yes CR 7 , A 3 Yes CR 9 ; 2) A 1 is a nitrogen atom, A 3 Yes CR 9 ; or 3) A 1 Represents CR 7 And A 3 Represents a nitrogen atom.

[0041] (4) The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to (1) or (2) above, wherein in the above formula (1), A 1 , A 2 and A 3 CR 7 , CR 8 and CR 9 express.

[0042] (5) The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to (1) or (2) above, wherein in the above formula (I), A 1 is a nitrogen atom, and A 2 and A 3 CR 8 and CR 9 .

[0043] (6) The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to (1) or (2) above, wherein in the above formula (I), A 1 Yes CR 7 , A 2 is a nitrogen atom, and A 3 Yes CR 9 .

[0044] (7) The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to (1) or (2) above, wherein in the above formula (I), A 1 Yes CR 7 , A 2 Yes CR 8 , and A 3 It's a nitrogen atom.

[0045] (8) The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to (1) or (2) above, wherein in the above formula (I), A 1 and A 3 are nitrogen atoms and A 2 Yes CR 8 .

[0046] (9) The compounds of Examples 1 to 288 described below or their pharmaceutically acceptable salts.

[0047] Effect of the Invention

[0048] The present inventors have conducted various studies to solve the above problems, and as a result, the novel benzimidazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof exhibits excellent STING pathway activation inhibitory activity, and the present invention has been completed. The compounds provided by the present invention are effective as preventive or therapeutic drugs (pharmaceutical compositions) for diseases known to be associated with STING-mediated cellular responses, such as inflammatory diseases, autoimmune diseases, cancer, etc. In addition, by combining with therapeutic agents for other inflammatory diseases, autoimmune diseases and cancers, effects on immune responses, etc. can be expected, and it can be used as a therapeutic drug (pharmaceutical composition). In addition, it can be used as a STING inhibitor and can be used as a reagent for experimental studies. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] [ Figure 1 ] Example showing the IL-6 production inhibitory effect of representative compounds on a mouse model stimulated by a STING agonist (Test Example 2)

[0050] [ Figure 2 ] Example showing the IFN-β production inhibitory effect of representative compounds on a mouse model stimulated by a STING agonist (Test Example 2)

[0051] [ Figure 3 ] Example showing the inhibitory effect of representative compounds on TNF-α production in a mouse model stimulated by a STING agonist (Test Example 2) DETAILED DESCRIPTION

[0052] Hereinafter, the present invention will be described in detail.

[0053] The novel benzimidazole derivatives of the present invention are compounds represented by the general formula (I):

[0054] [Chemical formula 2]

[0055]

[0056] It has a basic skeleton in which a bicyclic nitrogen-containing heteroaromatic ring is substituted with a nitrogen atom at the 2nd position of the benzimidazole ring.

[0057] More specifically, in the above formula (I), A 1 Represents nitrogen atom or CR 7 , A 2 Represents nitrogen atom or CR 8 , and A 3 Represents nitrogen atom or CR9 .

[0058] In addition, R 1 It may be a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted carbamoyl group, a 4-morpholinecarbonyl group, a cyano group, a carboxyl group or an alkoxycarbonyl group.

[0059] R 2 , R 3 , R 4 and R 5 R is each independently and optionally selected from the group consisting of a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted cycloalkyloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted heterocyclicoxy group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted aminosulfonyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, or a nitro group. 2 and R 3 or R 3 and R 4 or R 4 and R 5 may be bonded to each other to form a ring.

[0060] R 6 It may be a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted amino group.

[0061] R 7 , R 8 and R 9 Each may be independently and optionally selected from the group consisting of a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted carbamoyl group.

[0062] An embodiment of the benzimidazole derivatives of the present invention of formula (I) includes benzimidazole derivatives or pharmaceutically acceptable salts, wherein A 1 , A 2 and A 3 CR 7 , CR 8 and CR 9 express.

[0063] Another embodiment of the benzimidazole derivatives of the present invention of formula (I) includes benzimidazole derivatives or pharmaceutically acceptable salts, wherein A 1 is a nitrogen atom; A 2 and A 3 CR 8 and CR 9 .

[0064] Another embodiment of the benzimidazole derivatives of the present invention of formula (I) includes benzimidazole derivatives or pharmaceutically acceptable salts, wherein A 1 Yes CR 7 , A 2 is a nitrogen atom and A 3 Yes CR 9 .

[0065] Another embodiment of the benzimidazole derivatives of the present invention of formula (I) includes benzimidazole derivatives or pharmaceutically acceptable salts, wherein A 1 Yes CR 7 , A 2 Yes CR 8 And A 3 It's a nitrogen atom.

[0066] Another embodiment of the benzimidazole derivatives of the present invention of formula (I) includes benzimidazole derivatives or pharmaceutically acceptable salts, wherein A 1 and A 3 are nitrogen atoms and A 2 Yes CR 8 .

[0067] Another embodiment of the benzimidazole derivatives of the present invention of formula (I) includes the compounds of the following Examples 1 to 288 or pharmaceutically acceptable salts thereof.

[0068] The terms used in this specification are explained as follows.

[0069] Unless otherwise specified, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0070] Unless otherwise specified, unsubstituted alkyl (also referred to simply as alkyl) means a straight or branched chain saturated hydrocarbon group (C1-4 alkyl) having 1 to 4 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

[0071] Unsubstituted alkenyl (also simply referred to as alkenyl) means a straight or branched hydrocarbon group (C2-6 alkenyl) having 2 to 6 carbon atoms and having at least one carbon-carbon double bond. Specific examples include vinyl, allyl, 1-propenyl, isopropenyl and 2-methylallyl.

[0072] Unsubstituted alkynyl (also simply referred to as alkynyl) means a straight or branched hydrocarbon group (C2-6 alkynyl) having 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. Specific examples include ethynyl, 1-propynyl, 2-propynyl, 1-butenyl, 2-butenyl and 3-butenyl.

[0073] The unsubstituted cycloalkyl group (also simply referred to as cycloalkyl) means a cyclic alkyl group having 3 to 7 carbon atoms (C3-7 cycloalkyl group), specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0074] Unsubstituted cycloalkenyl (also referred to as cycloalkenyl) means a cyclic hydrocarbon group having 3 to 7 carbon atoms (C3-7 cycloalkenyl) and having at least one double bond. Specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.

[0075] Unsubstituted alkoxy (also simply referred to as alkoxy) is a monovalent substituent (C1-4 alkoxy) in which an alkyl group is bonded to the substituted position via an oxygen atom (-O-). Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and the like.

[0076] Unsubstituted cycloalkyloxy (also simply referred to as cycloalkyloxy) is a monovalent substituent in which the cycloalkyl group is a monovalent substituent (C3-7 cycloalkyloxy) bonded to the substituent position via an oxygen atom (-O-). Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and the like.

[0077] The unsubstituted aryl group (also simply referred to as aryl) means a monocyclic or bicyclic aromatic group having 6 to 14 carbon atoms, such as phenyl, naphthyl and indenyl.

[0078] Unsubstituted heteroaryl (also referred to as heteroaryl) is a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms independently selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms. Specific examples include bicyclic heteroaryl groups, especially pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl, isoquinolyl, imidazopyridinyl, benzopyranyl and the like.

[0079] In the present specification, a 5- or 6-membered monocyclic nitrogen-containing heteroaryl group such as pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like is preferably used.

[0080] An unsubstituted aryloxy group (also simply referred to as an aryloxy group) is a monovalent substituent in which an aryl group is bonded to a substituted position via an oxygen atom (-O-). Specific examples include phenoxy, naphthoxy, indenyloxy, and the like.

[0081] Unsubstituted heteroaryloxy (also simply referred to as heteroaryloxy) is a monovalent substituent in which the heteroaryl group is bonded to the substituted position via an oxygen atom (-O-). Specific examples include furanyloxy, thienyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, oxazolyloxy, thiazolyloxy, triazolyloxy, tetrazolyloxy, pyridyloxy, pyrazinyloxy, pyrimidinyloxy, pyridazinyloxy, and the like.

[0082] The unsubstituted heterocyclic group (also referred to as heterocyclic group) means a 3- to 8-membered saturated or partially saturated heterocyclic group containing at least one heteroatom selected from nitrogen, sulfur and oxygen atoms. Specific examples include morpholino, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and the like.

[0083] The unsubstituted heterocyclic oxy group (also simply referred to as heterocyclic oxy group) is a monovalent substituent in which a heterocyclic group is bonded to a substitution position via an oxygen atom (-O-). Specific examples include methylpiperidinyloxy, oxetanyloxy, pyranyloxy, and the like.

[0084] The unsubstituted arylsulfonyl group (also simply referred to as an arylsulfonyl group) is a monovalent substituent in which an aryl group is bonded via a sulfonyl group (-SO2-). Specific examples include benzenesulfonyl, naphthylsulfonyl, and the like.

[0085] The alkoxy group of the alkoxycarbonyl group is the same as the above alkoxy group.

[0086] In the above formula (I), "R 2 and R 3 or R 3 and R 4 or R4 and R 5 The ring portion of " contains at least one heteroatom selected from a nitrogen atom and an oxygen atom. An optionally substituted saturated or unsaturated hetero 5-membered or hetero 6-membered ring is exemplified. A specific example is 1,4-dioxane condensed with an aromatic ring.

[0087] Substituents for the above terms will now be described.

[0088] A halogen atom is exemplified as a substituent of the substituted alkyl group, and one or more of the same or different halogen atoms may be substituted at any position. Specifically, a trifluoromethyl group is exemplified as a substituted alkyl group.

[0089] Other substituents of the substituted alkyl group include hydroxyl, methoxy, dimethylamino, cyclopropyl, dimethylcarbamoyl, cyano, morphonyl group, etc. One or more of the same or different substituents including a halogen atom may be substituted at any position of the alkyl group.

[0090] The substituents for the substituted alkenyl group, substituted alkynyl group, and substituted alkoxy group are the same as the substituents for the substituted alkyl group.

[0091] Examples of the substituent on the substituted amino group include the alkyl groups described above, and one alkyl group or two identical or two different alkyl groups may be used for substitution. Specifically, a dimethylamino group is exemplified as the substituted amino group.

[0092] Examples of the substituent on the substituted carbamoyl group include the alkyl groups described above, and one alkyl group or two identical or two different alkyl groups may be used for substitution. In addition, phenyl and propargyl groups can be cited as specific examples of substituents other than the alkyl group.

[0093] Examples of substituents for the substituted cycloalkyl group, substituted cycloalkenyl group, substituted aryl group and substituted heteroaryl group include a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, a nitro group, a cyano group or a methylsulfonyl group. Substituents for the substituted aryloxy group, the substituted heteroaryloxy group and the substituted arylsulfonyl group are the same as those for the substituted aryl group, the substituted heteroaryl group and the substituted aryl group, respectively.

[0094] In the compound of the present invention represented by formula (1), R 1 to R 9 The definitions and preferred ranges are as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.

[0095] R 1Examples include a hydrogen atom, a halogen atom, an optionally substituted C1-4 alkyl group (e.g., an optionally halogen-substituted C1-4 alkyl group), a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-7 cycloalkyl group, a C3-7 cycloalkenyl group, a C1-4 alkoxy group, a phenyl group, a C1-4 alkoxycarbonyl group, a carboxyl group, a cyano group, a phenylcarbamoyl group, a 2-propynylcarbamoyl group, a 4-morpholinecarbonyl group, etc. The halogenated C1-4 alkyl group is exemplified by a trifluoromethyl group.

[0096] R 2 to R 5 The group may independently and optionally include a hydrogen atom, a halogen atom, an optionally substituted C1-4 alkyl group (e.g., optionally substituted with halogen and / or C1-4 alkoxy), an optionally substituted C2-6 alkenyl group (e.g., C1-4 alkoxy, optionally substituted with halogen and / or cyclopropyl), an optionally substituted C2-6 alkynyl group (e.g., C1-4 alkoxy, optionally substituted with cyclopropyl and / or dimethylamino), a C3-7 cycloalkyl group (e.g., cyclopropyl), an optionally substituted C1-4 alkoxy group (e.g., optionally substituted with C1-4 alkoxy), a C3-7 cycloalkyloxy group (e.g., cyclohexyloxy), an optionally substituted phenyl group (e.g., optionally substituted with halogen or morpholinomethyl) substituted with methyl, substituted with phenyl, substituted with methylsulfonyl, dimethylamino, cyano, optionally substituted with halogen atoms and / or dimethylaminomethyl, optionally substituted with monocyclic nitrogen-containing heteroaryl (e.g., pyridyl, methylpyrazolyl, etc.), optionally substituted with monocyclic nitrogen-containing heteroaryloxy (e.g., pyridyloxy, methylpyrazinyloxy, etc.), heterocyclic (e.g., dihydropyranyl, tetrahydropyranyl, piperidinyl), heterocyclic oxy (e.g., oxetanyloxy, tetrahydropyranyloxy, piperidinyl)oxy, etc.), substituted aminosulfonyl (e.g., N-methyl, N-phenylaminosulfonyl, etc.), dimethylcarbamoyl, benzyloxy, cyano, nitro, carboxyl, methoxycarbonyl, etc. Here, the halogenated C1-4 alkyl includes a trifluoromethyl group, and the halogenated C1-4 alkoxy includes a trifluoromethyloxy group.

[0097] R 2 and R 3 , R 3 and R 4 or R 4 and R 5 They may be bonded to each other to form a ring, and the formed ring is exemplified by 1,4-dioxane condensed with an aromatic ring.

[0098] R 6It can be a hydrogen atom, an optionally substituted C1-4 alkyl group (for example, optionally substituted with hydroxyl, cyclopropyl, C1-4 alkoxy, dimethylamino, dimethylcarbamoyl or methylsulfonyl), a C2-6 alkenyl, a C2-6 alkynyl, a C3-7 cycloalkyl group, an optionally substituted amino group (for example, dimethylamino, methylamino, amino, etc.), an optionally substituted heteroaryl group (for example, pyridyl, methylimidazolyl, etc.) or a heterocyclic group (for example, oxetanyl, pyrrolidinyl, etc.).

[0099] R 7 to R 9 It may include a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C2-6 alkenyl group, a C3-7 cycloalkyl group, a C1-4 alkoxy group, a phenyl group, a monocyclic nitrogen-containing heteroaryl group (e.g., a pyridyl group, a methylpyrazolyl group, etc.), a hydroxyl group, a dimethylamino group, or a dimethylcarbamoyl group.

[0100] Compound (I) of the present invention may have isomers depending on, for example, the type of substituent. In this specification, although the chemical structure of only one form of isomer is described, the present invention also includes all isomers (geometric isomers, optical isomers, tautomers, etc.) that may appear in the structure, and also includes single isomers and mixtures thereof.

[0101] In the present invention, "hydrogen atom" includes 1 H and 2 H(D). By mixing any one or two or more of the compounds represented by formula (I) 1 H is converted into 2 The deuterium conversion product obtained by H(D) is also included in the compound represented by formula (I).

[0102] In addition, pharmaceutically acceptable salts of the compound (I) of the present invention include inorganic acid salts of hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid, etc. and organic acid salts of formic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. In addition, the present invention also includes alkali metal salts with sodium, potassium, etc., alkaline earth metal salts with magnesium, calcium, etc., organic amine salts with lower alkylamines and lower alcoholamines, etc., basic amino acid salts with lysine, arginine and ornithine, etc., and ammonium salts, etc.

[0103] The compound (I) of the present invention and its pharmaceutically acceptable salt include internal salts and solvates such as hydrates.

[0104] Compound (I) of the present invention and its pharmaceutically acceptable salt can be produced, for example, by the following method. In the production method shown below, if the defined group changes under the conditions of the method or is not suitable for carrying out the method, it can be easily produced by the commonly used methods in organic synthetic chemistry, for example, by means of protection or deprotection of functional groups [TWGreene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc., 1999]. In addition, the order of reaction steps (such as introducing substituents) can be changed as needed.

[0105] The following general reaction scheme is used to detail the synthesis of the benzimidazole derivatives disclosed in the present invention. The compounds of the present invention of formula (I) disclosed herein can be prepared by the methods described in the following schemes 1-5 and by the general synthesis methods provided in the examples. They can be produced by modifying the general synthesis methods, commercially available starting materials, starting materials that can be synthesized from commercially available compounds by known methods or methods similar thereto, or methods well known to those skilled in the art.

[0106] Each variable depicted 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.

[0107] Abbreviations and symbols used in the following description have the following meanings.

[0108] DMF: N, N-dimethylformamide

[0109] NMP: N-methylpyrrolidone

[0110] THF: Tetrahydrofuran

[0111] DMSO: dimethyl sulfoxide

[0112] Boc: tert-Butyloxycarbonyl

[0113] Boc2O: di-tert-butyl dicarbonate

[0114] CDI: 1,1′-Carbonyldiimidazole

[0115] EDCI / HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0116] DIPEA: N,N-diisopropylamine

[0117] [Method for producing compound (I) of the present invention]

[0118] The compounds of the present invention represented by formula (I) can be prepared, for example, by the following Scheme 1:

[0119] [Process 1]

[0120] [Chemical formula 3]

[0121]

[0122] (A 1 , A 2 , A 3 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each as defined above).

[0123] Compound (I) of the present invention can be produced by subjecting the benzimidazole skeleton to a nucleophilic substitution reaction using compound (II). That is, compound (I) of the present invention can be obtained by reacting compound (II) with 0.5 to 5 molar equivalents of compound (III) in a solvent in the presence of an acid. Any solvent can be used as long as it is inert to the reaction, and is not particularly limited. For example, DMF, THF, NMP, 1,4-dioxane, ethanol, isopropanol, n-butanol, 2-butanol, etc. can be used, but preferably NMP or 1,4-dioxane, etc. can be used. The acid used in the reaction is not particularly limited, and an inorganic acid or an organic acid can be used. For example, hydrochloric acid, p-toluenesulfonic acid, etc. are generally used. The amount of the acid used can be an equivalent or excess relative to compound (II). Preferably, in the case of hydrochloric acid, 4N hydrochloric acid / 1,4-dioxane solution, etc. are mentioned, and in the case of p-toluenesulfonic acid, it is 1 to 5 molar equivalents. The reaction can be carried out in the range of 0°C to 200°C for several minutes to several days. This can be carried out by reacting for 5 to 48 hours.

[0124] Furthermore, the compound represented by formula (I) can also be obtained under the same conditions as in Scheme 1 using a compound in which the amino group of compound (II) is protected by a protecting group which can be deprotected under acidic conditions, such as a Boc group.

[0125] Compound (II) used as a starting material in Scheme 1 is commercially available, or it can be prepared from compound (IV) using, for example, Scheme 2 below.

[0126] [Process 2]

[0127] [Chemical formula 4]

[0128]

[0129] (A 1 , A 2 , A 3 and R 1 Same as defined above).

[0130] Compound (II) can be produced by reducing the nitro group of compound (IV). That is, compound (II) can be obtained by subjecting compound (IV) in a solvent to a reduction method commonly used in synthetic organic chemistry, such as catalytic reduction using palladium carbon or metal reduction using tin, zinc, iron or the like, to form a nitro group.

[0131] Furthermore, a compound in which the amino group of compound (II) is protected with a Boc group can be obtained by reacting compound (IV) with Boc2O in a solvent in the presence of a metal such as ammonium chloride and zinc.

[0132] Compound (IV) used as a starting material in Scheme 2 is available as a commercial product, or can be produced from Compound (V) according to, for example, the following Scheme 3.

[0133] [Process 3]

[0134] [Chemical formula 5]

[0135]

[0136] (A 1 , A 2 , A 3 and R 1 Same as defined above).

[0137] Compound (IV) can be produced by nitrating compound (V). That is, compound (IV) can be obtained by reacting compound (V) under nitration reaction conditions generally used in organic chemistry, such as under a mixed acid of fuming nitric acid, concentrated sulfuric acid and nitric acid. Although the nitrating agent is not particularly limited, for example, 1 to 5 molar equivalents of potassium nitrate can be used in the presence of concentrated sulfuric acid. The reaction can be carried out at -20°C to 50°C for several minutes to several days, but is preferably carried out at -20°C to 0°C for 10 minutes to 1 hour.

[0138] In addition, compound (IV) can also be produced by a known method or a similar method [e.g. Bioorg. Med. Chem. 2007, 15, 3248-3265 or Tetrahedron Letters 2012, 53, 4841-4842]. That is, compound (IV) can be obtained by reacting compound (V) with 1 to 5 molar equivalents of a nitrating agent and 1 to 5 molar equivalents of an acyl chloride in a solvent.

[0139] Compound (V) used as a starting material in Scheme 3 is available as a commercial product, or can be produced by a known method or a method analogous thereto [eg, J. Org. Chem. 2010, 75, 11-15].

[0140] Compound (III) used as a starting material in Scheme 1 is available as a commercial product or can be produced from Compound (VI), for example, in Scheme 4 below.

[0141] [Process 4]

[0142] [Chemical formula 6]

[0143]

[0144] (where R 2 , R 3 , R 4 , R5 and R 6 each as defined above).

[0145] Compound (III) can be produced by chlorinating compound (VI). That is, compound (III) can be obtained by treating compound (VI) with a chlorinating agent such as phosphorus oxychloride, or optionally in the presence of a solvent. The reaction can be carried out at a temperature ranging from 0°C to 200°C for several minutes to several days, but preferably at 70°C to 150°C for 1 hour to 24 hours.

[0146] Compound (VI) used as a starting material in Scheme 4 is obtained as a commercial product, or can be produced from Compound (VII), for example, in the following Scheme 5.

[0147] [Process 5]

[0148] [Chemical formula 7]

[0149]

[0150] (where R 2 , R 3 , R 4 , R5 and R 6 each as defined above).

[0151] Compound (VI) can be produced by converting two adjacent amino groups of compound (VII) into cyclic urea. That is, compound (VI) can be obtained by reacting compound (VII) with a carbonylation agent such as triphosgene or CDI in a solvent. Any solvent can be used as long as it is inert to the reaction. Dichloromethane, NMP, DMF, THF, etc. can be used, but THF is preferably used. The reaction can be carried out in the range of 0°C to 150°C for several minutes to several days, but preferably at room temperature to 100°C for 10 minutes to 24 hours.

[0152] Compound (VII) used as a starting material in Scheme 5 is commercially available, or it can be produced by a known method or a method analogous thereto [e.g., J. Med. Chem. 2011, 54, 7920-7933 and J. Org. Chem. 2017, 82, 9243-9252].

[0153] The compounds of the present invention represented by formula (I) can be produced by the method shown in Scheme 1 and by the method shown in Scheme 6 below.

[0154] [Process 6]

[0155] [Chemical formula 8]

[0156]

[0157] (A 1 , A 2 , A 3 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each as defined above).

[0158] Compound (I) of the present invention can be produced by cyclizing the thiourea derivative obtained by reacting compound (VII) with compound (VIII). That is, compound (I) of the present invention is a thiourea derivative obtained by reacting compound (VII) with 0.5 to 1.5 molar equivalents of compound (VIII) in a solvent. It can be obtained by using the condensation conditions commonly used in synthetic organic chemistry, such as the cyclization reaction of a condensing agent such as EDCI / HCl using 1 to 3 molar equivalents. In the synthesis of thiourea derivatives, any solvent can be used as long as it is inert to the reaction, and chloroform, THF, DMF, NMP, etc. can be used, but DMF can be preferably used. The reaction can be carried out in the range of 0°C to 100°C for several minutes to several days, but preferably at room temperature to 80°C for 10 minutes to 24 hours. The thiourea derivative obtained by the reaction can be directly used in the next reaction without purification, but the purified product can also be subjected to condensation cyclization reaction. In the condensation cyclization reaction, any solvent can be used as long as it is inert to the reaction, and is not subject to specific restrictions. For example, DMF, THF, NMP, etc. can be used, but DMF can be preferably used. The reaction can be carried out at a range of 0°C to 100°C for several minutes to several days. Preferably, the reaction can be carried out at room temperature to 80°C for 5 hours to 24 hours.

[0159] Compound (VIII) used as a starting material in Scheme 6 can be produced from compound (II) as shown in Scheme 7, for example.

[0160] [Process 7]

[0161] [Chemical formula 9]

[0162]

[0163] (A 1 , A 2 , A 3 and R 1 Same as defined above).

[0164] Compound (VIII) can be produced by converting the amino group of compound (II) into an isothiocyanate group. That is, compound (VIII) can be obtained by reacting compound (II) with 1 to 3 molar equivalents of an isothiocyanate reagent such as thiophosgene in the presence of 1 to 3 molar equivalents of a base such as DIPEA in a solvent. Any solvent can be used as long as it is inert to the reaction, and chloroform, THF, etc. can be used, but THF is preferably used. The reaction can be carried out at 0°C to room temperature for several minutes to several days, but is preferably carried out at room temperature for 10 minutes to 24 hours.

[0165] The compound (I) of the present invention having a desired functional group at a desired position can be obtained by appropriately combining the above methods and performing a method commonly used in organic synthetic chemistry (e.g., alkylation reaction of an amino group, reaction of converting a carboxyl group into a substituted or unsubstituted carboxamide group, cross-coupling reaction such as Suzuki-Miyaura reaction, and reduction of a carbon-carbon double bond by hydrogenation reaction).

[0166] [Uses of the Compound (I) of the Present Invention]

[0167] The compound (I) or pharmaceutically acceptable salt of the present invention can be prepared in the form of conventional pharmaceutical formulations (pharmaceutical compositions) suitable for oral, parenteral or topical administration.

[0168] Preparations for oral administration include solid preparations, such as tablets, granules, powders and capsules, and liquid preparations, such as syrups. These preparations can be prepared by conventional methods. Solid preparations can be prepared by using conventional pharmaceutical carriers, such as lactose, starch (such as corn starch), microcrystalline cellulose (such as microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium), talc, magnesium stearate, etc. Capsules can be prepared by encapsulating the prepared granules or powders. Syrups can be prepared by dissolving or suspending the compound (I) of the present invention or its pharmaceutically acceptable salt in an aqueous solution containing sucrose, carboxymethyl cellulose, etc.

[0169] Preparations for parenteral administration include injections, such as infusions. Injection preparations can also be prepared by conventional methods and include tonicity agents (e.g., mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose and mannose), stabilizers (e.g., sodium sulfite and albumin) and preservatives (e.g., benzyl alcohol and methyl paraben) as needed.

[0170] The dosage of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may vary depending on the severity of the disease, the age and weight of the patient, the dosage form, etc., but the usual range for adults is 1 mg to 1,000 mg per day, which can be administered by oral or parenteral routes in a single dose or in 2 or 3 divided doses.

[0171] The compound (I) or pharmaceutically acceptable salt of the present invention can also be used as a STING inhibitor and as a reagent for experiments and studies.

[0172] Furthermore, the radiolabeled compound (I) of the present invention can also be used as a molecular probe for PET.

[0173] Example

[0174] The present invention will be described in more detail with reference to the following Examples and Test Examples, but the present invention is not limited to these Examples.

[0175] 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 depending on the compound and the measurement conditions, exchangeable hydrogen may not be clearly observed. In addition, br means a broad signal (broad). For HPLC preparative chromatography, commercially available ODS columns are used, and water / acetonitrile (containing formic acid) or water / methanol (containing formic acid) are used as eluents to perform classification in gradient mode.

[0176] Example 1

[0177] Preparation of N-(5-bromo-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0178] [Chemical formula 10]

[0179]

[0180] To a 1,4-dioxane solution (1 mL) containing tert-butyl 2-chloro-1H-benzo[d]imidazole-1-carboxylate (20 mg, 0.079 mmol) and 5-bromo-1H-indol-3-amine (18.38 mg, 0.087 mmol) was added 4N hydrochloric acid / 1,4-dioxane solution (0.087 mmol), and the mixture was stirred at 120° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 10: 0-9: 1) to obtain the title compound (4 mg).

[0181] 1 H NMR(400MHz, DMSO-d6)δ 11.02 (s, 1H), 10.71 (s, 1H), 9.06 (s, 1H), 7.85 (d, J = 2.0Hz, 1H), 7.82 (d, J = 2.5Hz, 1H ), 7.27-7.17 (m, 1H), 7.21 (dd, J=8.6, 2.0Hz, 3H), 6.93 (s, 2H); LCMS (m / z) 329.1[M+H] + .

[0182] Example 2

[0183] Preparation of N-(5-phenyl-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0184] [Chemical formula 11]

[0185]

[0186] (First step)

[0187] To an 80% 1,4-dioxane aqueous suspension (2.5 mL) containing 5-bromo-3-nitro-1H-indole (80 mg, 0.332 mmol), phenylboronic acid (50.6 mg, 0.415 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27.1 mg, 0.033 mmol) was added sodium carbonate (106 mg, 0.996 mmol), and heated to reflux for 18 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to the reaction mixture to separate the organic layer. The aqueous layer was extracted with ethyl acetate, and the obtained organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1) to produce 3-nitro-5-phenyl-1H-indole (44 mg).

[0188] LCMS (m / z) 239.2 [M+H] + .

[0189] (Second step)

[0190] 3-nitro-5-phenyl-1H-indole (43 mg, 0.180 mmol) was dissolved in ethanol (2 mL), and 10% palladium on carbon (10 mg) was added. The reaction was carried out at room temperature under a hydrogen atmosphere for 3 hours. After filtering the insoluble material, the filtrate was concentrated to give 5-phenyl-1H-indole-3-amine (30 mg).

[0191] LCMS (m / z) 209.2 [M+H] + .

[0192] (Third step)

[0193] 5-phenyl-1H-indole-3-amine (29mg, 0.139mmol) and 2-chloro-1H-benzo[d]imidazole (25.5mg, 0.167mmol) are added to 4N hydrochloric acid / 1,4-dioxane solution (1mL) and stirred for 2 hours at 100°C. The reaction mixture is cooled to room temperature, and ethyl acetate and saturated sodium bicarbonate aqueous solution are added, and the organic layer is separated. The water layer is extracted with ethyl acetate, and the obtained organic layer is merged, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by HPLC preparative chromatography to obtain the title compound (1.1mg) in the form of formate.

[0194] 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 1H), 7.73-7.70 (m, 1H), 7.62-7.57 (m, 2H), 7.53-7.46 (m, 3H), 7.39-7.33 (m, 2H), 7.28-7.21 (m, 3H), 7.10-7.05 (m, 2H); LCMS (m / z) 325.2 [M+H] + .

[0195] Example 3

[0196] Preparation of N-(5-bromo-1H-indol-3-yl)-5-phenoxy-1H-benzo[d]imidazol-2-amine

[0197] [Chemical formula 12]

[0198]

[0199] (First step)

[0200] 4-Phenoxybenzene-1,2-diamine (426 mg, 2.13 mmol) and CDI (517 mg, 3.19 mmol) were added to THF (15 mL) and stirred at room temperature for 0.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 1: 0-0: 1) to obtain 5-phenoxy-1,3-dihydro-2H-benzo [d] imidazole-2-one (280 mg).

[0201] LCMS (m / z) 227.2 [M+H]+.

[0202] (Second step)

[0203] A mixture of 5-phenoxy-1,3-dihydro-2H-benzo[d]imidazole-2-one (280 mg, 1.24 mmol) and phosphorus oxychloride (4.6 mL) was stirred at 100° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and ice was added, and ethyl acetate and saturated sodium bicarbonate aqueous solution were added, and the organic layer was separated. The obtained organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2-chloro-5-phenoxy-1H-benzo[d]imidazole (280 mg).

[0204] LCMS (m / z) 245.2 [M+H] + .

[0205] (Third step)

[0206] 5-Bromo-1H-indole-3-amine (12 mg, 0.057 mmol) and 2-chloro-5-phenoxy-1H-benzo[d]imidazole (13.9 mg, 0.057 mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (1 mL) and stirred at 120° C. for 1 hour. To complete the reaction, 5-bromo-1H-indole-3-amine (6 mg, 0.029 mmol) was further added and stirred at 120° C. for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1, then ethyl acetate: methanol = 1: 0-0: 1) to obtain the title compound (8.3 mg).

[0207] 1 H NMR(400MHz, DMSO-d6)δ 11.03(s, 1H), 10.75-10.65(m, 1H), 9.11(s, 1H), 7.85-7.80(m, 2H), 7.40-7.28(m, 3H), 7.27- 7.14(m, 2H), 7.11-6.99(m, 1H), 6.99-6.83(m, 3H), 6.78-6.59(m, 1H); LCMS(m / z)421.2[M+H] + .

[0208] Example 4

[0209] Preparation of N-(5-bromo-1H-indol-3-yl)-5-chloro-1H-benzo[d]imidazol-2-amine

[0210] [Chemical formula 13]

[0211]

[0212] 5- bromo-1H- indole-3-amine (30mg, 0.142mmol) and 2,5- dichloro-1H- benzo [d] imidazole (26.6mg, 0.142mmol) are added to 4N hydrochloric acid / 1,4- dioxane solution (1.5mL) and stirred overnight under reflux. After the reaction mixture is cooled to room temperature, the solvent is distilled off under reduced pressure, and the residue is crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1). The mixture is further purified by HPLC preparative chromatography to obtain the title compound (23mg) in the form of formate.

[0213] 1H NMR(400MHz, DMSO-d6)δ 11.06 (s, 1H), 10.94-10.84 (m, 1H), 9.21 (s, 1H), 8.15 (s, 1H), 7.82 (d, J=1.9Hz, 1H), 7.79 (d, J=2.5Hz, 1H), 7.35 (d, J=8.6Hz, 1H), 7.26-7.11 (m, 3H), 6.92 (brs, 1H); LCMS (m / z) 363.1[M+H] + .

[0214] Example 5

[0215] Preparation of N-(5-bromo-1H-indol-3-yl)-4-methyl-1H-benzo[d]imidazol-2-amine

[0216] [Chemical formula 14]

[0217]

[0218] 5-bromo-1H-indole-3-amine (30 mg, 0.142 mmol) and 2-chloro-4-methyl-1H-benzo[d]imidazole (22.5 mg, 0.135 mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (3 mL) and stirred overnight under reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was crudely purified by silica gel chromatography (chloroform: methanol=1: 0-9: 1), and further purified by HPLC preparative chromatography to obtain the title compound (6 mg) in the form of formate.

[0219] 1 H NMR(400MHz, DMSO-d6)δ 10.99 (s, 1H), 10.70 (s, 1H), 9.03 (s, 1H), 8.20 (s, 1H), 7.86-7.80 (m, 2H), 7.34 (d, J=8.6Hz, 1H ), 7.20 (dd, J=8.6, 1.9Hz, 1H), 7.02 (s, 1H), 6.77 (brs, 2H), 2.42 (s, 3H); LCMS (m / z) 343.1 [M+H] + .

[0220] Example 6

[0221] Preparation of N-(5-bromo-1H-indol-3-yl)-5-methoxy-1H-benzo[d]imidazol-2-amine

[0222] [Chemical formula 15]

[0223]

[0224] 5-bromo-1H-indole-3-amine (30 mg, 0.142 mmol) and 2-chloro-5-methoxy-1H-benzo [d] imidazole (23.36 mg, 0.128 mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (2 mL) and stirred overnight under reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1), and further purified by HPLC preparative chromatography to obtain the title compound (16 mg) in the form of formate.

[0225] 1 H NMR(400MHz, DMSO-d6)δ 10.97 (s, 1H), 10.52 (brs, 1H), 9.01 (s, 1H), 8.16 (s, 1H), 7.86 (d, J = 1.9Hz, 1H), 7.81 (d, J = 2.4Hz, 1H), 7.33 (d, J = 8 .6Hz, 1H), 7.20 (dd, J=8.6, 1.9Hz, 1H), 7.09 (s, 1H), 6.83 (s, 1H), 6.54 (s, 1H), 3.73 (s, 3H); LCMS (m / z) 357.1[M+H] + .

[0226] Example 7

[0227] Preparation of 5-bromo-N-(5-bromo-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0228] [Chemical formula 16]

[0229]

[0230] 5-bromo-1H-indole-3-amine (30 mg, 0.142 mmol) and 5-bromo-2-chloro-1H-benzo[d]imidazole (29.6 mg, 0.128 mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (2 mL) and stirred overnight under reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was crudely purified by silica gel chromatography (chloroform: methanol=1: 0-9: 1), and further purified by HPLC preparative chromatography to obtain the title compound (16 mg) in the form of formate.

[0231] 1H NMR(400MHz, DMSO-d6)δ 11.06 (s, 1H), 11.00-10.86 (m, 1H), 9.25 (s, 1H), 8.16 (s, 1H), 7.83 (d, J=1.9Hz, 1H), 7.79 (s, 1H), 7.39-7.31 (m, 2H), 7.21 (dd, J=8.6, 1.9Hz, 1H), 7.19-6.99 (m, 2H); LCMS (m / z) 407.1 [M+HI + .

[0232] Example 8

[0233] Preparation of N-(5-bromo-1H-indol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

[0234] [Chemical formula 17]

[0235]

[0236] 5-Bromo-1H-indole-3-amine (30 mg, 0.142 mmol) and 2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (28.2 mg, 0.128 mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (2 mL) and stirred overnight under reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was crudely purified by silica gel chromatography (chloroform: methanol=1: 0-9: 1), and further purified by HPLC preparative chromatography to give the title compound (20 mg) in the form of formate.

[0237] 1 H NMR(400MHz, DMSO-d6)δ 11.27-11.07(m, 2H), 9.44-9.37(m, 1H), 8.17(s, 1H), 7.86-7.79(m, 2H), 7.49( d, J=19.9Hz, 1H), 7.41-7.32(m, 2H), 7.31-7.19(m, 2H); LCMS (m / z) 397.1[M+H] + .

[0238] Example 9

[0239] Preparation of N-(4-bromo-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0240] [Chemical formula 18]

[0241]

[0242] (First step)

[0243] Zinc powder (1.36 g, 20.83 mmol) and ammonium chloride (557 mg, 10.42 mmol) were added to methanol / water (10:3, 13 mL) containing 4-bromo-3-nitro-1H-indole (500 mg, 2.08 mmol) at 0°C, and stirred for 30 minutes at 0°C. Boc2O (545 mg, 2.50 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture and the organic layer was separated. The water layer was extracted with ethyl acetate, and the obtained organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain tert-butyl (4-bromo-1H-indol-3-yl)carbamate (250 mg).

[0244] LCMS (m / z) 311.4 [M+H] + .

[0245] (Second step)

[0246] To a mixture of tert-butyl (4-bromo-1H-indol-3-yl)carbamate (200 mg, 0.64 mmol) and 4N hydrochloric acid / 1,4-dioxane solution (4 mL) was added 2-chloro-1H-benzo[d]imidazole (98 mg, 0.64 mmol) and stirred at 120° C. for 16 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to make it alkaline, and the mixture was extracted with 10% methanol / dichloromethane. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was purified using HPLC preparative chromatography to give the title compound (11 mg) in the form of a formate salt.

[0247] 1 H NMR(500MHz, DMSO-d6)δ 11.38 (s, 1H), 10.81 (brs, 1H), 8.20 (s, 1H), 7.69 (d, J=1.5Hz, 1H), 7.43 (dd, J =0.6, 8.2Hz, 1H), 7.20-7.02(m, 5H), 6.91-6.78(m, 2H); LCMS (m / z) 327.4[M+H] + .

[0248] Example 10

[0249] N-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-phenoxy-

[0250] Preparation of 1H-benzo[d]imidazol-2-amine

[0251] [Chemical formula 19]

[0252]

[0253] 5- bromo-1H- pyrrolo [2,3-b] pyridine -3- amine (30mg, 0.141mmol) and 2- chloro-5-phenoxy -1H- benzo [d] imidazole (31.2mg, 0.127mmol) are added to a mixed solvent (2: 1, 3mL) of 4N hydrochloric acid / 1,4- dioxane solution and DMF. The mixture is stirred overnight under reflux. After the reaction mixture is cooled to room temperature, the solvent is distilled off under reduced pressure, and the residue is crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1), and further purified by HPLC preparative chromatography to obtain the title compound (13mg) in the form of formate.

[0254] 1 H NMR(400MHz, DMSO-d6)δ 11.61 (s, 1H), 11.11-10.92 (m, 1H), 9.37 (s, 1H), 8.32 (d, J = 2.2Hz, 1H), 8.28 (d, J = 2.2Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.33 (t, J=7.8Hz, 2H), 7.29-7.15 (m, 1H), 7.08-7.01 (m, 1H), 6.98-6.84 (m, 3H), 6.74-6.62 (m, 1H); LCMS (m / z) 422.2 [M+H] + .

[0255] Embodiment 11

[0256] N-(5-bromo-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-phenoxy-

[0257] Preparation of 1H-benzo[d]imidazol-2-amine

[0258] [Chemical formula 20]

[0259]

[0260] (First step)

[0261] Potassium nitrate (180 mg, 1.776 mmol) was added to concentrated sulfuric acid (3 mL) and stirred at 0° C. for 5 minutes. 5-Bromo-1H-pyrrolo[2,3-c]pyridine (250 mg, 1.269 mmol) was added, and the mixture was further stirred for 30 minutes at 0° C. Ice water was added to the reaction mixture, and the precipitated solid was collected by filtration and dried to give 5-bromo-3-nitro-1H-pyrrolo[2,3-c]pyridine (280 mg).

[0262] 1 H NMR (400MHz, DMSO-d6) δ 13.30 (s, 1H), 8.92 (d, J = 2.2Hz, 1H), 8.74 (d, J = 1.0Hz, 1H), 8.13 (d, J = 1.0Hz, 1H); LCMS (m / z) 242.01 [M+H] + .

[0263] (Second step)

[0264] A mixed solution of acetic acid / concentrated hydrochloric acid (1:1, 6 mL) containing 5-bromo-3-nitro-1H-pyrrolo[2,3-c]pyridine (230 mg, 0.95 mmol) was added to tin(II) chloride (901 mg, 4.75 mmol) and stirred at room temperature for 35 minutes. A 2M aqueous sodium hydroxide solution was added to terminate the reaction, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 5-bromo-1H-pyrrolo[2,3-c]pyridine-3-amine (50 mg).

[0265] 1 H NMR (400MHz, DMSO-d6) δ 10.79 (s, 1H), 8.33 (d, J = 1.0Hz, 1H), 7.73 (t, J = 0.9Hz, 1H), 6.91 (d, J = 2.3Hz, 1H), 4.32 (s, 2H); LCMS (m / z) 212.07 [M+H] + .

[0266] (Third step)

[0267] 5-bromo-1H-pyrrolo[2,3-c]pyridin-3-amine (40 mg, 0.189 mmol) was added with a NMP solution (2 mL) containing 2-chloro-5-phenoxy-1H-benzo[d]imidazole (46.2 mg, 0.189 mmol) and p-toluenesulfonic acid monohydrate (53.8 mg, 0.283 mmol), and stirred at 120° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 1: 0-9: 1) to obtain the title compound (30 mg).

[0268] 1 H NMR(400MHz, DMSO-d6)δ 11.52 (s, 1H), 10.90 (brs, 1H), 9.30 (s, 1H), 8.53 (d, J = 1.0Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.88 (t, J = 0.8Hz, 1H), 7 .38-7.27 (m, 2H), 7.23 (brs, 1H), 7.04 (t, J=7.3Hz, 1H), 6.96-6.89 (m, 3H), 6.69 (brs, 1H); LCMS (m / z) 422.2[M+H] + .

[0269] Example 12

[0270] N-(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-

[0271] Preparation of 1H-benzo[d]imidazol-2-amine

[0272] [Chemical formula 21]

[0273]

[0274] (First step)

[0275] Potassium nitrate (180 mg, 1.776 mmol) was added to concentrated sulfuric acid (3 mL) and stirred at room temperature for 1 minute. The reaction solution was cooled to 0 ° C and 5-bromo-1H-pyrrolo[3,2-b]pyridine (250 mg, 1.269 mmol) was added and the mixture was stirred at 0 ° C for 25 minutes. Ice water was added to the reaction mixture, and the precipitated solid was collected by filtration and dried to give 5-bromo-3-nitro-1H-pyrrolo[3,2-b]pyridine (300 mg).

[0276] 1H NMR (400MHz, DMSO-d6) δ12.97 (s, 1H), 8.88 (d, J = 3.7Hz, 1H), 7.95 (d, J = 8.6Hz, 1H), 7.54 (d, J = 8.6Hz, 1H); LCMS (m / z) 244.01 [M+H] + .

[0277] (Second step)

[0278] A mixed solution of acetic acid / concentrated hydrochloric acid (1:1, 6 mL) containing 5-bromo-3-nitro-1H-pyrrolo[3,2-b]pyridine (230 mg, 0.950 mmol) was added to tin(II) chloride (901 mg, 4.75 mmol) and stirred at room temperature for 30 minutes. A 2M aqueous sodium hydroxide solution was added to terminate the reaction, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 5-bromo-1H-pyrrolo[3,2-b]pyridine-3-amine (160 mg).

[0279] 1 H NMR (400MHz, DMSO-d6) δ 10.60 (s, 1H), 7.57 (d, J = 8.4Hz, 1H), 7.12 (d, J = 8.4Hz, 1H), 6.96 (d, J = 2.5Hz, 1H), 4.10 (s, 2H); LCMS (m / z) 214.02 [M+H] + .

[0280] (Third step)

[0281] 5-bromo-1H-pyrrolo[3,2-b]pyridin-3-amine (33 mg, 0.156 mmol) was added with a NMP solution (1 mL) containing 2-chloro-5-phenoxy-1H-benzo[d]imidazole (38.1 mg, 0.156 mmol) and p-toluenesulfonic acid monohydrate (44.4 mg, 0.233 mmol), and stirred at 120° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 3) to obtain the title compound (20 mg).

[0282] 1H NMR (400 MHz, methanol-d4) δ 7.80-7.68 (m, 2H), 7.32-7.19 (m, 4H), 7.07-7.01 (m, 1H), 6.96-6.91 (m, 3H), 6.76 (d, J = 7.8 Hz, 1H); LCMS (m / z) 422.2 [M+H] + .

[0283] Example 13

[0284] N-(5-bromo-1H-indol-3-yl)-5-(pyridin-3-yloxy)-

[0285] Preparation of 1H-benzo[d]imidazol-2-amine

[0286] [Chemical formula 22]

[0287]

[0288] (First step)

[0289] Pyridine-3-ol (609 mg, 6.41 mmol) and potassium carbonate (885 mg, 6.41 mmol) were added to a DMF solution (10 mL) containing 5-fluoro-2-nitroaniline (500 mg, 3.20 mmol), and stirred at 100° C. for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2-nitro-5-(pyridin-3-yloxy)aniline (741 mg).

[0290] 1 H NMR(400MHz, DMSO-d6)δ 8.54-8.48 (m, 2H), 8.06-8.00 (m, 1H), 7.68 (ddd, J=8.4, 2.8, 1.4Hz, 1H), 7.54 (ddd, J=8.4, 4.7, 0. 7Hz, 1H), 7.49 (s, 2H), 6.39 (d, J=2.7Hz, 1H), 6.34 (dd, J=9.4, 2.7Hz, 1H); LCMS (m / z) 232.11[M+H] + .

[0291] (Second step)

[0292] 2-Nitro-5-(pyridin-3-yloxy)aniline (740mg, 3.20mmol) was dissolved in ethanol (20mL), and 10% palladium on carbon (170mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. In order to complete the reaction, the obtained mixture was dissolved in a mixed solvent of ethanol / ethyl acetate (2:1, 30mL). 10% palladium on carbon (170mg) was added, and the mixture was further stirred overnight at room temperature under a hydrogen atmosphere. After filtering the insoluble material, the filtrate was concentrated under reduced pressure to obtain 4-(pyridin-3-yloxy)benzene-1,2-diamine (640mg).

[0293] LCMS (m / z) 202.17 [M+H] + .

[0294] (Third step)

[0295] 4-(pyridine-3-yloxy)benzene-1,2-diamine (640mg, 3.18mmol) and CDI (774mg, 4.77mmol) are added in THF (20mL) and stirred at room temperature for 2 hours.Ethyl acetate is added in the reaction mixture, and the mixture is washed with saturated aqueous sodium bicarbonate solution.The organic layer obtained is dried over anhydrous sodium sulfate, and solvent is distilled out under reduced pressure.Ethanol is added in the obtained residue so that it is suspended, and solid is collected by filtration.With ethanol washing solid and dry, 5-(pyridine-3-yloxy)-1,3-dihydro-2H-benzo [d] imidazoles-2-one (480mg) is obtained.

[0296] 1 H NMR(400MHz, DMSO-d6)δ 10.67 (d, J=9.6Hz, 2H), 8.36-8.27 (m, 2H), 7.37 (ddd, J=8.5, 4.5, 0.8Hz, 1H), 7.32 (ddd, J=8.4, 2.9, 1.5Hz, 1H), 6.94 (d, J=8.2Hz, 1H), 6.72-6.64 (m, 2H); LCMS (m / z) 228.12[M+H] + .

[0297] (Step 4)

[0298] Phosphorus oxychloride (1.9 mL) was added to 5-(pyridin-3-yloxy)-1,3-dihydro-2H-benzo[d]imidazole-2-one (75 mg, 0.33 mmol) and stirred overnight at 100 ° C. The reaction mixture was cooled to room temperature, and ice was added, and ethyl acetate and saturated sodium bicarbonate aqueous solution were added, and the organic layer was separated. The obtained organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-chloro-5-(pyridin-3-yloxy)-1H-benzo[d]imidazole (60 mg).

[0299] LCMS (m / z) 246.06 [M+H] + .

[0300] (Fifth step)

[0301] 2-Chloro-5-(pyridin-3-yloxy)-1H-benzo[d]imidazole (60 mg, 0.244 mmol) and p-toluenesulfonic acid monohydrate (69.7 mg, 0.366 mmol) were added to a NMP solution (2 mL) containing 5-bromo-1H-indol-3-amine (51.5 mg, 0.244 mmol), and stirred at 120° C. for 3.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-9: 1) to obtain the title compound (12 mg).

[0302] 1 H NMR(400MHz, DMSO-d6)δ 11.08-11.01 (m, 1H), 10.81-10.71 (m, 1H), 9.18-9.12 (m, 1H), 8.41-8.20 (m, 2H), 7.85 (d, J=2.5Hz, 1H), 7. 81 (dd, J=12.6, 2.5Hz, 1H), 7.44-7.15 (m, 5H), 6.99-6.91 (m, 1H), 6.77-6.65 (m, 1H); LCMS (m / z) 422.2 [M+H] +

[0303] Embodiment 14

[0304] Preparation of N-(5-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0305] [Chemical formula 23]

[0306]

[0307] (First step)

[0308] Benzoyl chloride (1.24 g, 8.89 mmol) was added to acetonitrile (15 mL) containing 5-fluoro-1H-indole (1 g, 7.41 mmol) and silver nitrate (1.5 g, 8.89 mmol) at 0°C and stirred at room temperature for 2 hours. The insoluble material was filtered through celite, and a saturated aqueous sodium bicarbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate: petroleum ether=15:85) to obtain 5-fluoro-3-nitro-1H-indole (1 g).

[0309] LCMS (m / z) 181.1 [M+H] + .

[0310] (Second step)

[0311] By the same method as in the first step of Example 9, tert-butyl (5-fluoro-1H-indol-3-yl)carbamate (1 g) was obtained using 5-fluoro-3-nitro-1H-indole (1 g, 5.55 mmol).

[0312] LCMS (m / z) 251.3 [M+H] + .

[0313] (Third step)

[0314] 2-chloro-1H-benzo [d] imidazoles (0.146g, 0.969mmol) and p-toluenesulfonic acid monohydrate (0.309g, 1.8mmol) were added in NMP (4mL) containing (5-fluoro-1H-indol-3-yl) tert-butyl carbamate (0.3g, 1.2mmol) and stirred for 4 hours at 120 ℃. The reaction mixture was poured onto ice and the obtained solid was collected by filtration and dried under reduced pressure. The obtained crude product was purified by HPLC preparation chromatography to obtain the title compound (36mg).

[0315] 1 H NMR(500MHz, DMSO-d6)δ 10.90 (s, 1H), 10.80 (s, 1H), 8.98 (s, 1H), 7.80 (d, J=2.4Hz, 1H), 7.38-7 .33(m, 2H), 7.26-7.11(m, 2H), 6.97-6.83(m, 3H); LCMS(m / z)267.1[M+H] + .

[0316] Embodiment 15

[0317] Preparation of N-(5-chloro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0318] [Chemical formula 24]

[0319]

[0320] (First step)

[0321] Tert-butyl (5-chloro-1H-indol-3-yl)carbamate (0.200 g) was obtained in the same manner as in the first step of Example 9 using 5-chloro-3-nitro-1H-indole (0.300 g, 1.54 mmol).

[0322] LCMS (m / z) 267.4 [M+H] + .

[0323] (Second step)

[0324] 2-Chloro-1H-benzo[d]imidazole (0.136 g, 0.90 mmol) was added to a 4N hydrochloric acid / 1,4-dioxane solution (2 mL) containing tert-butyl (5-chloro-1H-indol-3-yl)carbamate (0.20 g, 0.75 mmol) and stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and basified with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was crudely purified by silica gel chromatography (ethyl acetate: petroleum ether=3:7), and then purified by HPLC preparative chromatography to give the title compound (10 mg) in the form of a formate salt.

[0325] 1 H NMR(500MHz, DMSO-d6)δ 10.98 (brs, 2H), 9.20 (s, 1H), 8.22 (s, 1H), 7.84 (d, J=2.4Hz, 1H), 7.72 (d, J=1.8Hz, 1H), 7.38 (d, J=8. 5Hz, 1H), 7.21 (d, J=4.0Hz, 2H), 7.12-7.07 (m, 1H), 6.92 (dd, J=3.1, 5.8Hz, 2H); LCMS (m / z) 283.2[M+H] + .

[0326] Example 16

[0327] Preparation of N-(5-iodo-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0328] [Chemical formula 25]

[0329]

[0330] (First step)

[0331] 5-Iodo-1H-indole (4 g, 16.46 mmol) was used to obtain 5-iodo-3-nitro-1H-indole (2.7 g) by the same manner as in the first step of Example 14.

[0332] LCMS (m / z) 289.1 [M+H] + .

[0333] (Second step)

[0334] 5-Iodo-3-nitro-1H-indole (0.5 g, 1.74 mmol) was used to obtain tert-butyl (5-iodo-1H-indol-3-yl)carbamate (0.3 g) in the same manner as in the first step of Example 9.

[0335] LCMS (m / z) 359.2 [M+H] + .

[0336] (Third step)

[0337] Tert-butyl (5-iodo-1H-indol-3-yl)carbamate (0.141 g, 0.39 mmol) was used to obtain the title compound (10 mg) as formate salt by the same method as in the third step of Example 14.

[0338] 1 H NMR(500MHz, DMSO-d6)δ 11.85(brs, 1H), 10.90(brs, 1H), 9.84(brs, 1H), 8.42(s, 1H), 8.15(s, 1H), 7.84(d, J=2.4Hz, 1H), 7.33 (dd, J=1.4, 8.4Hz, 1H), 7.25-7.15 (m, 3H), 6.94-6.86 (m, 2H); LCMS (m / z) 375.3[M+H] + .

[0339] Example 17

[0340] Preparation of N-(7-bromo-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0341] [Chemical formula 26]

[0342]

[0343] (First step)

[0344] 7-Bromo-3-nitro-1H-indole (0.5 g, 2.08 mmol) was used to obtain a preparation of tert-butyl (7-bromo-1H-indol-3-yl)carbamate (0.25 g) in the same manner as in the first step of Example 9.

[0345] LCMS (m / z) 313.2 [M+H] + .

[0346] (Second step)

[0347] Tert-butyl (7-bromo-1H-indol-3-yl)carbamate (0.1 g, 0.32 mmol) was used to obtain the title compound (42 mg) in the same manner as in the third step of Example 14.

[0348] 1 H NMR(500MHz, DMSO-d6)δ 11.02 (s, 1H), 10.70 (brs, 1H), 9.07 (s, 1H), 7.83 (d, J = 2.4Hz, 1H), 7.67 (d, J = 7.9Hz, 1H), 7.34 (d, J=7.5Hz, 1H), 7.22 (brs, 2H), 6.98-6.89 (m, 3H); LCMS (m / z) 327.1 [M+H] + .

[0349] Embodiment 18

[0350] Preparation of N-(5-bromo-1H-indol-3-yl)-1-methyl-1H-benzo[d]imidazol-2-amine

[0351] [Chemical formula 27]

[0352]

[0353] The title compound (15 mg) was obtained in the same manner as in the third step of Example 14 using 2-chloro-1-methyl-1H-benzo[d]imidazole (0.2 g, 1.2 mmol) and 5-bromo-1H-indol-3-amine (0.303 g, 1.44 mmol).

[0354] 1H NMR(500MHz, DMSO-d6)δ 11.05 (brs, 1H), 8.56 (s, 1H), 8.03 (d, J=1.8Hz, 1H), 7.94 (d, J=2.1Hz, 1H), 7.35 (d, J=8.5Hz, 1H), 7. 29-7.24 (m, 2H), 7.20 (dd, J=1.5, 8.5Hz, 1H), 7.03-6.97 (m, 2H), 3.74 (s, 3H); LCMS (m / z) 341.4[M+H] + .

[0355] Embodiment 19

[0356] Preparation of 2-[(5-bromo-1H-indol-3-yl)amino]-1H-benzo[d]imidazole-5-carbonitrile

[0357] [Chemical formula 28]

[0358]

[0359] 2-Chloro-1H-benzo[d]imidazole-5-carbonitrile (30 mg, 0.169 mmol) and p-toluenesulfonic acid monohydrate (48.2 mg, 0.253 mmol) were added to a NMP solution (2 mL) containing 5-bromo-1H-indol-3-amine (35.7 mg, 0.169 mmol) and stirred at 120° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-9: 1), and further purified by an ion exchange column (SCX) to obtain the title compound (16 mg).

[0360] 1 H NMR(400MHz, DMSO-d6)δ 11.34-11.09 (m, 2H), 9.43 (brs, 1H), 7.80 (brs, 2H), 7.68-7.46 (m, 1H), 7.40-7.30 (m, 3H), 7.23 (dd, J=8.6, 2.0Hz, 1H); LCMS (m / z) 352.1[M+H] + .

[0361] Embodiment 20

[0362] 2-[(5-Bromo-1H-indol-3-yl)amino]-1H-benzo

[0363] [d] Preparation of methyl imidazole-4-carboxylate

[0364] [Chemical formula 29]

[0365]

[0366] 5- bromo-1H- indole-3-amine (88mg, 0.418mmol) and 2- chloro-1H- benzo [d] imidazole-4-methyl formates (80mg, 0.380mmol) are added to 4N hydrochloric acid / 1,4- dioxane solution (3mL) and stirred for 2 hours under reflux. In addition, 5- bromo-1H- indole-3-amine (80mg, 0.379mmol) is added and stirred for 1 hour under reflux. After the reaction mixture is cooled to room temperature, solvent is distilled out under reduced pressure, and residue is crudely purified by silica gel chromatography (chloroform: methanol=1: 0-9: 1), and further purified by HPLC preparative chromatography to obtain the title compound (5mg) in formate form.

[0367] 1 H NMR(400MHz, DMSO-d6)δ 11.00 (brs, 2H), 9.36 (brs, 1H), 8.35 (brs, 1H), 7.91 (d, J=2.3Hz, 1H), 7.79 (brs, 1H), 7.58-7.50 (m, 2H), 7. 36 (d, J=8.7Hz, 1H), 7.23 (dd, J=8.7, 1.9Hz, 1H), 7.10 (t, J=7.8Hz, 1H), 3.95 (s, 3H); LCMS (m / z) 387.1[M+H] + .

[0368] Embodiment 21

[0369] 2-Bromo-N-(5-phenoxy-1H-benzo[d]imidazol-2-yl)-5H-pyrrolo[2,3-b]

[0370] Preparation of pyrazine-7-amine

[0371] [Chemical formula 30]

[0372]

[0373] (First step)

[0374] 2- bromo-7-nitro-5H- pyrrolo- [2,3-b] pyrazine (60mg, 0.247mmol) is dissolved in the mixed solvent (2: 1,3mL) of methanol / saturated aqueous ammonium chloride solution, and zinc powder (161mg, 2.469mmol) is added and stirred at room temperature for 10 minutes. In addition, by Boc2O (64.7mg, 0.296mmol) is added in the reaction solution and stirred at room temperature for 30 minutes. After the reaction mixture is diluted with ethyl acetate, it is filtered using diatomaceous earth, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel chromatography (chloroform: methanol=1: 0-19: 1), and (2- bromo-5H- pyrrolo- [2,3-b] pyrazine-7-yl) tert-butyl carbamate (30mg) is obtained.

[0375] 1 H NMR (400MHz, DMSO-d6) δ 12.13 (s, 1H), 9.09 (s, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 1.45 (s, 9H).

[0376] (Second step)

[0377] 2-Chloro-5-phenoxy-1H-benzo[d]imidazole (28.1 mg, 0.115 mmol) and p-toluenesulfonic acid monohydrate (27.3 mg, 0.144 mmol) were added to tert-butyl (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)carbamate (30 mg, 0.096 mmol) in NMP (2 mL) and stirred at 120° C. for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1), and further purified by an ion exchange column (SCX) to obtain the title compound (19 mg).

[0378] 1 H NMR(400MHz, DMSO-d6)δ 12.10 (brs, 1H), 10.58 (brs, 1H), 9.57 (brs, 1H), 8.41 (s, 1H), 8.37 (brs, 1H), 7.37-7.24 (m, 3H), 7.05 (t, J=7.4Hz, 1H), 6.97 (d, J=2.3Hz, 1H), 6.94 (d, J=8.1Hz, 2H), 6.71 (brs, 1H); LCMS (m / z) 421.2[M+H] + .

[0379] Embodiment 22

[0380] Preparation of 3-[(5-phenoxy-1H-benzo[d]imidazol-2-yl)amino]-1H-indole-5-carboxylic acid methyl ester

[0381] [Chemical formula 31]

[0382]

[0383] (First step)

[0384] To silver nitrate (1.7 g, 10 mmol) was added acetonitrile (50 mL) containing N-bromosuccinimide (1.78 g, 10 mmol) and stirred at 80° C. for 10 minutes. 1H-Indole-5-carboxylic acid methyl ester (1.75 g, 10 mmol) was added, and the mixture was further stirred at 80° C. for 3 hours. After filtering the insoluble matter through celite, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1) to obtain 3-nitro-1H-indole-5-carboxylic acid methyl ester (2.3 g).

[0385] 1 H NMR (400MHz, DMSO-d6) δ12.96 (s, 1H), 8.81 (d, J=3.4Hz, 1H), 8.77-8.72 (m, 1H), 7.95 (d d, J=8.6, 1.7Hz, 1H), 7.68 (dd, J=8.6, 0.7Hz, 1H), 3.90 (s, 3H); LCMS (m / z) 221.17[M+H] + .

[0386] (Second step)

[0387] 3-nitro-1H-indole-5-methyl formate (100mg, 0.454mmol) is added to the mixed solvent of methanol / saturated aqueous ammonium chloride solution (2: 1,4.5mL) and zinc powder (297mg, 4.54mmol), and stirred at room temperature for 10 minutes.By Boc2O (119mg, 0.545mmol) is added to the reaction solution and stirred at room temperature for 1 hour.After the reaction mixture is diluted with ethyl acetate, it is filtered using diatomaceous earth, and the filtrate is concentrated under reduced pressure.The obtained residue is purified by silica gel chromatography (chloroform: methanol=1: 0-97: 3), and 3-[(tert-butoxycarbonyl) amino]-1H-indole-5-methyl formate (70mg) is obtained.

[0388] 1H NMR(400MHz, DMSO-d6)δ 11.13 (s, 1H), 9.41 (s, 1H), 8.61 (s, 1H), 7.69 (dd, J=8.6, 1.7Hz, 1H), 7.52 (s, 1H), 7.39-7.33 (m, 1H), 3.84 (s, 3H), 1.49 (s, 9H).

[0389] (Third step)

[0390] 2-Chloro-5-phenoxy-1H-benzo[d]imidazole (56 mg, 0.229 mmol) and p-toluenesulfonic acid monohydrate (68.8 mg, 0.362 mmol) were added to NMP (2 mL) containing methyl 3-[(tert-butoxycarbonyl)amino]-1H-indole-5-carboxylate (70 mg, 0.241 mmol) and stirred for 2.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1) and further purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-97: 3) to obtain the title compound (2 mg).

[0391] 1 H NMR(400MHz, DMSO-d6)δ 11.23-11.17(m, 1H), 10.69-10.57(m, 1H), 9.42-9.38(m, 1H), 8.49(brs, 1H), 7.95-7.88(m, 1H), 7.77-7.72(m, 1H), 7.47-7.40(m, 1H ), 7.38-7.29(m, 2H), 7.29-7.19(m, 1H), 7.08-7.00(m, 1H), 6.98-6.88(m, 3H), 6.74-6.63(m, 1H), 3.86(s, 3H); LCMS (m / z) 399.3[M+H] + .

[0392] Embodiment 23

[0393] N-(5-bromo-1H-indol-3-yl)-5-(phenylsulfonyl)-1H-benzo

[0394] [d] Preparation of imidazole-2-amine

[0395] [Chemical formula 32]

[0396]

[0397] (First step)

[0398] 5-Chloro-2-nitroaniline (500 mg, 2.9 mmol) and sodium benzenesulfite (1.16 g, 5.79 mmol) were added to NMP (5 mL) and stirred at 150° C. for 0.5 hours. Water was added under ice cooling, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give 2-nitro-5-(phenylsulfonyl)aniline (722 mg).

[0399] LCMS (m / z) 279.2 [M+H] + .

[0400] (Second step)

[0401] 2-Nitro-5-(phenylsulfonyl)aniline (600 mg, 2.156 mmol) was dissolved in ethanol (18 mL), and 10% palladium on carbon (115 mg) was added. The reaction was carried out at room temperature under a hydrogen atmosphere for 18 hours. The insoluble material was filtered off, and the filtrate was concentrated to give 4-(phenylsulfonyl)benzene-1,2-diamine (535 mg).

[0402] LCMS (m / z) 249.2 [M+H]+.

[0403] (Third step)

[0404] By the same method as in the first step of Example 3, using 4-(phenylsulfonyl)benzene-1,2-diamine (535 mg, 2.155 mmol), 5-(phenylsulfonyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (493 mg) was obtained.

[0405] LCMS (m / z) 275.1 [M+H]+.

[0406] (Step 4)

[0407] 5-(Phenylsulfonyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.182 mmol) was used to obtain 2-chloro-5-(phenylsulfonyl)-1H-benzo[d]imidazole (25.7 mg) by the same method as in the second step of Example 3.

[0408] LCMS (m / z) 293.1 [M+H]+.

[0409] (Fifth step)

[0410] 5-Bromo-1H-indol-3-amine (10.45 mg, 0.049 mmol) and p-toluenesulfonic acid monohydrate (13.45 mg, 0.071 mmol) were added to a solution of 2-chloro-5-(phenylsulfonyl)-1H-benzo[d]imidazole (13.8 mg, 0.047 mmol) in 1,4-dioxane (1 mL) and stirred for 1 hour at 120° C. The reaction mixture was cooled to 0° C., and the precipitated solid was collected by filtration and washed successively with 1N aqueous sodium hydroxide solution, water and ethyl acetate to obtain the title compound (3.7 mg).

[0411] 1 H NMR (400MHz, DMSO-d6) δ11.50 (s, 1H), 7.95-7.91 (m, 2H), 7.80 (d, J=1.9Hz, 1H), 7.79-7.56 (m , 4H), 7.48-7.40 (m, 3H), 7.28 (d, J=8.5Hz, 1H), 7.11 (d, J=7.9Hz, 2H); LCMS (m / z) 467.2[M+H] + .

[0412] Embodiment 24

[0413] Preparation of 4-bromo-N-(5-bromo-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine

[0414] [Chemical formula 33]

[0415]

[0416] 5-Bromo-1H-indol-3-amine (0.11 g, 0.52 mmol) was added to 4-bromo-2-chloro-1H-benzo[d]imidazole (0.1 g, 0.43 mmol) to obtain the title compound (58 mg) in the same manner as in the third step of Example 11.

[0417] 1 H NMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 11.05 (s, 1H), 9.31 (s, 1H), 7.85-7.79 (m, 2H), 7.37 (d, J=8.8H z, 1H), 7.22 (dd, J=2.0, 8.6Hz, 1H), 7.20-7.10 (m, 2H), 6.82 (t, J=7.8Hz, 1H); LCMS (m / z) 404.9[M+H] + .

[0418] Embodiment 25

[0419] Preparation of N-(5-bromo-1H-indol-3-yl)-4-fluoro-1H-benzo[d]imidazol-2-amine

[0420] [Chemical formula 34]

[0421]

[0422] To 2-chloro-4-fluoro-1H-benzo[d]imidazole (0.1 g, 0.59 mmol) was added 5-bromo-1H-indol-3-amine (0.148 g, 0.7 mmol) to obtain the title compound (50 mg) in the same manner as in the third step of Example 11.

[0423] 1 H NMR(500MHz, DMSO-d6)δ 11.06 (brs, 1H), 11.02 (brs, 1H), 9.21 (s, 1H), 7.92-7.78 (m, 2H), 7.36 (d, J=8.5Hz, 1H), 7. 22 (dd, J=1.8, 8.5Hz, 1H), 7.03 (d, J=7.6Hz, 1H), 6.92-6.73 (m, 2H); LCMS (m / z) 345.0[M+H] + .

[0424] Embodiment 26

[0425] N-(5-bromo-1H-indol-3-yl)-5-[3-(dimethylamino)phenoxy]-

[0426] Preparation of 1H-benzo[d]imidazol-2-amine

[0427] [Chemical formula 35]

[0428]

[0429] (First step)

[0430] 5-Fluoro-2-nitroaniline (5 g, 32.05 mmol) was added to 3-(dimethylamino)phenol (4.4 g, 32.05 mmol) to obtain 3-(3-amino-4-nitrophenoxy)-N,N-dimethylaniline (5 g) by the same method as in the first step of Example 13.

[0431] LCMS (m / z) 274.1 [M+H]+.

[0432] (Second step)

[0433] 3-(3-Amino-4-nitrophenoxy)-N,N-dimethylaniline (4 g, 14.65 mmol) was dissolved in a mixed solvent of ethanol / water (60 mL, 2:1) and iron powder (4.08 g, 73.26 mmol) and ammonium chloride (7.84 g, 146.52 mmol) were added and stirred at 90°C for 2 hours. The reaction mixture was filtered through celite, and the filtrate was diluted with water and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:1) to obtain 4-[3-(dimethylamino)phenoxy]benzene-1,2-diamine (3 g).

[0434] LCMS (m / z) 244.4 [M+H] + .

[0435] (Third step)

[0436] CDI (2.8 g, 17.28 mmol) was added to THF (30 mL) containing 4-[3-(dimethylamino)phenoxy]benzene-1,2-diamine (2.8 g, 11.52 mmol) and stirred at 60° C. for 4 hours. The reaction mixture was diluted with saturated brine and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether=3:2) to obtain 5-[3-(dimethylamino)phenoxy]-1,3-dihydro-

[0437] 2H-Benzo[d]imidazol-2-one (3 g).

[0438] LCMS (m / z) 270.4 [M+H] + .

[0439] (Step 4)

[0440] Phosphorus oxychloride (6.93 mL) and N,N-dimethylaniline (0.2 mL) were added to 5-[3-(dimethylamino)phenoxy]-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.5 g, 1.86 mmol) and stirred at 100° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made basic by adding a saturated aqueous solution of sodium bicarbonate and extracted with 10% methanol / dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether=1:1) to obtain 3-[(2-chloro-1H-benzo[d]imidazol-5-yl)oxy]-

[0441] N,N-Dimethylaniline (0.45 g).

[0442] LCMS (m / z) 288.5 [M+H] + .

[0443] (Fifth step)

[0444] 5-Bromo-1H-indol-3-amine (0.33 g, 1.57 mmol) was added to 3-[(2-chloro-1H-benzo[d]imidazol-5-yl)oxy]-N,N-dimethylaniline (0.3 g, 1.04 mmol) to give the title compound (37 mg) in the same manner as in the third step of Example 11.

[0445] 1 H NMR (500MHz, methanol-d4) δ7.63 (d, J=2.0Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.5Hz , 1H), 7.24 (dd, J=1.8, 8.5Hz, 1H), 7.18-7.15 (m, 1H), 7.08 (t, J=8.1Hz, 1H) , 6.89 (s, 1H), 6.72-6.65 (m, 1H), 6.44 (dd, J=2.3, 8.4Hz, 1H), 6.35 (t, J=2 .4Hz, 1H), 6.23 (dd, J=1.5, 8.0Hz, 1H), 2.86 (s, 6H); LCMS (m / z) 462.0[M+H] + .

[0446] Embodiment 27

[0447] Preparation of 3-[(5-phenoxy-1H-benzo[d]imidazol-2-yl)amino]-1H-indole-5-carboxylic acid

[0448] [Chemical formula 36]

[0449]

[0450] (First step)

[0451] 3-nitro-1H-indole-5-carboxylic acid methyl ester (2.3 g, 10.45 mmol) was added to a mixed solvent of THF / 1,4-dioxane / 2N aqueous sodium hydroxide solution (1:1:1, 60 mL) and stirred at 60° C. for 5 hours. 2N hydrochloric acid was added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The suspension was filtered and the solid was washed with water and dried to give 3-nitro-1H-indole-5-carboxylic acid (1.34 g).

[0452] LCMS (m / z) 205.07 [MH] - .

[0453] (Second step)

[0454] 3-nitro-1H-indole-5-carboxylic acid (1.34g, 65mmol) is dissolved in a mixed solvent (35: 26, 61mL) of methanol / saturated aqueous ammonium chloride solution, and zinc powder (4.25g, 65.0mmol) is added and stirred at room temperature for 15 minutes. Boc2O (1.7g, 7.8mmol) is added to the reaction mixture and stirred at room temperature for 1 hour. After the reaction mixture is diluted with ethyl acetate, it is filtered using diatomaceous earth, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel chromatography (chloroform: methanol = 1: 0-7: 3) to obtain 3-[(tert-butoxycarbonyl) amino]-1H-indole-5-carboxylic acid (570mg).

[0455] LCMS (m / z) 275.10 [MH] - .

[0456] (Third step)

[0457] 3-[(tert-Butyloxycarbonyl)amino]-1H-indole-5-carboxylic acid (100 mg, 0.362 mmol) and 2-chloro-5-phenoxy-1H-benzo[d]imidazole (81 mg, 0.329 mmol) were added to a mixed solvent (6:1, 3.5 mL) of 4N hydrochloric acid / 1,4-dioxane solution and DMF, and stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was crudely purified by silica gel chromatography (chloroform: methanol = 1:0-9:1), and further purified by HPLC preparative chromatography to obtain the title compound (2.7 mg).

[0458] 1 H NMR(400MHz, DMSO-d6)δ 11.13 (brs, 1H), 10.77-10.59 (m, 1H), 9.38 (brs, 1H), 8.47 (brs, 1H), 7.92-7.83 (m, 1H), 7.73 (d, J=8.6Hz, 1H), 7.4 4-7.30(m, 3H), 7.29-7.18(m, 1H), 7.08-7.00(m, 1H), 6.98-6.88(m, 3H), 6.74-6.61(m, 1H); LCMS(m / z)385.2[M+H] + .

[0459] Embodiment 28

[0460] Preparation of morpholino{3-[(5-phenoxy-1H-benzo[d]imidazol-2-yl)amino]-1H-indol-5-yl}methanone

[0461] [Chemical formula 37]

[0462]

[0463] To a pyridine solution (0.5 mL) containing 3-[(5-phenoxy-1H-benzo[d]imidazol-2-yl)amino]-1H-indole-5-carboxylic acid (10 mg, 0.026 mmol) were added morpholine (2.72 mg, 0.029 mmol) and EDCI / HCl (5.49 mg, 0.031 mmol) and stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous ammonium chloride solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-19: 1) to obtain the title compound (4 mg).

[0464] 1 H NMR (400MHz, DMSO-d6) δ11.07-11.01 (m, 1H), 10.80-10.66 (m, 1H), 9.21-9.15 (m, 1H), 7.84-7.75 (m, 2H), 7.41 (d, J=8.4Hz, 1H), 7.36 -7.29(m, 2H), 7.26-7.14(m, 2H), 7.07-6.99(m, 1H), 6.97-6.84(m, 3H), 6.72-6.60(m, 1H), 3.63-3.50(m, 8H); LCMS (m / z) 454.3[M+H] + .

[0465] Embodiment 29

[0466] 3-[(5-phenoxy-1H-benzo[d]imidazol-2-yl)amino]-

[0467] Preparation of N-(prop-2-yn-1-yl)-1H-indole-5-carboxamide

[0468] [Chemical formula 38]

[0469]

[0470] To a pyridine solution (1 mL) containing 3-[(5-phenoxy-1H-benzo[d]imidazol-2-yl)amino]-1H-indole-5-carboxylic acid (50 mg, 0.13 mmol) were added propargylamine (10.75 mg, 0.195 mmol) and EDCI / HCl (37.4 mg, 0.195 mmol) and stirred at room temperature for 22 hours. Ethyl acetate was added to the reaction mixture and washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-9: 1) and further purified by silica gel chromatography (chloroform: methanol = 1: 0-9: 1) to obtain the title compound (2.5 mg).

[0471] 1 H NMR(400MHz, DMSO-d6)δ 11.10-11.04(m, 1H), 10.66-10.56(m, 1H), 9.21-9.19(m, 1H), 8.77-8.72(m, 1H ), 8.29 (brs, 1H), 7.85-7.79 (m, 1H), 7.67-7.62 (m, 1H), 7.39 (d, J=8.7Hz, 1H), 7 .36-7.29(m, 2H), 7.27-7.16(m, 1H), 7.09-6.99(m, 1H), 6.96-6.89(m, 3H), 6.7 2-6.58 (m, 1H), 4.09-4.03 (m, 2H), 3.09 (t, J=2.4Hz, 1H); LCMS (m / z) 422.2[M+H] + .

[0472] Embodiment 30

[0473] 3-[(5-phenoxy-1H-benzo[d]imidazol-2-yl)amino]-

[0474] Preparation of N-phenyl-1H-indole-5-carboxamide

[0475] [Chemical formula 39]

[0476]

[0477] Aniline (1672 mg, 0.18 mmol) and EDCI / HCl (34.4 mg, 0.18 mmol) were added to a pyridine solution (1 mL) containing 3-[(5-phenoxy-1H-benzo[d]imidazol-2-yl)amino]-1H-indole-5-carboxylic acid (46 mg, 0.12 mmol) and stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture and washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-19: 1) and further purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1) to obtain the title compound (4 mg).

[0478] 1 H NMR (400MHz, DMSO-d6) δ11.14-11.08 (m, 1H), 10.69-10.58 (m, 1H), 10.15 (s, 1H), 9.29-9.25 (m, 1H), 8.39 (d, J=1.5Hz, 1H), 7.92-7.74 (m, 4H) , 7.46 (d, J=8.6Hz, 1H), 7.38-7.28 (m, 4H), 7.28-7.18 (m, 1H), 7.11-7. 00(m, 2H), 6.98-6.89(m, 3H), 6.73-6.61(m, 1H); LCMS(m / z)460.2[M+H] + .

[0479] Embodiment 31

[0480] N-(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-(trifluoromethyl)-

[0481] Preparation of 1H-benzo[d]imidazol-2-amine

[0482] [Chemical formula 40]

[0483]

[0484] (First step)

[0485] 5-bromo-3-nitro-1H-pyrrolo[3,2-b]pyridine (100mg, 0.413mmol) was dissolved in a mixed solvent (2:1,3mL) of methanol / saturated aqueous ammonium chloride solution, and zinc powder (270mg, 4.13mmol) was added and stirred at room temperature for 10 minutes. Boc2O (108mg, 0.496mmol) was added to this mixture and stirred at room temperature for 1 hour. After the reaction mixture was diluted with ethanol, it was filtered using diatomaceous earth, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (120mg).

[0486] (Second step)

[0487] Tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (40 mg, 0.128 mmol) and 2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (28.3 mg, 0.128 mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (2 mL), and the mixture was stirred at reflux for 1.5 hours. In order to complete the reaction, DMF (1 mL) was added to the mixture and further stirred at reflux for 2.5 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was crudely purified by amine-modified silica gel chromatography (chloroform: methanol=1: 0-97: 3), and further purified by HPLC preparative chromatography to obtain the title compound (8 mg) in the form of formate.

[0488] 1 H NMR(400MHz, DMSO-d6)δ 11.32(brs, 1H), 10.92-10.76(m, 1H), 9.61-9.48(m, 1H), 8.24-8.17(m, 2H), 7.78(d, J=8.5H z, 1H), 7.63-7.53 (m, 1H), 7.43 (brd, J=8.3Hz, 1H), 7.33-7.21 (m, 2H); LCMS (m / z) 398.1[M+H] + .

[0489] Embodiment 32

[0490] Preparation of N-(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-chloro-1H-benzo[d]imidazol-2-amine

[0491] [Chemical formula 41]

[0492]

[0493] Tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (40mg, 0.128mmol) and 2,5-dichloro-1H-benzo[d]imidazole (23.96mg, 0.128mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (2mL), and the mixture was stirred at reflux for 1.5 hours. In order to complete the reaction, DMF (1mL) was added to the mixture and further stirred at reflux for 2.5 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was crudely purified by amine-modified silica gel chromatography (chloroform: methanol=1: 0-97: 3), and further purified by HPLC preparative chromatography to obtain the title compound (9mg) in the form of formate.

[0494] 1 H NMR(400MHz, DMSO-d6)δ 11.28(brs, 1H), 10.66-10.55(m, 1H), 9.37(brs, 1H), 8.23(s, 1H), 8.18(brs, 1H), 7.77( d, J=8.5Hz, 1H), 7.34-7.23 (m, 3H), 6.95 (dd, J=18.4, 8.3Hz, 1H); LCMS (m / z) 364.0[M+H] + .

[0495] Embodiment 33

[0496] Preparation of N-(5-bromo-1H-indol-3-yl)-5-fluoro-1H-benzo[d]imidazol-2-amine

[0497] [Chemical formula 42]

[0498]

[0499] 5-Bromo-1H-indol-3-amine (0.148 g, 0.7 mmol) was added to 2-chloro-5-fluoro-1H-benzo[d]imidazole (0.1 g, 0.59 mmol) to obtain the title compound (40 mg) in the same manner as in the third step of Example 14.

[0500] 1H NMR (400MHz, DMSO-d6) δ11.07-10.97(m, 1H), 10.83-10.69(m, 1H), 9.14-9.04(m, 1H), 7.89-7.76(m, 2H), 7.37- 7.29(m, 1H), 7.24-7.17(m, 1H), 7.14-7.11(m, 1H), 7.03-6.93(m, 1H), 6.82-6.64(m, 1H); LCMS(m / z)345.0[M+H] + .

[0501] Embodiment 34

[0502] Preparation of methyl 2-[(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)amino]-1H-benzo[d]imidazole-5-carboxylate

[0503] [Chemical formula 43]

[0504]

[0505] 2-Chloro-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (32 mg, 0.152 mmol) and p-toluenesulfonic acid monohydrate (43.3 mg, 0.228 mmol) were added to a solution (2 mL) of NMP containing tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (45.1 mg, 0.144 mmol) and stirred at 120°C for 5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was collected by filtration. The crude product obtained was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-97: 3), and further purified by HPLC preparative chromatography to give the title compound (4 mg) in the form of a formate salt.

[0506] 1 H NMR(400MHz, DMSO-d6)δ 11.33(brs, 1H), 10.95-10.71(m, 1H), 9.61-9.43(m, 1H), 8.30(brs, 1H), 8.23-8.17(m, 1H), 7.93-7.84( m, 1H), 7.78 (d, J=8.5Hz, 1H), 7.69-7.60 (m, 1H), 7.37-7.27 (m, 2H), 3.83 (s, 3H); LCMS (m / z) 388.1 [M+H] + .

[0507] Embodiment 35

[0508] N-(5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-

[0509] Preparation of 1H-benzo[d]imidazol-2-amine

[0510] [Chemical formula 44]

[0511]

[0512] (First step)

[0513] 5-Chloro-3-nitro-1H-pyrrolo[3,2-b]pyridine (50 mg, 0.253 mmol) was dissolved in a mixed solvent (2:1, 3 mL) of methanol / saturated aqueous ammonium chloride solution, and zinc powder (165 mg, 2.53 mmol) was added and stirred at room temperature for 10 minutes. Boc2O (66.3 mg, 0.304 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was diluted with ethyl acetate, it was filtered using celite, and the filtrate was concentrated under reduced pressure to give tert-butyl (5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (60 mg).

[0514] (Second step)

[0515] 2-Chloro-5-phenoxy-1H-benzo[d]imidazole (43.9 mg, 0.179 mmol) and p-toluenesulfonic acid monohydrate (63.9 mg, 0.336 mmol) were added to a NMP solution (1.5 mL) containing tert-butyl (5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (60 mg, 0.224 mmol), and stirred at 120° C. for 3 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was collected by filtration. The crude product obtained was crudely purified by amine-modified silica gel chromatography (chloroform: methanol=1:0-19:1), and further purified by silica gel chromatography (chloroform: methanol=1:0-19:1) to obtain the title compound (11 mg).

[0516] 1H NMR(400MHz, DMSO-d6)δ 11.23 (s, 1H), 10.53-10.42 (m, 1H), 9.28 (s, 1H), 8.20 (brs, 1H), 7.85 (d, J=8.4Hz, 1H), 7.33 (dd, J=8.5, 7.3Hz, 2H), 7.27 (b rd, J=8.4Hz, 1H), 7.18 (d, J=8.5Hz, 1H), 7.04 (t, J=7.4Hz, 1H), 7.00-6.90 (m, 3H), 6.74-6.61 (m, 1H); LCMS (m / z) 376.1[M+H] + .

[0517] Embodiment 36

[0518] N-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-

[0519] Preparation of 1H-benzo[d]imidazol-2-amine

[0520] [Chemical formula 45]

[0521]

[0522] (First step)

[0523] Potassium nitrate (75 mg, 0.742 mmol) was added to concentrated sulfuric acid (1.5 mL) and stirred at room temperature for 1 minute. After the reaction mixture was cooled to -20 ° C, 5-methoxy-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.675 mmol) was added and stirred at -20 ° C for 30 minutes. Ice water was added to the reaction mixture, and 28% ammonia water was added to make it alkaline. The precipitated solid was collected by filtration and dried to obtain 5-methoxy-3-nitro-1H-pyrrolo[3,2-b]pyridine (87 mg).

[0524] 1 H NMR (400MHz, DMSO-d6) δ 8.62 (s, 1H), 7.87 (d, J = 8.8Hz, 1H), 6.78 (d, J = 8.9Hz, 1H), 3.94 (s, 3H); LCMS (m / z) 194.13 [M+H] + .

[0525] (Second step)

[0526] 5-methoxy-3-nitro-1H-pyrrolo-[3,2-b]pyridine (87mg, 0.45mmol) is added to the mixed solvent (2: 1,4.5mL) of methanol / saturated aqueous ammonium chloride solution, and zinc powder (294mg, 4.5mmol) is added and stirred at room temperature for 10 minutes.By Boc2O (118mg, 0.54mmol) is added to the reaction mixture and stirred at room temperature for 20 minutes.After the reaction mixture is diluted with ethanol, it is filtered using diatomaceous earth, and the filtrate is concentrated under reduced pressure.The obtained residue is purified by silica gel chromatography (chloroform: methanol=1: 0-97: 3), and 5-methoxy-1H-pyrrolo-[3,2-b]pyridine-3-yl) tert-butyl carbamate (60mg) is obtained.

[0527] (Third step)

[0528] 2-Chloro-5-phenoxy-1H-benzo[d]imidazole (39 mg, 0.16 mmol) and p-toluenesulfonic acid monohydrate (65 mg, 0.342 mmol) were added to a NMP solution (1.5 mL) containing tert-butyl (5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (60 mg, 0.228 mmol) and stirred at 120 ° C for 3.5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added and the precipitated solid was collected by filtration. The crude product obtained was crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1) and further purified by ion exchange column (SCX) to obtain the title compound (8 mg).

[0529] 1 H NMR(400MHz, DMSO-d6)δ 11.02 (brs, 1H), 7.83 (brs, 1H), 7.74 (d, J=8.7Hz, 1H), 7.37-7.29 (m, 2H), 7.25 (d, J=8.4Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 6.97-6.90 (m, 3H), 6.70 (brd, J=8.4Hz, 1H), 6.61 (d, J=8.7Hz, 1H), 3.90 (s, 3H); LCMS (m / z) 372.2[M+H] + .

[0530] Embodiment 37

[0531] 2-[(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)amino]-1H-

[0532] Preparation of benzo[d]imidazole-5-carboxylic acid

[0533] [Chemical formula 46]

[0534]

[0535] By (5- bromo -1H- pyrrolo [3,2-b] pyridin-3-yl) carbamic acid tert-butyl ester (127mg, 0.407mmol) and 2- chloro -1H- benzo [d] imidazole -5- carboxylic acid (76mg, 0.387mmol) add 4N hydrochloric acid / l, in 4- dioxane solution (3mL), and stir the mixture under reflux for 2.5 hours. In order to complete the reaction, DMF (1mL) is added to the mixture and further stirred for 1.5 hours under reflux. After the reaction mixture is cooled to room temperature, the solvent is distilled off under reduced pressure, and the residue is crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-0: 1), and further purified by HPLC preparative chromatography to obtain the title compound (4mg) in the form of formate.

[0536] 1 H NMR(400MHz, DMSO-d6)δ 11.37-11.28(m, 1H), 10.92-10.76(m, 1H), 9.55-9.39(m, 1H), 8.45(s, 1H), 8.23-8.17(m, 1H), 7. 86 (brs, 1H), 7.78 (d, J=8.4Hz, 1H), 7.67-7.59 (m, 1H), 7.33-7.26 (m, 2H); LCMS (m / z) 374.0 [M+H] + .

[0537] Embodiment 38

[0538] N-(7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-1H-

[0539] Preparation of benzo[d]imidazol-2-amine

[0540] [Chemical formula 47]

[0541]

[0542] (First step)

[0543] Potassium nitrate (93 mg, 0.918 mmol) was added to concentrated sulfuric acid (1.5 mL) and stirred at room temperature for 1 minute. After the reaction mixture was cooled to 0 ° C, 7-chloro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.655 mg) was added and stirred at 0 ° C for 1 hour. Ice water was added to the reaction mixture, and 28% ammonia water was added to make it alkaline. The precipitated solid was collected by filtration and dried to obtain 7-chloro-3-nitro-1H-pyrrolo[3,2-b]pyridine (68 mg).

[0544] 1 1H NMR (400MHz, DMSO-d6) δ 13.44 (s, 1H), 8.93 (s, 1H), 8.56 (d, J = 5.1Hz, 1H), 7.56 (d, J = 5.1Hz, 1H); LCMS (m / z) 198.08 [M+H] + .

[0545] (Second step)

[0546] 7- chloro-3-nitro-1H-pyrrolo-[3,2-b]pyridine (68mg, 0.344mmol) is dissolved in the mixed solvent (2: 1,3mL) of methanol / saturated aqueous ammonium chloride solution, and zinc powder (225mg, 3.44mmol) is added and stirred at room temperature for 10 minutes.By Boc2O (90mg, 0.413mmol) is added in the reaction mixture and stirred for 1.5 hours.After the reaction mixture is diluted with ethanol, it is filtered using diatomaceous earth, and the filtrate is concentrated under reduced pressure.The obtained residue is purified by silica gel chromatography (chloroform: methanol=1: 0-49: 1), and (7- chloro-1H-pyrrolo-[3,2-b]pyridine-3-yl) tert-butyl carbamate (45mg) is obtained.

[0547] 1 H NMR (400MHz, DMSO-d6) δ 11.58 (s, 1H), 8.78 (s, 1H), 8.25 (d, J=5.0Hz, 1H), 7.71 (s, 1H), 7.28 (d, J=5.0Hz, 1H), 1.46 (s, 9H).

[0548] (Third step)

[0549] To tert-butyl (7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (40 mg, 0.149 mmol) was added a solution of 2-chloro-5-phenoxy-1H-benzo[d]imidazole in NMP (1 mL) (29.2 mg, 0.120 mmol) and p-toluenesulfonic acid monohydrate (42.6 mg, 0.224 mmol), and stirred at 120° C. for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was collected by filtration. The obtained solid was crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1), and further purified by ion exchange column (SCX) to obtain the title compound (14 mg).

[0550] 1 H NMR(400MHz, DMSO-d6)δ 11.63 (brs, 1H), 9.56 (brs, 1H), 8.30 (d, J=5.0Hz, 1H), 8.16 (d, J=2.7Hz, 1H), 7.49 (brs, 1H), 7.37-7.27 (m, 4H ), 7.08-7.02 (m, 1H), 6.99 (d, J = 2.3Hz, 1H), 6.97-6.90 (m, 2H), 6.72 (brd, J = 8.3Hz, 1H); LCMS (m / z) 376.1 [M+H] + .

[0551] Embodiment 39

[0552] Preparation of N-(5-bromo-1H-indol-3-yl)-1-methyl-6-phenoxy-1H-benzo[d]imidazol-2-amine

[0553] [Chemical formula 48]

[0554]

[0555] (First step)

[0556] 60% sodium hydride (19.11 mg, 0.478 mmol) was added to DMF (1 mL) containing 2-nitro-5-phenoxy aniline (100 mg, 0.434 mmol) under ice cooling and stirred for 10 minutes. DMF (1 mL) containing iodomethane (67.8 mg, 0.478 mmol) was added to the mixture and stirred at room temperature for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain N-methyl-2-nitro-5-phenoxy aniline (106 mg).

[0557] LCMS (m / z) 245.1 [M+H] + .

[0558] (Second step)

[0559] By the same method as in the second step of Example 23, N1-methyl-5-phenoxybenzene-1,2-diamine (90 mg) was obtained using N-methyl-2-nitro-5-phenoxyaniline (102 mg, 0.59 mmol).

[0560] LCMS (m / z) 215.2 [M+H] + .

[0561] (Third step)

[0562] N1-methyl-5-phenoxybenzene-1,2-diamine (86.5 mg, 0.403 mmol) was used to obtain 1-methyl-6-phenoxy-1,3-dihydro-2H-benzo[d]imidazol-2-one (55.2 mg) by the same method as in the first step of Example 3.

[0563] LCMS (m / z) 241.2 [M+H] + .

[0564] (Step 4)

[0565] 1-Methyl-6-phenoxy-1,3-dihydro-2H-benzo[d]imidazol-2-one (53 mg, 0.221 mmol) was used to obtain 2-chloro-1-methyl-6-phenoxy-1H-benzo[d]imidazole (32.4 mg) by the same method as in the second step of Example 3.

[0566] LCMS (m / z) 259.1 [M+H] + .

[0567] (Fifth step)

[0568] 2-Chloro-1-methyl-6-phenoxy-1H-benzo[d]imidazole (6 mg, 0.023 mmol) and 5-bromo-1H-indol-3-amine (5.38 mg, 0.026 mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (0.504 mL) and stirred at 120° C. for 48 hours. After the reaction mixture was cooled to 0° C., the precipitated solid was collected by filtration, washed with ethyl acetate, and purified by HPLC preparative chromatography to give the title compound (1.9 mg) as a formate salt.

[0569] 1H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 8.03 (d, J = 2.0Hz, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.36-7.30 (m, 3H), 7.27 (d, J = 8 .3Hz, 1H), 7.21 (dd, J=8.5, 2.0Hz, 1H), 7.08-7.01 (m, 2H), 6.95-6.90 (m, 2H), 6.73 (dd, J=8.5, 2.4Hz, 1H), 3.70 (s, 3H); LCMS (m / z) 433.1[M+H] + .

[0570] Embodiment 40

[0571] N-(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-methyl-6-phenoxy-

[0572] Preparation of 1H-benzo[d]imidazol-2-amine

[0573] [Chemical formula 49]

[0574]

[0575] 2-Chloro-1-methyl-6-phenoxy-1H-benzo[d]imidazole (5 mg, 0.019 mmol) and tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (6.64 mg, 0.021 mmol) were added to 4N hydrochloric acid / 1,4-dioxane solution (0.5 mL) and stirred at 120° C. for 6 days. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified using HPLC preparative chromatography to give the title compound (1.3 mg) as formate.

[0576] 1 H NMR (400MHz, DMSO-d6) δ11.32 (s, 1H), 8.74 (s, 1H), 8.39 (s, 1H), 8.22 (d, J = 2.7Hz, 1H), 7.78 (d, J = 8.4Hz, 1H), 7.36-7.30 (m, 2H), 7.28 (dd, J = 8.4, 7.2Hz, 2H), 7.08 (d, J=2.4Hz, 1H), 7.06-7.01 (m, 1H), 6.96-6.90 (m, 2H), 6.73 (dd, J=8.4, 2.4Hz, 1H), 3.71 (s, 3H); LCMS (m / z) 434.2[M+H] + .

[0577] Embodiment 41

[0578] N-(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-methyl-5-phenoxy-

[0579] Preparation of 1H-benzo[d]imidazol-2-amine

[0580] [Chemical formula 50]

[0581]

[0582] (First step)

[0583] By the same method as in the first step of Example 39, using 2-nitro-4-phenoxyaniline (230 mg, 1 mmol), N-methyl-2-nitro-4-phenoxyaniline (241 mg) was obtained.

[0584] LCMS (m / z) 245.2 [M+H] + .

[0585] (Second step)

[0586] By the same method as in the second step of Example 23, N1-methyl-4-phenoxybenzene-1,2-diamine (193 mg) was obtained using N-methyl-2-nitro-4-phenoxyaniline (237 mg, 0.97 mmol).

[0587] LCMS (m / z) 215.2 [M+H1] + .

[0588] (Third step)

[0589] By the same method as in the third step of Example 26, 1-methyl-5-phenoxy-1,3-dihydro-2H-benzo[d]imidazol-2-one (142 mg) was obtained using N1-methyl-4-phenoxybenzene-1,2-diamine (190 mg, 0.887 mmol).

[0590] LCMS (m / z) 241.2 [M+H] + .

[0591] (Step 4)

[0592] 1-Methyl-5-phenoxy-1,3-dihydro-2H-benzo[d]imidazol-2-one (140 mg, 0.583 mmol) was used to obtain 2-chloro-1-methyl-5-phenoxy-1H-benzo[d]imidazole (68 mg) by the same method as in the second step of Example 3.

[0593] LCMS (m / z) 259.2 [M+H]+.

[0594] (Fifth step)

[0595] The title compound (2.5 mg) was obtained as a formate salt using the same method as the third step of Example 14 using 2-chloro-1-methyl-5-phenoxy-1H-benzo[d]imidazole (12 mg, 0.046 mmol) and tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (15.93 mg, 0.051 mmol).

[0596] 1 H NMR (400MHz, DMSO-d6) δ11.33 (s, 1H), 8.79 (s, 1H), 8.30 (s, 1H), 8.18 (d, J = 2.7Hz, 1H), 7.77 (d, J = 8.5Hz, 1H), 7.35- 7.25 (m, 4H), 7.06-7.00 (m, 1H), 6.96-6.88 (m, 3H), 6.73 (dd, J=8.4, 2.3Hz, 1H), 3.75 (s, 3H); LCMS (m / z) 434.2[M+H] + .

[0597] Embodiment 42

[0598] N-(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-methyl-6

[0599] Preparation of -(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

[0600] [Chemical formula 51]

[0601]

[0602] (First step)

[0603] 2-chloro-1-nitro-4-(trifluoromethyl)benzene (400mg, 1.773mmol) was added 2M methylamine / THF solution (2.22mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. In order to complete the reaction, the obtained residue was treated with 2M methylamine / THF solution (2.22mL) again to obtain N-methyl-2-nitro-5-(trifluoromethyl)aniline (379mg) by similar reaction.

[0604] LCMS (m / z) 221.3 [M+H] + .

[0605] (Second step)

[0606] N-methyl-2-nitro-5-(trifluoromethyl)aniline (377 mg, 1.712 mmol) was dissolved in ethanol (6 mL), 10% palladium on carbon (91 mg) was added, and the reaction was carried out at room temperature for 2 hours under a hydrogen atmosphere. Insoluble matter was filtered off, and the filtrate was concentrated to give N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine (300 mg).

[0607] LCMS (m / z) 191.1 [M+H] + .

[0608] (Third step)

[0609] To THF (10 mL) containing N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine (297 mg, 1.562 mmol) was added THF (10 mL) containing CDI (380 mg, 2.343 mmol) and stirred at 70° C. for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1) to obtain 1-methyl-6-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-one (202 mg).

[0610] LCMS (m / z) 217.1 [M+H] + .

[0611] (Step 4)

[0612] 1-Methyl-6-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (201 mg, 0.93 mmol) was used to obtain 2-chloro-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (103 mg) by the same method as the second step of Example 3.

[0613] LCMS (m / z) 235.1 [M+H] + .

[0614] (Fifth step)

[0615] To 2-chloro-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (15 mg, 0.064 mmol) was added a NMP solution (0.3 mL) containing tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (21.95 mg, 0.07 mmol) and p-toluenesulfonic acid monohydrate (18.24 mg, 0.096 mmol), and stirred at 120° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1, then ethyl acetate: methanol = 1: 0-0: 1), followed by ion exchange column (SCX) to obtain the title compound (7.3 mg).

[0616] 1 H NMR (400MHz, DMSO-d6) δ11.41 (s, 1H), 9.02 (s, 1H), 8.18 (d, J=2.7Hz, 1H), 7.79 (d, J=8.5Hz, 1H), 7.66 (s, 1H), 7.43-7.26 (m, 3H), 3.82 (s, 3H); LCMS (m / z) 410.2[M+H] + .

[0617] Embodiment 43

[0618] N-(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-methyl-5-

[0619] Preparation of (trifluoromethyl)-1H-benzo[d]imidazol-2-amine

[0620] [Chemical formula 52]

[0621]

[0622] (First step)

[0623] 1-Methyl-5-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (316 mg, 1.462 mmol) was used to obtain 2-chloro-1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (246 mg) by the same method as the second step of Example 3.

[0624] LCMS (m / z) 235.1 [M+H] + .

[0625] (Second step)

[0626] To 2-chloro-1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (11 mg, 0.047 mmol) was added a solution of tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (16.10 mg, 0.052 mmol) in NMP (0.3 mL) and p-toluenesulfonic acid monohydrate (13.38 mg, 0.07 mmol) and stirred at 120° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was treated with an ion exchange column (SCX) and purified using HPLC preparative chromatography to give the title compound (1.5 mg) as a formate salt.

[0627] 1 H NMR (400MHz, DMSO-d6) δ11.42 (s, 1H), 9.01 (s, 1H), 8.52 (s, 1H), 8.20 (d, J = 2.7Hz, 1H), 7.79 (d, J = 8.4Hz, 1H), 7 .55 (s, 1H), 7.46 (d, J = 8.3Hz, 1H), 7.35-7.32 (m, 1H), 7.30 (d, J = 8.5Hz, 1H), 3.81 (s, 3H); LCMS (m / z) 410.1 [M+H] + .

[0628] Embodiment 44

[0629] N-(5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-methyl-6-

[0630] Preparation of phenoxy-1H-benzo[d]imidazol-2-amine

[0631] [Chemical formula 53]

[0632]

[0633] To 2-chloro-1-methyl-6-phenoxy-1H-benzo[d]imidazole (18 mg, 0.07 mmol) was added a solution of NMP (0.5 mL) containing tert-butyl (5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (20.49 mg, 0.077 mmol) and p-toluenesulfonic acid monohydrate (19.85 mg, 0.104 mmol) and stirred at 120° C. for 1 hour. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with chloroform. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1, followed by ethyl acetate: methanol = 1: 0-0: 1) to obtain the title compound (7.4 mg).

[0634] 1 H NMR (400MHz, DMSO-d6) δ11.30 (s, 1H), 8.74 (s, 1H), 8.24 (d, J = 2.7Hz, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.36-7.30 (m, 2H), 7.27 (d, J = 8.4Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.08 (d, J=2.3Hz, 1H), 7.07-7.00 (m, 1H), 6.95-6.90 (m, 2H), 6.73 (dd, J=8.4, 2.3Hz, 1H), 3.71 (s, 3H); LCMS (m / z) 390.2[M+H] + .

[0635] Examples 45 to 47

[0636] According to the method described in Example 44 above, and as necessary, by appropriately combining methods commonly used in synthetic organic chemistry, the following example compounds [Table 1] were produced using corresponding starting materials.

[0637] In addition, the physicochemical data of each compound are shown in [Table 2].

[0638] [Table 1]

[0639]

[0640] [Table 2]

[0641]

[0642] Embodiment 48

[0643] N-[5-(cyclohex-1-en-1-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl]-5-

[0644] Preparation of phenoxy-1H-benzo[d]imidazol-2-amine

[0645] [Chemical formula 54]

[0646]

[0647] N-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-1H-benzo[d]imidazol-2-amine (75 mg, 0.178 mmol) was added to a mixed solvent of 1,4-dioxane / water (10:1, 2.2 mL) with 1-cyclohexene-1-yl-boronic acid (33.7 mg, 0.268 mmol) and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (12.64 mg, 0.018 mmol) and cesium fluoride (81 mg, 0.535 mmol), and reacted at 100° C. for 30 minutes using a microwave reactor. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure. The obtained residue was crudely purified by silica gel chromatography (chloroform: methanol=1:0-0:1) and further purified by HPLC preparative chromatography to give the title compound (2 mg) in the form of a formate salt.

[0648] 1 H NMR (400 MHz, methanol-d4) δ 8.49 (s, 1H), 7.83 (d, J = 8.7Hz, 1H), 7.56 (s, 1H), 7.48 (d, J = 8.7Hz, 1H), 7.40-7.33(m, 2H), 7.29(d, J=8.5Hz, 1H), 7.15-7.08(m, 1H), 7.04-6.99( m, 2H), 6.94-6.87 (m, 2H), 6.66-6.59 (m, 1H), 2.69-2.63 (m, 2H), 2.31-2 .24(m, 2H), 1.85-1.75(m, 2H), 1.75-1.66(m, 2H); LCMS(m / z)422.2[M+H] + .

[0649] Embodiment 49

[0650] N-(6-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-1H-benzo

[0651] [d] Preparation of imidazole-2-amine

[0652] [Chemical formula 55]

[0653]

[0654] (First step)

[0655] 6- bromo-3-nitro-1H-pyrrolo-[3,2-b] pyridine (301mg, 1.244mmol) is dissolved in a mixed solvent (2: 1, 15mL) of methanol / saturated aqueous ammonium chloride solution, and zinc powder (813mg, 12.44mmol) is added and stirred at room temperature for 10 minutes.By Boc2O (326mg, 1.492mmol) is added to this mixture and stirred at room temperature for 1 hour.After the reaction mixture is diluted with ethanol, it is filtered using diatomaceous earth, and the filtrate is concentrated under reduced pressure.The obtained residue is purified by silica gel chromatography (chloroform: methanol=1: 0-97: 3) to obtain tert-butyl (6- bromo-1H-pyrrolo-[3,2-b] pyridine-3-yl) carbamate (250mg).

[0656] 1 H NMR (400MHz, DMSO-d6) δ 11.15 (s, 1H), 8.74 (s, 1H), 8.34 (d, J=2.0Hz, 1H), 7.96 (d, J=2.0Hz, 1H), 7.68 (s, 1H), 1.45 (s, 9H).

[0657] (Second step)

[0658] To tert-butyl (6-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (150 mg, 0.707 mmol) was added a solution of 2-chloro-5-phenoxy-1H-benzo[d]imidazole in NMP (3 mL) (156 mg, 0.637 mmol) and p-toluenesulfonic acid monohydrate (202 mg, 1.061 mmol), and stirred at 120° C. for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by amine-modified silica gel chromatography (chloroform: methanol=1:0-19:1) to obtain the title compound (20 mg).

[0659] 1 H NMR(400MHz, DMSO-d6)δ 11.19 (brs, 1H), 10.61 (brs, 1H), 9.48 (brs, 1H), 8.40 (d, J=2.0Hz, 1H), 8.12 (s, 1H), 8.04 (d, J=2.0Hz, 1H), 7.38-7.31 ( m, 2H), 7.28 (d, J=8.4Hz, 1H), 7.05 (t, J=7.4Hz, 1H), 7.00-6.90 (m, 3H), 6.71 (brd, J=8.3Hz, 1H); LCMS (m / z) 420.1 [M+H] + .

[0660] Embodiment 50

[0661] N-(5-cyclohexyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-1H-

[0662] Preparation of benzo[d]imidazol-2-amine

[0663] [Chemical formula 56]

[0664]

[0665] N-[5-(Cyclohex-1-ene-1-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl]-5-phenoxy-1H-benzo[d]imidazol-2-amine (16 mg, 0.038 mmol) was dissolved in a mixed solvent of ethanol / ethyl acetate (1:1, 3 mL) and 10% palladium on carbon (4.04 mg) was added, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere, and further stirred at 50 ° C overnight. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. In order to complete the reaction, the obtained residue was dissolved in an ethanol solvent (1 mL) and washed with 10% palladium on carbon (4.04 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified using HPLC preparative chromatography to obtain the title compound (0.35 mg) in the form of a formate salt.

[0666] 1 H NMR (400MHz, methanol-d4)δ 8.55 (s, 1H), 7.79 (d, J=8.5Hz, 1H), 7.62 (s, 1H), 7.37-7.30 (m, 2H), 7.27 (d, J=8.5H z, 1H), 7.17 (d, J=8.5Hz, 1H), 7.09-7.01 (m, 1H), 7.00-6.96 (m, 3H), 6.80 (dd, J=8.4 , 2.3Hz, 1H), 2.94-2.82(m, 1H), 2.12-2.03(m, 1H), 1.95-1.87(m, 3H), 1.85-1.76(m , 2H), 1.76-1.63(m, 2H), 1.58-1.45(m, 1H), 1.40-1.30(m, 1H); LCMS (m / z) 422.3[MH] - .

[0667] Embodiment 51

[0668] 5-Phenoxy-N-(6-phenyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-benzo

[0669] [d] Preparation of imidazole-2-amine

[0670] [Chemical formula 57]

[0671]

[0672] N-(6-Bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-1H-benzo[d]imidazol-2-amine (12 mg, 0.029 mmol) was added to a mixed solvent of 1,4-dioxane / water (10:1, 0.55 mL) with phenylboronic acid (5.22 mg, 0.043 mmol) and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (12.02 mg, 0.00286 mmol) and cesium fluoride (13.01 mg, 0.086 mmol), and reacted at 100° C. for 30 minutes using a microwave reactor. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol=1:0-19:1) to obtain the title compound (7 mg).

[0673] 1 H NMR (400 MHz, DMSO-d6) δ 11.08-11.02 (m, 1H), 10.74-10.65 (m, 1H), 9.32 (s, 1H), 8.65 (s, 1H), 8.12 (brd, J=13.5Hz, 1H), 7.98 (d, J=2.0Hz, 1H), 7.79-7.72 (m, 2H), 7.51 (dd, J= 8.3, 7.0Hz, 2H), 7.43-7.37(m, 1H), 7.36-7.24(m, 3H), 7.04(t, J=7.4Hz, 1 H), 7.01-6.90 (m, 3H), 6.68 (dd, J=23.8, 8.8Hz, 1H); LCMS (m / z) 418.2[M+H] + .

[0674] Embodiment 52

[0675] N-(7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-1H-benzo

[0676] [d] Preparation of imidazole-2-amine

[0677] [Chemical formula 58]

[0678]

[0679] (First step)

[0680] Potassium nitrate (107 mg, 1.059 mmol) was added to concentrated sulfuric acid (1.5 mL) and stirred at room temperature for 1 minute and cooled to 0° C. 7-methyl-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.757 mmol) was added to the reaction mixture and stirred at 0° C. for 40 minutes. Ice water was added to the reaction mixture, and 28% ammonia water was added to make it alkaline. The precipitated solid was collected by filtration and dried to give 7-methyl-3-nitro-1H-pyrrolo[3,2-b]pyridine (115 mg).

[0681] 1 H NMR (400MHz, DMSO-d6) δ 12.93 (s, 1H), 8.84 (s, 1H), 8.45 (d, J = 4.8Hz, 1H), 7.19 (dd, J = 4.8, 0.9Hz, 1H), 2.55 (d, J = 0.9Hz, 3H); LCMS (m / z) 178.09 [M+H] + .

[0682] (Second step)

[0683] 7-Methyl-3-nitro-1H-pyrrolo[3,2-b]pyridine (114 mg, 0.643 mmol) was added to a mixed solvent of methanol / saturated aqueous ammonium chloride solution (2: 1, 4.5 mL) and zinc powder (421 mg, 6.43 mmol) and stirred at room temperature for 10 minutes. Boc2O (169 mg, 0.772 mmol) was added to this mixture and stirred at room temperature for 1 hour. The reaction mixture was diluted with methanol, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-97: 3) to obtain tert-butyl (7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (120 mg).

[0684] LCMS (m / z) 248.16 [M+H] + .

[0685] (Third step)

[0686] To tert-butyl (7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (110 mg, 0.445 mmol) was added a solution of 2-chloro-5-phenoxy-1H-benzo[d]imidazole in NMP (2 mL) (76 mg, 0.311 mmol) and p-toluenesulfonic acid monohydrate (127 mg, 0.667 mmol), and stirred at 120 ° C for 2.5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was collected by filtration. The obtained solid was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-19: 1), and further purified by HPLC preparative chromatography to give the title compound (44 mg) in the form of a formate salt.

[0687] 1 H NMR (400MHz, methanol-d4)δ 8.42 (brs, 1H), 8.28 (d, J = 4.8Hz, 1H), 7.81 (s, 1H), 7.36-7.31 (m, 2H), 7.29 (d, J = 8.6Hz, 1H), 7.15 (dd, J = 4.9, 0.9Hz, 1H), 7.12-7.04 (m, 1H), 7.01-6.92 (m, 3H), 6.86 (dd, J=8.6, 2.3Hz, 1H), 2.65 (d, J=0.8Hz, 3H); LCMS (m / z) 356.2[M+H] + .

[0688] Embodiment 53

[0689] N-(5-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-phenoxy-1H-benzo

[0690] [d] Preparation of imidazole-2-amine

[0691] [Chemical formula 59]

[0692]

[0693] (First step)

[0694] Trimethylboroxane (75 mg, 0.601 mmol) and potassium carbonate (221 mg, 1.602 mmol) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridinyl)dichloropalladium(II) (27.2 mg, 0.04 mmol) were added to a 1,4-dioxane solution (3 mL) containing tert-butyl 5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (125 mg, 0.4 mmol), and stirred at 130° C. for 1.5 hours using a microwave reactor. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and the obtained residue was purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-97: 3) to obtain (5-methyl-1H-pyrrolo[tert-butyl 3,2-b]pyridin-3-yl)carbamate (35 mg).

[0695] (Second step)

[0696] 2-Chloro-5-phenoxy-1H-benzo[d]imidazole (27.7 mg, 0.113 mmol) and p-toluenesulfonic acid monohydrate (40.4 mg, 0.212 mmol) were added to a NMP solution (1.5 mL) containing tert-butyl (5-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (35 mg, 0.142 mmol) and stirred at 120 ° C for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was collected by filtration. The crude product obtained was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-97: 3), and further purified by HPLC preparative chromatography to obtain the title compound (8 mg) in the form of a formate salt.

[0697] 1 H NMR(400MHz, DMSO-d6)δ 10.82-10.80 (m, 1H), 9.07 (brs, 1H), 8.19 (s, 1H), 7.99 (d, J = 2.7Hz, 1H), 7.66 (d, J = 8.3Hz, 1H), 7.38-7.29 (m, 2H), 7.26 (d, J = 8.3Hz , 1H), 7.07-7.00 (m, 2H), 6.96 (d, J=2.4Hz, 1H), 6.95-6.90 (m, 2H), 6.66 (dd, J=8.3, 2.4Hz, 1H), 2.59 (s, 3H); LCMS (m / z) 356.1[M+H] + .

[0698] Embodiment 54

[0699] 5-Phenoxy-N-(7-phenyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-benzo

[0700] [d] Preparation of imidazole-2-amine

[0701] [Chemical formula 60]

[0702]

[0703] (First step)

[0704] 7-Chloro-3-nitro-1H-pyrrolo[3,2-b]pyridine (95 mg, 0.481 mmol) was dissolved in a mixed solution of 1,4-dioxane solution / water (2:1, 3 mL) with phenylboric acid (88 mg, 0.721 mmol) and sodium carbonate (204 mg, 1.923 mmol) and tetrakis(triphenylphosphine)palladium(0) (111 mg, 0.096 mmol), and reacted at 150° C. using a microwave reactor for 30 minutes. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and the obtained residue was crudely purified by amine-modified silica gel chromatography (chloroform: methanol=1:0-4:1) to obtain an intermediate. This intermediate was dissolved in a mixed solvent of methanol / saturated aqueous ammonium chloride solution (2:1, 4.5 mL) and zinc powder (301 mg, 4.60 mmol) was added, and after stirring at room temperature for 10 minutes, Boc2O (120 mg, 0.552 mmol) was added, and the mixture was further stirred at room temperature for 40 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by amine-modified silica gel chromatography (hexane: ethyl acetate = 1:0-1:1) to obtain tert-butyl (7-phenyl-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (90 mg).

[0705] (Second step)

[0706] 2-Chloro-5-phenoxy-1H-benzo[d]imidazole (49.8mg, 0.204mmol) and p-toluenesulfonic acid monohydrate (83mg, 0.436mmol) were added to tert-butyl (7-phenyl-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (90mg, 0.291mmol) and stirred at 120°C for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was collected by filtration. The obtained solid was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-97: 3), and further purified by silica gel chromatography (chloroform: methanol = 1: 0-97: 3) to obtain the title compound (23mg).

[0707] 1H NMR(400MHz, DMSO-d6)δ 11.01 (s, 1H), 10.72 (brs, 1H), 9.35 (s, 1H), 8.43 (d, J=4.8Hz, 1H), 8.09 (d, J=2. 6Hz, 1H), 7.82-7.75(m, 2H), 7.66-7.57(m, 2H), 7.59-7.49(m, 1H), 7.36-7.31(m , 2H), 7.29 (d, J=8.7Hz, 1H), 7.26 (d, J=4.8Hz, 1H), 7.07-7.01 (m, 1H), 7.00 (d, J =2.3Hz, 1H), 6.96-6.91(m, 2H), 6.69(brd, J=8.4Hz, 1H); LCMS (m / z) 418.2[M+H] + .

[0708] Embodiment 55

[0709] 5-phenoxy-N-[5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]-

[0710] Preparation of 1H-benzo[d]imidazol-2-amine

[0711] [Chemical formula 61]

[0712]

[0713] (First step)

[0714] Potassium nitrate (243 mg, 2.407 mmol) was added to concentrated sulfuric acid (5 mL) and stirred at room temperature for 1 minute. The reaction mixture was cooled to 0 ° C, and 5- (trifluoromethyl) -1H- pyrrolo [3, 2-b] pyridine (320 mg, 1.719 mmol) was added and stirred at 0 ° C for 1.5 hours. Ice water was added to the reaction mixture, and the precipitated solid was collected by filtration and dried to give 3- nitro -5- (trifluoromethyl) -1H- pyrrolo [3, 2-b] pyridine (360 mg).

[0715] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.22 (d, J = 8.5Hz, 1H), 7.82 (d, J = 8.6Hz, 1H); LCMS (m / z) 232.06 [M+H] + .

[0716] (Second step)

[0717] 3-Nitro-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine (360 mg, 1.558 mmol) was dissolved in a mixed solvent (2:1, 15 mL) of methanol / saturated aqueous ammonium chloride solution, and zinc powder (1.02 g, 15.58 mmol) was added and stirred at room temperature for 10 minutes. Boc2O (408 mg, 1.869 mmol) was added to the mixture and stirred at room temperature for 50 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by amine-modified silica gel chromatography (chloroform: methanol = 1:0-97:3) to obtain [5-(trifluoromethyl)-1H-pyrrolo[3, tert-butyl 2-b]pyridin-3-yl]carbamate (310 mg).

[0718] (Third step)

[0719] 2-Chloro-5-phenoxy-1H-benzo[d]imidazole (30.1 mg, 0.123 mmol) and p-toluenesulfonic acid monohydrate (50.2 mg, 0.264 mmol) were added to a NMP solution (1.5 mL) containing tert-butyl [5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]carbamate (53 mg, 0.176 mmol) and stirred at 120° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was collected by filtration. The crude product obtained was purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-19: 1) to obtain the title compound (22 mg).

[0720] 1 H NMR(400MHz, DMSO-d6)δ 11.48-11.42 (m, 1H), 10.61-10.53 (m, 1H), 9.24 (s, 1H), 8.43-8.36 (m, 1H), 8.04-7.97 (m, 1H), 7.62 (dd, J=8.4, 0.8Hz, 1H ), 7.39-7.25(m, 3H), 7.08-7.03(m, 1H), 7.02-6.97(m, 1H), 6.96-6.91(m, 2H), 6.75-6.65(m, 1H); LCMS(m / z)410.2[M+H] + .

[0721] Embodiment 56

[0722] N-(5-chloro-1H-indol-3-yl)-1-methyl-5-(trifluoromethyl)-1H-benzo

[0723] [d] Preparation of imidazole-2-amine

[0724] [Chemical formula 62]

[0725]

[0726] (First step)

[0727] Thiophosgene (374 mg, 3.25 mmol) and DIPEA (764 mg, 5.91 mmol) were added to THF (15 mL) containing 5-chloro-1H-indole-3-amine hydrochloride (600 mg, 2.95 mmol), and stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine in that order. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5-chloro-3-isothiocyanato-1H-indole (617 mg).

[0728] 1 H NMR(400MHz, DMSO-d6)δ 11.77 (s, 1H), 7.84 (d, J=2.9Hz, 1H), 7.58 (d, J=2.0Hz, 1H), 7.48 (d, J=8.7Hz, 1H), 7.23 (dd, J=8.7, 2.0Hz, 1H); LCMS (m / z) 207.1[MH] - .

[0729] (Second step)

[0730] A DMF solution (10 mL) of 5-chloro-3-isothiocyanato-1H-indole (411 mg, 1.97 mmol) containing N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (356 mg, 1.87 mmol) was added and stirred at 50° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated brine in the order described. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-4: 1) to obtain a thiourea compound (413 mg). The obtained thiourea compound (410 mg, 1.03 mmol) was dissolved in DMF (8 mL), EDCI-HCl (296 mg, 1.54 mmol) was added to the solution, and the mixture was stirred at 50° C. for 2 hours. In order to complete the reaction, the mixture was further stirred at 60° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated brine in that order. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 0-1: 1) to obtain the title compound (273 mg).

[0731] 1 H NMR(400MHz, DMSO-d6)δ 11.07 (s, 1H), 8.80 (s, 1H), 7.92 (d, J = 2.5Hz, 1H), 7.85 (dt, J = 2.2, 0.6Hz, 1H), 7.56-7.54 (m, 1H), 7.45 (d, J = 8.3Hz, 1H), 7.40 (dd, J=8.6, 0.6Hz, 1H), 7.35-7.31 (m, 1H), 7.11 (dd, J=8.5, 2.1Hz, 1H), 3.80 (s, 3H); LCMS (m / z) 365.1[M+H] + .

[0732] Embodiment 57

[0733] N-(5-chloro-1H-indol-3-yl)-1-cyclopropyl-5-(trifluoromethyl)-1H-benzo

[0734] [d] Preparation of imidazole-2-amine

[0735] [Chemical formula 63]

[0736]

[0737] N1-cyclopropyl-4-(trifluoromethyl)benzene-1,2-diamine (607 mg, 2.81 mmol) was added to a DMF solution (10 mL) of 5-chloro-3-isothiocyanato-1H-indole (617 mg, 2.96 mmol) and stirred at 50°C for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and a saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was crudely purified by silica gel chromatography (chloroform: methanol = 1: 0-19: 1) to obtain a thiourea compound (758 mg). The obtained thiourea compound (758 mg, 1.78 mmol) was dissolved in DMF (10 mL), EDCI-HCl (513 mg, 68 mmol) was added and stirred at 60°C for 1.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated brine in the order described. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography (hexane: ethyl acetate = 1: 0-1: 1) and amine-modified silica gel chromatography (hexane: ethyl acetate = 1: 0-0: 1, and further purified with chloroform: methanol = 1: 0-49: 1). The obtained crude product was suspended and washed with diethyl ether to obtain the title compound (295 mg).

[0738] 1 H NMR(400MHz, DMSO-d6)δ 11.09 (s, 1H), 8.65 (s, 1H), 7.84 (d, J=2.4Hz, 1H), 7.74 (d, J=2.1Hz, 1H), 7.52-7.50 (m, 1H), 7.48-7.43 (m, 1H), 7.41 (dd, J=8.6, 0.6Hz , 1H), 7.34-7.30 (m, 1H), 7.11 (dd, J=8.7, 2.1Hz, 1H), 3.30-3.26 (m, 1H), 1.37-1.27 (m, 2H), 1.09-1.00 (m, 2H); LCMS (m / z) 391.1[M+H] + .

[0739] Embodiment 58

[0740] N-(5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-6-(4-fluorophenoxy)-1-

[0741] Preparation of methyl-1H-benzo[d]imidazol-2-amine

[0742] [Chemical formula 64]

[0743]

[0744] (First step)

[0745] 4N hydrochloric acid / ethyl acetate solution (60 mL) was added to tert-butyl (5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (4.5 g, 16.81 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction suspension was filtered and the solid was dried to obtain 5-chloro-1H-pyrrolo[3,2-b]pyridin-3-amine hydrochloride (3.4 g).

[0746] 1 H NMR (400MHz, DMS0-d6) δ 11.90 (s, 1H), 10.26 (s, 3H), 7.97 (d, J = 8.6Hz, 1H), 7.86 (d, J = 3.1Hz, 1H), 7.31 (d, J = 8.6Hz, 1H); LCMS (m / z) 168.0 [M+H] + .

[0747] (Second step)

[0748] Thiophosgene (2.11 g, 18.33 mmol) and DIPEA (4.31 g, 33.3 mmol) were added to THF (100 mL) containing 5-chloro-1H-pyrrolo[3,2-b]pyridine-3-amine hydrochloride (3.4 g, 16.66 mmol), and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was washed with water and saturated brine in that order. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 5-chloro-3-isothiocyanato-1H-pyrrolo[3,2-b]pyridine (3.49 g).

[0749] 1 H NMR (400MHz, DMSO-d6) δ 12.01 (s, 1H), 8.06 (d, J = 3.2Hz, 1H), 7.94 (d, J = 8.5Hz, 1H), 7.31 (d, J = 8.6Hz, 1H); LCMS (m / z) 210.0 [M+H] + .

[0750] (Third step)

[0751] DMF (20 mL) containing 5-fluoro-N-methyl-2-nitroaniline (1 g, 5.88 mmol), 4-fluorophenol (988 mg, 8.82 mmol) and potassium carbonate (1.625 g, 11.75 mmol) were added and stirred overnight at 95° C. After the reaction mixture was cooled to room temperature, it was diluted with water. The precipitated solid was filtered, washed with water, and dried to give 5-(4-fluorophenoxy)-N-methyl-2-nitroaniline (954 mg).

[0752] 1 H NMR(400MHz, DMSO-d6)δ 8.32-8.26 (m, 1H), 8.10 (d, J=9.4Hz, 1H), 7.35-7.28 (m, 2H), 7.27-7.20 (m, 2H), 6.35 (d, J=2.5Hz, 1H), 6.20 (dd, J=9.5, 2.6Hz, 1H), 2.85 (d, J=5.0Hz, 3H); LCMS (m / z) 263.0[M+H] + .

[0753] (Step 4)

[0754] 5-(4-Fluorophenoxy)-N-methyl-2-nitroaniline (954 mg, 3.64 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and ethyl acetate (10 mL), 10% palladium / carbon (116 mg) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. Insoluble materials were filtered off, and the filtrate was concentrated to give 5-(4-fluorophenoxy)-N1-methylbenzene-1,2-diamine (845 mg).

[0755] 1 H NMR(400MHz, DMSO-d6)δ 7.17-7.06(m, 2H), 6.93-6.84(m, 2H), 6.55-6.48(m, 1H), 6.12-6.04(m, 2H), 4. 83 (q, J=5.0Hz, 1H), 4.35 (s, 2H), 2.65 (d, J=5.0Hz, 3H); LCMS (m / z) 233.1[M+H] + .

[0756] (Fifth step)

[0757] 5-(4-Fluorophenoxy)-N1-methylbenzene 1,2-diamine (110 mg, 0.474 mmol), EDCI-HCl (121 mg, 0.631 mmol), pyridine (250 mg, 3.16 mmol) were added to DMF (4 mL) containing 5-chloro-3-isothiocyanato-1H-pyrrolo[3,2-b]pyridine (66.2 mg, 0.316 mmol), and stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated brine in that order. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was crudely purified by amine-modified silica gel chromatography (chloroform: methanol = 1: 0-97: 3) and silica gel chromatography (chloroform: methanol = 1: 0-97: 3), followed by ion exchange column (SCX) to obtain the title compound (14 mg).

[0758] 1 H NMR(400MHz, DMSO-d6)δ 11.32 (s, 1H), 8.75 (s, 1H), 8.22 (s, 1H), 7.87 (d, J = 8.5Hz, 1H), 7.26 (d, J = 8.4Hz, 1H), 7.21-7.13 (m , 3H), 7.11-7.05 (m, 1H), 7.00-6.93 (m, 2H), 6.78-6.69 (m, 1H), 3.71 (s, 3H); LCMS (m / z) 408.1 [M+H] + .

[0759] Example 59-288

[0760] According to the method described in the above examples, the following example compounds [Table 3] were obtained by using the corresponding raw materials (commercial products, or compounds obtained by derivatizing commercially available compounds by known methods or methods similar thereto). Depending on the case, they were produced by appropriately combining methods commonly used in synthetic organic chemistry. In addition, the physicochemical data of each compound are shown in [Table 4].

[0761] [Table 3]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789] Table 3 continued

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796] [Table 4]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820] Table 4 continued

[0821]

[0822]

[0823]

[0824]

[0825]

[0826] Test Example 1

[0827] Inhibition assay of the intracellular human STING (hSTING) pathway using reporter cells

[0828] Since STING activates the transcription factor IRF3 upon ligand stimulation, the activity of STING can be assessed by a reporter assay using secreted alkaline phosphatase (SEAP reporter) integrated downstream of an IRF-inducible promoter.

[0829] That is, using HEK-Blue incorporating the SEAP reporter 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).

[0830] HEK-Blue TM ISG cells were seeded in a 96-well plate and cultured overnight at 37° C. in a 5% CO2 incubator. To each well of this cell culture plate, a test compound solution adjusted to a final concentration of 0.1 to 10 μM of the test compound was added, cultured in a c incubator for 1 hour, and then compound 3 (final concentration 10 nM) was added, and further cultured in a CO2 incubator for 21 hours. After collecting the culture supernatant of each well, the reporter activity was measured by a colorimetric reaction with alkaline phosphatase.

[0831] (Evaluation method of inhibitory activity)

[0832] The reporter activity of the group without adding the test compound and adding compound 3 was set to 100%, and the reporter activity of the group without adding the test compound and adding compound 3 was set to 0%. 50 Values ​​were determined by regression analysis of the inhibition ratio determined from the reporter activity at each compound concentration and the test compound concentration (log).

[0833] (Evaluation results)

[0834] Table 5 shows the inhibitory activity of representative compounds of the present invention against hSTING. hSTING inhibition is indicated as follows: ***: less than 0.1 μM, **: 0.1 μM to less than 1 μM, *: 1 μM to less than 10 μM, and 10 μM or more is indicated by -.

[0835] [Table 5]

[0836] [Table 5]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843] Table 5 continued

[0844]

[0845]

[0846] This result indicates that compound (I) of the present invention has a strong STING pathway inhibitory activity.

[0847] Test Example 2

[0848] Cytokine production inhibition test using STING agonist-stimulated mouse model

[0849] A mouse STING agonist, CMA (10-carboxymethyl-9-acridone), was administered to mice to stimulate the STING pathway, and the amount of cytokines (IFN-β, IL-6, TNF-α) released into the blood was evaluated for the inhibitory effects of the compounds of the present invention (compounds of Examples 3, 56, 57 and 58).

[0850] (Adjustment of test compound solution)

[0851] DMSO, polyethylene glycol #400 and 30% (w / v) hydroxypropyl-β-cyclodextrin were sequentially added to the test compound and the wells were mixed (5:20:75 solvent composition) to prepare a test compound solution. For the solvent administration group, a solution having the same solvent composition but not containing the test compound was used.

[0852] (Response to CMA stimulation)

[0853] C57BL / 6N mice (female, 6 to 9 weeks old) were orally administered with a vehicle or a test compound solution adjusted to a test dose (4 mice per group). One hour after administration, CMA (Tokyo Kasei Kogyo) suspended in a 0.5% methylcellulose solution was intraperitoneally administered to mice at a dose of 224 mg / kg. Two hours after CMA administration, blood was collected from each mouse, and the plasma concentrations of IFN-β, IL-6, and TNF-α were measured using Duoset ELISA kits (R&D Systems).

[0854] (Evaluation results)

[0855] The results are shown in Figure 1-3 All test results are indicated by *, ** or ***.

[0856] Dunnett's multiple comparison test (compared with vehicle group)

[0857] ***p<0.001

[0858] **p<0.01

[0859] *p<0.05

[0860] like Figures 1 to 3 As shown in the Figure 2, compared with the solvent group, the representative compounds of the present invention significantly inhibited or tended to inhibit the production of cytokines induced by STING stimulation. This result indicates that the compound (I) of the present invention has an inhibitory effect on the production of IFN-β, IL-6 and TNF-α induced by STING activation in mice.

[0861] Test Example 3

[0862] Inhibition test of human IFN-β production stimulated by cGAMP

[0863] The inhibitory activity of the test compounds against STING activation was evaluated by measuring the amount of IFN-β produced when THP-1 cells, a human monocytic cell line, were stimulated with the endogenous ligand cGAMP.

[0864] After inoculating THP-1 cells (ATCC) in a 96-well plate, PMA (Santa Cruz Biotechnology) was adjusted to a concentration of 100 nM after addition and cultured in a 5% CO2 incubator at 37°C. It was cultured overnight (RPMI1640 medium containing 10% FBS, 50 U / mL penicillin / 50 μg / mL streptomycin). The test compound solution adjusted to a final concentration of 0.001 to 1 μM was added to each well of this plate and cultured in a CO2 incubator for 1 hour (DMSO final concentration 0.1%). 0.12 μg / well of 2′3′-cGAMP (Invivogen, #tlrl-nacga23) was introduced into the cells by transfection using Lipofectamine 2000 (Invitrogen) and cultured for another 18 hours in a CO2 incubator. After collecting the culture supernatant from each well, the amount of human IFN-β produced in the culture supernatant was measured by ELISA using R&D human IFN-β Duoset (R&D Systems).

[0865] (Evaluation method of inhibitory activity)

[0866] Assuming that the human IFN-β production in the group without test compound and cGAMP addition is 100%, and the human IFN-β production in the group without test compound and cGAMP is 0%, then IC 50The values ​​were determined by regression analysis of the inhibition ratio determined from the amount of human IFN-β production at each compound concentration and the test compound concentration (logarithm).

[0867] (Evaluation results)

[0868] Table 6 shows the IFN-β production inhibitory activity of representative compounds of the present invention. For IFN-β production inhibitory activity, the IC values ​​of less than 0.01 μM 50 Values ​​are marked with ***, 0.01 μM or more and less than 0.1 μM are marked with **, 0.1 μM or more and less than 1 μM are marked with *, and 1 μM or more is indicated with -.

[0869] [Table 6]

[0870] [Table 6]

[0871]

[0872]

[0873]

[0874]

[0875] This result indicates that compound (I) of the present invention exhibits strong IFN-β production inhibitory activity, indicating that it strongly inhibits the activation of the STING pathway.

[0876] Industrial Applicability

[0877] The compounds provided by the present invention are effective as preventive or therapeutic drugs (pharmaceutical compositions) for diseases known to be associated with STING-mediated cellular responses, such as inflammatory diseases, autoimmune diseases, cancer, etc. In addition, by combining with therapeutic agents for other inflammatory diseases, autoimmune diseases and cancers, effects on immune responses, etc. can be expected, and they can be used as therapeutic drugs (pharmaceutical compositions). In addition, they can be used as STING inhibitors and can be used as reagents for experimental studies.

Claims

1. A benzimidazole derivative or a pharmaceutically acceptable salt thereof, represented by the following formula (I): [Chemical formula 1] in, A 1 Represents nitrogen atom or CR 7 , A 2 Represents nitrogen atom or CR 8 , A 3 Represents nitrogen atom or CR 9 , R 1 is a hydrogen atom, a halogen atom, a C1-4 alkyl group optionally substituted by halogen, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-7 cycloalkyl group, a C3-7 cycloalkenyl group, a C1-4 alkoxy group, a phenyl group, a C1-4 alkoxycarbonyl group, a carboxyl group, a cyano group, a phenylcarbamoyl group, a 2-propynylcarbamoyl group or a 4-morpholinecarbonyl group, R 2 , R 3 , R 4 and R 5 each independently and optionally selected from the group consisting of a hydrogen atom, a halogen atom, a C1-4 alkyl group optionally substituted with a halogen and / or a C1-4 alkoxy group, a C2-6 alkenyl group optionally substituted with a C1-4 alkoxy group, a halogen group and / or a cyclopropyl group, a C2-6 alkynyl group optionally substituted with a C1-4 alkoxy group, a cyclopropyl group and / or a dimethylamino group, a C3-7 cycloalkyl group, a C1-4 alkoxy group optionally substituted with a C1-4 alkoxy group, a C3-7 cycloalkyloxy group, a phenyl group optionally substituted with a halogen or a morpholinomethyl group, optionally a phenoxy group substituted with a methylsulfonyl group, a dimethylamino group, a cyano group, a halogen atom and / or a dimethylaminomethyl group, a monocyclic nitrogen-containing heteroaryl group selected from pyridyl and methylpyrazolyl, a monocyclic nitrogen-containing heteroaryloxy group selected from pyridyloxy and methylpyrazinyloxy, a heterocyclic ring selected from dihydropyranyl, tetrahydropyranyl and piperidinyl, a heterocyclic oxy group selected from oxetanyloxy, tetrahydroxypyranyloxy and piperidinyloxy, N-methyl, N-phenylaminosulfonyl, dimethylcarbamoyl, benzyloxy, cyano, nitro, carboxyl and methoxycarbonyl; wherein R 2 and R 3 , or R 3 and R 4 , or R 4 and R 5 can be bonded to each other to form a saturated heterocyclic 5-membered or heterocyclic 6-membered ring, R 6 is: a hydrogen atom, a C1-4 alkyl group optionally substituted by a hydroxyl group, a cyclopropyl group, a C1-4 alkoxy group, a dimethylamino group, a dimethylcarbamoyl group or a methylsulfonyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-7 cycloalkyl group, an amino group optionally substituted by a dimethylamino group, a methylamino group or an amino group, a heteroaryl group selected from a pyridyl group and a methylimidazolyl group, a heterocyclic group selected from an oxetanyl group and a pyrrolidinyl group, R 7 , R 8 and R 9 each independently and optionally selected from the group consisting of a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C2-6 alkenyl group, a C3-7 cycloalkenyl group, a C1-4 alkoxy group, a phenyl group, a monocyclic nitrogen-containing heteroaryl group selected from a pyridyl group and a methylpyrazolyl group, a hydroxyl group, a dimethylamino group and a dimethylcarbamoyl group, The following five compounds are excluded: N-(2-methyl-1H-indol-3-yl)-1H-benzimidazol-2-amine, N-1H-indol-3-yl-N-methyl-1H-benzimidazol-2-amine, N-1H-indol-3-yl-1-methyl-1H-benzimidazol-2-amine, N-(1-methyl-1H-indol-3-yl)-1H-benzimidazol-2-amine, and N-1H-indol-3-yl-1H-benzimidazol-2-amine.

2. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein 1) A 1 It is C-R7, A 2 Yes CR 8 , and A 3 Yes CR 9 ; 2) A 1 is a nitrogen atom, A 2 Yes CR 8 , and A 3 Yes CR 9 ; 3) A 1 Yes CR 7 , A 2 is a nitrogen atom, and A 3 Yes CR 9 ; 4) A 1 Yes CR 7 , A 2 Yes CR 8 , and A 3 is a nitrogen atom, or 5) A 1 and A 3 are nitrogen atoms and A 2 Yes CR 8 .

3. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A 2 Represents CR 8 ,and 1) A 1 Yes CR 7 And A 3 Yes CR 9 ; 2) A 1 is a nitrogen atom and A 3 Yes CR 9 ;or 3) A 1 Yes CR 7 And A 3 It's a nitrogen atom.

4. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: A 1 , A 2 and A 3 CR 7 , CR 8 and CR 9 express.

5. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: A 1 is a nitrogen atom, and A 2 and A 3 CR 8 and CR 9 express.

6. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: A 1 Yes CR 7 , A 2 is a nitrogen atom, and A 3 Yes CR 9 .

7. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: A 1 Yes CR 7 , A 2 Yes CR 8 , and A 3 It's a nitrogen atom.

8. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: A 1 and A 3 are nitrogen atoms and A 2 Yes CR 8 .

9. A compound selected from the following table or a pharmaceutically acceptable salt thereof:

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