Novel imidazo[4,5-b]pyridine compounds and uses thereof

Abstract

The present invention provides a novel imidazopyridine compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The novel compound according to the present invention effectively inhibits the enzymatic activity of Bruton's tyrosine kinase (BTK), and thus can be advantageously used as a pharmaceutical composition for the prevention or treatment of BTK-mediated diseases, such as autoimmune diseases or cancers.

Description

Novel imidazo[4,5-B]pyridine compounds and their uses

[0001] The present invention relates to a novel imidazo[4,5-b]pyridine compound having Bruton's tyrosine kinase enzyme inhibitory activity and its use.

[0002] Bruton's tyrosine kinase (BTK) is a Tec family tyrosine kinase that was first identified as a key component of the B-cell receptor (BCR) signaling pathway and a dual-function regulator of apoptosis. It promotes radiation-induced apoptosis but inhibits Fas-activated apoptosis in B cells. BTK is a nonreceptor cytoplasmic tyrosine kinase (nRTK) that transduces signals through various cell surface molecules and is expressed by all cells of the hematopoietic lineage except T cells, plasma cells, and natural killer cells.

[0003] Recently, the covalent irreversible BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib were approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain hematologic malignancies, and additional covalent irreversible BTK inhibitors have been reported. Despite these successes, the treatment of hematologic malignancies with covalent irreversible BTK inhibitors as monotherapy remains challenging because they often fail to achieve complete response or experience relapse in a significant proportion of patients. Therefore, novel BTK inhibitors that are selective, effective, and safe are needed to achieve therapeutic effects in combination therapy.

[0004] The covalent irreversible BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib target a noncatalytic cysteine ​​residue present only in 10 kinases close to the adenosine triphosphate (ATP) binding pocket, resulting in selective and extensive inhibition of BTK that persists even after the BTK inhibitor has been metabolized and cleared. In preclinical studies, these BTK inhibitors have shown antiproliferative effects in hematologic malignancies, as well as rapid anti-inflammatory effects, neutralization of pathogenic autoantibodies, and blockade of new autoantibody production. These preclinical results of covalent irreversible BTK inhibitors have subsequently led to phase 2 clinical trials for various autoimmune diseases.

[0005] In addition to the homologous cysteine ​​binding observed in 10 kinases with non-catalytic cysteine ​​residues, covalent irreversible BTK inhibitors can also bind irreversibly and non-selectively to endogenous thiols, especially when administered at high doses. Safety concerns associated with these off-target effects have led to the development of noncovalent BTK inhibitors. While achieving sufficient selectivity for BTK over other kinase constructs in the kinase genome for noncovalent targeting is crucial, the challenge is to develop noncovalent inhibitors that exhibit sufficiently high exposure, low clearance, and sustained on-target inhibition, similar to covalent irreversible inhibitors. Current advances in this non-covalent inhibitor field have led to the development of non-covalent BTK inhibitors such as BMS-986142, which has completed a phase 2 clinical study for rheumatoid arthritis (RA), and fenobrutinib, which has completed clinical trials in RA, systemic lupus erythematosus (SLE), and chronic spontaneous urticaria (CSU).

[0006] In this way, non-covalent BTK inhibitors are drugs that complement the shortcomings of existing covalent irreversible BTK inhibitors. In this study, a new non-covalent BTK inhibitor having an imidazopyridine skeleton was developed and the present invention was completed.

[0007] The present invention provides a novel imidazopyridine compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] In addition, the present invention provides a pharmaceutical composition comprising a novel imidazopyridine compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0009] The terminology used in this application is merely used to describe specific embodiments and is not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly indicates otherwise. In this application, terms such as "comprise" or "have" should be understood to indicate the presence of a feature, step, structure, or combination thereof described above, but do not preclude the presence or addition of one or more other features, steps, structures, or combinations thereof.

[0010] The meanings of terms and symbols used in this document are as follows.

[0011] In the present invention, the term “halogen” means a substituent selected from fluorine (F), chloro (Cl), bromo (Br), and iodo (I).

[0012] In the present invention, the term “unsubstituted” means a state in which no substituent is substituted and is absent or hydrogen.

[0013] In the present invention, the term "substituted" refers to a moiety having a substituent that replaces a hydrogen atom on one or more carbon atoms of the main chain. "Substituted" or "substituted with" is defined to include the implicit condition that such substitution results in a stable compound, for example, a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc., depending on the permissibility of the substituted atom and the substituent.

[0014] In the present invention, "C x-y " means having carbon number x or more and y or less.

[0015] The term “C1-C8 alkyl” in the present invention means a straight or branched chain saturated hydrocarbon of C1-C8, such as, for example, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, n-heptyl, 1-methylhexyl, cyclopentylmethyl, cyclohexylmethyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, etc. Preferred alkyl groups contain about 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms in the chain. By side chain is meant one or more lower alkyl groups, such as methyl, ethyl, or propyl, attached to a linear alkyl chain. "Alkyl" may be unsubstituted or optionally substituted with one or more substituents, which may be the same or different.

[0016] In the present invention, the term “C 1-3 “Alkylene” means a divalent hydrocarbon group in which a radical is additionally formed from the above alkyl, examples of which include, but are not limited to, methylene, ethylene, n-propylene, and isopropylene.

[0017] In the present invention, the term “C 2-5 “Alkenyl” is a C group having at least one carbon-carbon double bond obtained by removing one hydrogen atom from a single carbon atom of the parent alkene. 2-5 refers to an unsaturated branched, straight-chain or cyclic alkyl radical. The radical can be in the cis or trans configuration with respect to the double bond. Representative alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, etc.

[0018] In the present invention, the term “C1-C8 alkoxy” refers to a straight-chain or branched-chain alkoxy having 1 to 8 carbon atoms. Specifically, it may be methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, etc., but is not limited thereto.

[0019] In the present invention, the term “C1-C5 haloalkoxy” means a C1-C5 alkoxy group in which at least one hydrogen is replaced with a halogen atom (i.e., F, Cl, Br, or I), and specifically, “C1-C5 haloalkoxy” is fluoromethoxy, chloromethoxy, bromomethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, dichloromethoxy, trichloromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, It may be, but is not limited to, 2,2-dichloro-2-fluoroethoxy, pentafluoroethoxy, heptafluoropropoxy, or nonafluorobutoxy.

[0020] The term "C3-C8 heteroaryl" as used herein refers to an optionally substituted aromatic ring containing 3 to 8 carbon atoms, wherein at least one of the ring carbon atoms is replaced by a heteroatom selected from oxygen (O), nitrogen (N), and sulfur (S), or an aromatic ring (e.g., a bicyclic or tricyclic ring system) fused to one or more rings such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a carbocyclic ring, each of which may have an optional substituent. For example, pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and Monocyclic heteroaryl including tetrazine, etc. may be included, and indole, isoindole, indazole, benzimidazole, benzotriazole, benzopyrrole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, Oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinazolines, quinoxalines, phthalazines, naphthyridines (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and It may include, but is not limited to, polycyclic heteroaryl such as imidazo[2,1-b]thiazole. In addition, the heteroaryl may be substituted or unsubstituted, and when substituted, it may include halogen, C1-C3 alkyl, -OH, C1-C3 alkylene-OH, -NH2, -NO2, -CN, -O-phenyl, -O-(C3-C8 heteroaryl), -O-(C1-C3 alkylene)-phenyl, -O-(C1-C3 alkylene)-(C3-C8 heteroaryl), -NHC(=O)-phenyl,-NHC(=O)-(C1-C3 alkyl), -NHC(=O)-(C3-C8 heteroaryl), -NH-(C1-C3 alkyl), -NH-(C3-C8 cycloalkyl), -NH-(C3-C8 heteroaryl), NH-phenyl, -NH-(C1-C3 alkylene)-phenyl, -NH-(C1-C3 alkylene)-(C3-C8 cycloalkyl), -C(=O)O-(C1-C3 alkyl), -C(=O)NH-phenyl, or -C(=O)NH-(C1-C3 alkylene)-phenyl may be substituted. Additionally, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, if the polycyclic heteroaryl group is attached to the parent structure via an aromatic ring.

[0021] In the present invention, “C3-C8 heterocycloalkyl” includes a saturated monocyclic or polycyclic heterocyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), or a ring structure in which two or more rings share one or more pairs of carbon atoms (e.g., a fused ring, a spiro ring, a bridged ring, etc.). Heterocycloalkyl is oxiranyl, oxetanyl, morpholinyl, thiomorpholinyl, furyl, piperazinyl, pyranyl, 1,3-dioxanyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-yl, It may include, but is not limited to, 3-oxa-8-azabicyclo[3.2.1]octan-yl, hexahydro-2H-furo[3,2-b]pyrrole, azetidin-3-one, etc. In addition, the above heterocycloalkyl may be substituted or unsubstituted, and when substituted, halogen, C1-C3 alkyl, -OH, C1-C3 alkylene-OH, -NH2, -NO2, -CN, -O-phenyl, -O-(C3-C8 heteroaryl), -O-(C1-C3 alkylene)-phenyl, -O-(C1-C3 alkylene)-(C3-C8 heteroaryl), -NHC(=O)-phenyl, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)-(C3-C8 heteroaryl), -NH-(C1-C3 alkyl), -NH-(C3-C8 cycloalkyl), -NH-(C3-C8 heteroaryl), NH-phenyl, -NH-(C1-C3 alkylene)-phenyl, -NH-(C1-C3 alkylene)-(C3-C8 cycloalkyl), -C(=O)O-(C1-C3 alkyl), -C(=O)NH-phenyl, or -C(=O)NH-(C1-C3 alkylene)-phenyl may be substituted.When nitrogen is present in a heterocycloalkyl ring, it may exist in an oxidized state (i.e., N+-O-) as long as the properties of adjacent atoms and groups permit. Examples include piperidinyl N-oxide and morpholinyl-N-oxide. Furthermore, when sulfur is present in a heterocycloalkyl ring, it may exist in an oxidized state (i.e., S+-O- or -SO2-) as long as the properties of adjacent atoms and groups permit. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Furthermore, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl) if the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom.

[0022] In the present invention, “enantiomer” refers to a case where two molecules having optical activity form a mirror-symmetric relationship. It is generally used as a synonym for mirror image isomer, and includes the R-form, S-form, or racemic compound forms, respectively.

[0023] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and will not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0024] Novel imidazopyridine compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof

[0025] To solve the above-mentioned technical problem, the present invention provides a compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0026] [Chemical Formula 1]

[0027]

[0028] In the above chemical formula 1,

[0029] Is or And,

[0030] Is , , C3-C8 heteroaryl containing an unsubstituted or substituted nitrogen or oxygen atom or unsubstituted or substituted C2-C5 alkenyl-(C3-C8 heteroaryl containing a nitrogen or oxygen atom), wherein the substitution is at least one or more of halogen, C1-C3 alkyl, -OH, C1-C3 alkylene-OH, -NH2, -NO2 or -CN;

[0031] R1 is -NR a R b , unsubstituted or substituted -O-phenyl, unsubstituted or substituted C3-C8heterocycloalkyl containing nitrogen or oxygen atoms, or unsubstituted or substituted -(C1-C3alkylene)-(C3-C8heterocycloalkyl containing nitrogen or oxygen atoms), wherein substitution is substitution with at least one halogen, C1-C3alkyl, -OH, -NH2, -NO2 or -CN;

[0032] R2 is -C1-C8alkoxy, -C1-C5haloalkoxy, unsubstituted or substituted C3-C8heterocycloalkyl, unsubstituted or substituted C3-C8heteroaryl, -NR a R b , -OH, -NO2 or -CN;

[0033] R3 is halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C1-C5 haloalkoxy, unsubstituted or substituted C3-C8 heterocycloalkyl, unsubstituted or substituted C3-C8 heteroaryl, -NR a R b , -OH, -NO2 or -CN;

[0034] R4 is halogen, -C1-C8 alkyl, -C1-C8 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C8 heterocycloalkyl, unsubstituted or substituted C3-C8 heteroaryl, -OH, -NO2 or -CN,

[0035] R a and R b may be the same or different, and each independently represents hydrogen or C1-C8 alkyl;

[0036] m is 0 or 1;

[0037] n and p are each independently 1 or 2.

[0038]

[0039] Specifically, the C1-C8 alkyl, C2-C5 alkenyl, C1-C3 alkylene, C1-C8 alkoxy, C1-C5 haloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heteroaryl mentioned in the above R1 to R4 may be selected from the specific substituents mentioned below:

[0040] The above C1-C8 alkyl may be straight-chain or branched-chain methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl.

[0041] The above C2-C5 alkenyl may be a straight-chain or branched ethenyl (-CH=CH2), propenyl, or butenyl, and the above C1-C3 alkylene may be a straight-chain or branched methylene, ethylene, propylene, and the like.

[0042] The above C1-C8 alkoxy may be straight-chain or branched methoxy, ethoxy, propoxy, butoxy, or pentyloxy.

[0043] The above C1-C5 haloalkoxy may be fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, etc.

[0044] The above C3-C8 heterocycloalkyl may be tetrahydrofuranyl, tetrahydrothiophenyl, azetidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, or hexahydro-2H-furo[3,2-b]pyrrole.

[0045] The above C3-C8 heteroaryl may be furanyl, thiophenyl, thiazolyl, oxazolyl, pyrrolyl, pyranyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridonyl, pyrimidinyl, etc.

[0046]

[0047] Specifically Is , , , , C3-C8 heteroaryl containing an unsubstituted or substituted nitrogen or oxygen atom, or C2-C5 alkenyl-(C3-C8 heteroaryl containing a nitrogen or oxygen atom) which may be unsubstituted or substituted.

[0048] More specifically, the above Is , , , , , , , , , , unsubstituted or substituted pyridine, unsubstituted or substituted furan, or unsubstituted or substituted -C2-C5alkenyl-furan.

[0049]

[0050] Specifically, the R1 may be -NH2, -NH-CH3, -NH-CH2CH3, -N-(CH3)2, -N-(CH2CH3)2, unsubstituted or substituted -O-phenyl, unsubstituted or substituted pyrrolidine, unsubstituted or substituted piperidine, unsubstituted or substituted piperazine, unsubstituted or substituted tetrahydrofuran, unsubstituted or substituted morpholine, unsubstituted or substituted C1-C3 alkylene-pyrrolidine, unsubstituted or substituted C1-C3 alkylene-piperidine, unsubstituted or substituted C1-C3 alkylene-piperazine, unsubstituted or substituted C1-C3 alkylene-tetrahydrofuran, unsubstituted or substituted C1-C3 alkylene-morpholine.

[0051]

[0052] Specifically, R2 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentoxy, unsubstituted or substituted C3-C5 heterocycloalkyl, unsubstituted or substituted C3-C5 heteroaryl, -NH2, -NH-(C1-C5 alkyl), -N-(C1-C5 alkyl)2, -OH, -NO2, or -CN;

[0053] Specifically, R3 can be chloro (Cl), fluorine (F), methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentoxy, unsubstituted or substituted C3-C5 heterocycloalkyl, unsubstituted or substituted C3-C5 heteroaryl, -NH2, -NH-(C1-C5 alkyl), -N-(C1-C5 alkyl)2, -OH, -NO2, or -CN.

[0054] Specifically, the R4 is halogen, -C1-C6 alkyl, -C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C5 heterocycloalkyl, unsubstituted or substituted C3-C5 heteroaryl, -OH, -NO2 or -CN, wherein the substitution is at least one or more of halogen, C1-C3 alkyl, -OH, -O-phenyl, -O-(C3-C8 heteroaryl), -O-(C1-C3 alkylene)-phenyl, -O-(C1-C3 alkylene)-(C3-C8 heteroaryl), -NHC(=O)-phenyl, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)-(C3-C8 heteroaryl), -NH-(C1-C3 alkyl), -NH-(C3-C8 cycloalkyl), -NH-(C3-C8 heteroaryl), NH-phenyl, -NH-(C1-C3 alkylene)-phenyl, -NH-(C1-C3 alkylene)-(C3-C8 cycloalkyl), -C(=O)O-(C1-C3 alkyl), -C(=O)NH-phenyl, -C(=O)NH-(C1-C3 alkylene)-phenyl may be substituted.

[0055] More specifically, the R4 is chloro (Cl), bromine (Br), iodo (I), methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, unsubstituted or substituted phenyl, unsubstituted or substituted tetrahydrofuran, unsubstituted or substituted tetrahydrothiophene, unsubstituted or substituted pyrrolidine, unsubstituted or substituted piperidine, unsubstituted or substituted piperazine, unsubstituted or substituted furan, unsubstituted or substituted thiophene, unsubstituted or substituted pyrrole, unsubstituted or substituted pyridine, unsubstituted or substituted pyrimidine, -OH, -NO2 or -CN,

[0056] wherein the substitution is at least one halogen, C1-C3 alkyl, -OH, -O-phenyl, -O-(C3-C8 heteroaryl), -O-(C1-C3 alkylene)-phenyl, -O-(C1-C3 alkylene)-(C3-C8 heteroaryl), -NHC(=O)-phenyl, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)-(C3-C8 heteroaryl), -NH-(C1-C3 alkyl), -NH-(C3-C8 cycloalkyl), -NH-(C3-C8 heteroaryl), NH-phenyl, -NH-(C1-C3 alkylene)-phenyl, -NH-(C1-C3 alkylene)-(C3-C8 cycloalkyl), -C(=O)O-(C1-C3 alkyl), -C(=O)NH-phenyl, -C(=O)NH-(C1-C3 alkylene)-phenyl may be substituted.

[0057] More preferably Is , , , , , , , , , , , , , , , , , , , , , , , , , , , , and is one selected from the group consisting of,

[0058] Here R a and R b are each independently hydrogen or C1-C6 alkyl,

[0059] R5 is C1-C6 alkyl,

[0060] R6 to R 10 may be the same or different, and each independently represents halogen, C1-C6 alkyl or C1-C6 alkoxy,

[0061] R 11 is phenyl or -(C1-C3alkylene)-phenyl,

[0062] R 12 is phenyl or -C3-C8heteroaryl,

[0063] R 13 is halogen or -C1-C3 alkyl,

[0064] R 14 may be C3-C8cycloalkyl or -(C1-C3alkylene)-(C3-C8cycloalkyl).

[0065] According to an embodiment of the present invention, Is ,

[0066] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and It can be any one selected from the group consisting of .

[0067]

[0068] The compound represented by the above chemical formula 1 may be any one compound selected from the group consisting of compounds represented by the following chemical formulas 2 to 5:

[0069] [Chemical Formula 2]

[0070]

[0071] [Chemical Formula 3]

[0072]

[0073] [Chemical Formula 4]

[0074]

[0075] [Chemical Formula 5]

[0076]

[0077] [Chemical Formula 6]

[0078]

[0079] In the above chemical formulas 2 to 6, R1 to R4, n, m and p are as described above in the above chemical formula 1.

[0080] L is C2-C5 alkenyl,

[0081] may be unsubstituted or substituted, and may be furan or pyridine. Here, substitution is with halogen, C1-C3 alkyl, -OH, C1-C3 alkylene-OH, -NH2, -NO2 or -CN.

[0082]

[0083] According to a specific example of the present invention, the compound represented by the above chemical formula 1 may be any one selected from the group consisting of compounds described below:

[0084] 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(4-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine(6a);

[0085] 7-[2-(3-phenoxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-1-ium(6b);

[0086] 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-phenoxy-phenyl)-3H-imidazo[4,5-b]pyridine(6c);

[0087] 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol(6d);

[0088] 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol(6e);

[0089] 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,2,3-triol(6f);

[0090] 5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,2,4-triol (6g);

[0091] {4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-phenyl}-dimethyl-amine(6h);

[0092] 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-4-nitro-phenol(6i);

[0093] {5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-furan-2-yl}- methanol (6j);

[0094] 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(3-nitro-4-piperidin-1-yl-phenyl)-3H-imidazo[4,5-b] pyridine(6k);

[0095] 4-Chloro-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-phenol(6l);

[0096] 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(3-morpholin-4-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine(6m);

[0097] 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(4-morpholin-4-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine(6n);

[0098] 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-5-hydroxymethyl-2-methyl- pyridin-3-ol(6o);

[0099] 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-furan-2-yl-vinyl)-3H-imidazo[4,5-b]pyridine(6p);

[0100] 2,4-Dichloro-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene- 1,3-diol(6q);

[0101] 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-methoxy-2-nitrophenyl)-3H-imidazo[4,5-b]pyridine(6r);

[0102] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxybenzonitrile(6s);

[0103] 3-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine(6t);

[0104] 5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine(6u);

[0105] 6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-3-ol(6v);

[0106] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-nitrophenol(6w);

[0107] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxyphenol(6x);

[0108] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-ethoxyphenol(6y);

[0109] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-propoxyphenol(6z);

[0110] 5-Butoxy-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol(6aa);

[0111] 2-(2,4-Dibutoxyphenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridine(6ab);

[0112] 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3 -diol (6ac);

[0113] 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-ethylbenzene-1,3 -diol (6ad);

[0114] 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-isopropylbenzene-1,3 -diol (6ae);

[0115] 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methoxybenzene-1,3 -diol (6af);

[0116] 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-iodobenzene-1,3 -diol(6ag);

[0117] 4-Bromo-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1, 3-diol(6ah);

[0118] 4-chloro-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6ai);

[0119] 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-3-nitrophenol(6aj);

[0120] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxyaniline (6ak);

[0121] 3-amino-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol(6al);

[0122] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-hydroxybenzonitrile(6am);

[0123] 5-amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol(6ao);

[0124] (2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(methylamino)phenol (6ap);

[0125] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(ethylamino)phenol (6aq);

[0126] 5-(Diethylamino)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin- 2-yl)phenol)(6ar);

[0127] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(propylamino)phenol (6as);

[0128] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(dipropylamino)phenol(6at);

[0129] 5-(Butylamino)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol(6au);

[0130] 4-(3-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6ca);

[0131] 4-(3-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol(6cb);

[0132] 4-(3-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6cc);

[0133] 5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-[1,1'-biphenyl]-2,3',4-triol (7a);

[0134] 3'-(Benzyloxy)-5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)- [1,1'-biphenyl]-2,4-diol (7b);

[0135] N-(5'-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-2',4'-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide (7c);

[0136] 4-(6-chloropyridin-3-yl)-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(7d);

[0137] 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-(6-fluoropyridin-3-yl)benzene-1,3-diol (7e); and

[0138] 4-(6-((cyclopropylmethyl)amino)pyridin-3-yl)-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4, 5-b]pyridin-2-yl)benzene-1,3-diol (7k).

[0139]

[0140] In the present invention, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, and include, for example, inorganic ion salts manufactured with calcium, potassium, sodium, and magnesium; inorganic acid salts manufactured with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, and sulfuric acid; organic acid salts manufactured with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid; sulfonic acid salts manufactured with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid; Amino acid salts made from glycine, arginine, lysine, etc.; and amine salts made from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; however, the types of salts meant in the present invention are not limited by these listed salts.

[0141] Pharmaceutical composition

[0142] In another aspect of the present invention, a pharmaceutical composition is provided comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0143] In another aspect of the present invention, a pharmaceutical composition is provided comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0144] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier, and may be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.

[0145] The pharmaceutically acceptable carriers include, but are not limited to, those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the pharmaceutical composition of the present invention may include, but is not limited to, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, and other pharmaceutically acceptable additives.

[0146] In another aspect of the present invention, a pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease is provided, comprising a compound represented by the formula 1 defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the Bruton's tyrosine kinase (BTK)-mediated disease is an autoimmune disease, cancer, or a vascular-related disease.

[0147] As used herein, the term "BTK-mediated disease" refers to a disease caused by excessive signaling due to overactivity of BTK, and refers to a condition or disease for which prevention, improvement, or treatment can be expected by inhibiting BTK activity. The BTK-mediated disease may include autoimmune diseases, cancer, or vascular diseases.

[0148] As used herein, the term "autoimmune disease" refers to any group of diseases in which tissue damage is associated with a humoral or cell-mediated response to the body's own components.

[0149] The above autoimmune diseases include, for example, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodine thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, nystagmus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, autonomic dysfunction, asthma, chronic spontaneous urticaria, pemphigus, systemic lupus erythematosus, hidradenitis, These may include, but are not limited to, skin diseases, immunoglobulin G4-related disorders, endometriosis, interstitial cystitis, neuromyotonia, or vulvodynia.

[0150] As used herein, the term "cancer" refers to a physiological condition in mammals typically characterized by uncontrolled cell growth. In the present invention, cancer may include carcinoma, lymphoma, blastoma, sarcoma, leukemia, or lymphoid malignancy.

[0151] Further more specific examples of cancer may include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer such as small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular cancer, cancer of the stomach or abdomen such as gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular adenoma, breast cancer, colon cancer, rectal cancer, large bowel cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cell cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma and head and neck cancer.

[0152] Additionally, in the present invention, the cancer may be a B cell malignancy. The above B-cell malignancies include, for example, chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), B-cell prolymphocytic leukemia, diffuse large B-cell lymphoma (DLBCL), splenic marginal zone lymphoma (SMZL), Burkitt lymphoma, B-cell non-Hodgkin's lymphoma, follicular lymphoma, primary central nervous system lymphoma (PCNSL), or nodular lymphocyte dominant Hodgkin's lymphoma (NLPHL), hairy cell leukemia, splenic lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodular marginal zone lymphoma, pediatric nodular marginal zone lymphoma, primary cutaneous follicular center lymphoma, T-cell / histiocytic rich large B-cell lymphoma, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, or May be, but is not limited to, primary effusion lymphoma.

[0153] In the present invention, the term "vascular-related disease" includes, but is not limited to, acute myocardial infarction, stroke, coronary artery disease, peripheral vascular disease, deep vein thrombosis, pulmonary embolism, and thromboembolism.

[0154] The compound of the present invention exhibits inhibitory activity against Bruton's tyrosine kinase (BTK) enzyme, inhibits platelet aggregation, thereby preventing thrombosis and postoperative thrombosis, and can be used to treat BTK-mediated diseases such as autoimmune diseases, cancer, or vascular diseases.

[0155] In the present invention, the term “prevention” means any act of inhibiting or delaying the onset of a BTK-mediated disease by administering a composition.

[0156] In the present invention, the term “treatment” means any action by which the symptoms of the disease are improved or beneficially changed by administration of the composition.

[0157] The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method, and the dosage range varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and type and severity of the disease.

[0158] The route of administration of the pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans through any general route as long as it can reach the target tissue, but may be administered by subcutaneous injection using an osmotic pump, intradermal injection, intravein injection, intraperitoneal injection, intravitreal injection, intrathecal, inner ear, abdominal cavity, or intravenous, intramuscular, subcutaneous, intrauterine epidural, sublingual, or intracerebrovascular injection, but is not limited thereto.

[0159] The pharmaceutical composition of the present invention may contain 0.001 to 95 wt%, preferably 0.01 to 80 wt%, of the compound represented by Chemical Formula 1, its optical isomer, or its pharmaceutically acceptable salt, based on the total weight of the composition.

[0160] When the pharmaceutical composition of the present invention is formulated as a solid oral preparation, it includes tablets, pills, powders, granules, capsules, etc., and such solid preparations may include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., and include, but are not limited to, lubricants such as magnesium stearate and talc.

[0161] When the pharmaceutical composition of the present invention is formulated as an oral liquid, it includes a suspension, a solution, an emulsion, a syrup, etc., and includes, but is not limited to, a diluent such as water or liquid paraffin, a wetting agent, a sweetener, a fragrance, a preservative, etc.

[0162] When the pharmaceutical composition of the present invention is formulated for parenteral use, it includes a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized preparation, and a suppository. Non-aqueous solvents and suspensions include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for a suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin, and the like can be used, but are not limited to these.

[0163] In another aspect of the present invention, a Bruton's tyrosine kinase (BTK) inhibitor is provided, comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0164] In one aspect of the present invention, a method of treating a BTK-mediated disorder is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0165] In the present invention, the terms “compound represented by chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof” and “BTK-mediated disease” are as described above.

[0166] The term "subject" of the present invention refers to any animal that has developed or may develop a BTK-mediated disease, and typically may be an animal that can exhibit a beneficial effect by treatment with a compound represented by Chemical Formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, but includes, without limitation, any subject that has symptoms of a BTK-mediated disease or is likely to have such symptoms. As described above, by administering the pharmaceutical composition of the present invention to a subject, the above-described disease can be effectively prevented or treated. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent, or in combination with an existing BTK-mediated disease therapeutic agent, and can be administered sequentially or simultaneously with the existing therapeutic agent.

[0167] The term "therapeutically effective amount" as used herein means an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical prevention or treatment, and refers to an amount of the compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof that is effective for the prevention or treatment of the disease. The effective dosage level may be determined according to factors including the severity of the disease, the activity of the drug, the age, weight, health, and sex of the patient, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the excretion rate, the duration of treatment, drugs combined with or used concurrently with the composition of the present invention used, and other factors well known in the medical field. For example, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be administered at 0.0001 to 100 mg / kg per day, and the administration may be administered once a day or in several divided doses.

[0168] The term "administration" in the present invention means introducing a predetermined substance into a patient by an appropriate method, and the route of administration of the composition may be administered through any common route as long as it can reach the target tissue. In addition, the pharmaceutical composition of the present invention may be administered by any device that allows the active substance to move to the target tissue. For example, it may be administered by oral administration, intrathecal administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, inner ear administration, intrauterine epidural administration, sublingual administration, and intracerebrovascular injection, but is not limited thereto. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.

[0169] The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with conventional therapeutic agents. Taking all of the above factors into account, the pharmaceutical composition may be administered in an amount that achieves maximum efficacy with minimal side effects, as can be readily determined by those skilled in the art.

[0170] The therapeutic method of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding its symptoms by administering the compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In the management of a disease, the prophylactic or therapeutic dosage of a particular active ingredient will vary depending on the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The dosage and frequency of administration will vary depending on the age, weight, and response of the individual patient. An appropriate dosage regimen can be readily selected by one skilled in the art, taking these factors into account.

[0171] In addition, the treatment method of the present invention may further include administration of a therapeutically effective amount of an additional active agent helpful in treating a disease together with the compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the additional active agent may exhibit a synergistic or auxiliary effect together with the compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0172] In addition, the present invention provides a use of a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a drug for preventing or treating a BTK-mediated disease, wherein the Bruton's tyrosine kinase (BTK)-mediated disease is an autoimmune disease, cancer, or a vascular-related disease.

[0173] In addition, the present invention provides a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of a BTK-mediated disease, wherein the Bruton's tyrosine kinase (BTK)-mediated disease is an autoimmune disease, cancer, or a vascular-related disease.

[0174] In addition, the present invention provides a pharmaceutical composition comprising a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of a BTK-mediated disease, wherein the Bruton's tyrosine kinase (BTK)-mediated disease is an autoimmune disease, cancer, or a vascular-related disease.

[0175] In addition, the present invention provides the use of a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of a BTK-mediated disease, wherein the Bruton's tyrosine kinase (BTK)-mediated disease is an autoimmune disease, cancer, or a vascular disease.

[0176] The novel compound according to the present invention effectively inhibits the enzymatic activity of Bruton's tyrosine kinase (BTK), and thus can be usefully utilized as a pharmaceutical composition for preventing or treating BTK-mediated diseases such as autoimmune diseases, cancer, or vascular-related diseases.

[0177] Figure 1 is a graph measuring the IC50 (M) for CRP-XL of Example 30. All quantitative data are expressed as mean ± SEM (n = 3) and are expressed as *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

[0178] Figure 2 is a graph showing the phosphorylation degree of the GPVI platelet activation signal transduction pathway of Example 30. Figure 2a shows the quantitative phosphorylation degree of tyrosine 551 of BTK, Figure 2b shows the quantitative phosphorylation degree of tyrosine 223 of BTK, and Figure 2b shows the quantitative phosphorylation degree of tyrosine 753 of PLCγ2. All quantitative data are expressed as mean ± SEM (n = 3), and *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

[0179] Figure 3 is a graph showing changes in intracellular calcium ion concentration in Example 30 confirmed by Fluo3-AM. All quantitative data are expressed as mean ± SEM (n = 3) and are indicated as *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

[0180] Hereinafter, the present invention will be described in detail using examples to aid understanding. However, the examples according to the present invention may be modified in various ways, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0181] The reagents and solvents mentioned below were purchased from Korea Fisher Scientific Co., Ltd. and Sejin CI Co., Ltd., unless otherwise specified.

[0182] Additionally, all reactions were performed in oven-dried glassware under positive Ar pressure with magnetic stirring unless otherwise specified. Air- and moisture-sensitive liquids and solutions were transferred via syringes or stainless steel cannulas.

[0183] TLC was performed on 0.25 mm E. Merck silica gel 60 F254 plates and visualized with UV light (254 nm) or staining with cerium ammonium molybdate (CAM), potassium permanganate (KMnO4), ninhydrin, or p-anisaldehyde.

[0184] Flash chromatography was performed on E. Merck 230-400 mesh silica gel 60.

[0185] Medium-pressure liquid chromatography (MPLC) was performed on a prepacked column (silica gel, 10 μm) equipped with a UV detector. Reagents were purchased from commercial suppliers and used without further purification unless otherwise specified. Solvents were distilled with an appropriate desiccant (CaH2 or Na wire) under an Ar atmosphere of 760 mmHg, and all moisture- and / or oxygen-sensitive solids were handled and stored in a glovebox under an N2 atmosphere.

[0186] NMR spectra were recorded using an Agilent (Santa Clara, CA, USA) Unity 400 instrument or a Bruker (Switchen, Fallanden) vANCE EO anobay 00 Hz MR spectrometer system installed at the 24°C Ewha Pharmaceutical Development Research Core Center. NMR chemical shifts were measured using TMS ( 1 H, 0 ppm), CDCl3( 1 H, 7.26 ppm; 13 C, 77.2 ppm), DMSO-d6 ( 1 H, 2.50 ppm; 13 C, 39.5 ppm), (CD3)2CO ( 1 H, 2.05 ppm; 13 C, 206.3, 29.8 ppm), CD3OD ( 1 H, 3.31 ppm; 13 C, 49.1 ppm), and C6H5F ( 19 F, -113.15 ppm) are expressed as ppm relative to the reference value. 1 Data for H NMR were described in terms of chemical shift (δ in ppm), multiplicities (s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sep, septet; m, multiplet; and br, broad signal), coupling constants (Hz) and integration. Also 13 Data for C NMR are presented in chemical shifts (δ in ppm).

[0187] <Example>

[0188] Examples 1 to 35 below were synthesized based on the following reaction scheme 1.

[0189] [Reaction Formula 1]

[0190]

[0191] In the above reaction formula 1, R is as follows:

[0192]

[0193]

[0194] Manufacturing Example 1: Synthesis of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-nitropyridin-2-amine (3)

[0195]

[0196] In a 100 mL oven-dried round-bottom flask with a sidearm, 2-chloro-3-nitropyridine (1) (1.00 g, 6.30 mmol), 3,4-ethylenedioxyaniline (2) (1.14 g, 7.56 mmol), and K2CO3 (1.74 g, 12.6 mmol) were suspended in isopropanol (20.0 mL) at room temperature. The reaction mixture was stirred in an oil bath at 80 °C for 5 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified by column chromatography (7:1 hexanes / EtOAc) to give N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-nitropyridin-2-amine (3) (1.66 g, 96%) as a red solid.

[0197] TLC: R f 0.48 (2:1 hexanes / EtOAc). Mp: 119.0-120.1℃. 1 H NMR (400 MHz, CDCl3): δ 9.95 (s, 1H), 8.50 (dd, J = 8.3, 1.8 Hz, 1H), 8.46 (dd, J = 4.5, 1.8 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.79 (dd, J = 8.3, 4.5 Hz, 1H), 4.28 (q, J = 1.0 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ 155.7, 150.8, 143.7, 141.3, 135.7, 131.5, 128.6, 117.6, 116.8, 113.7, 112.8, 64.7, 64.5. HRMS (ESI) m / z calcd for C 13 H 12 N3O4 + ([M + H] + ) 274.0822, found 274.0825.

[0198] Manufacturing Example 2: Synthesis of N2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (4)

[0199]

[0200] Compound 3 (260 mg, 0.95 mmol) was dissolved in EtOH (6.00 mL) in a 50 mL oven-dried round-bottom flask with a side arm. 5% Pd / C (26.0 mg, 10 wt%) was added and stirred at room temperature for 3 h under a hydrogen-filled balloon. Upon completion of the reaction, the precipitate was collected using Celite ® The residue was filtered through a plug and washed with EtOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (4:1 hexanes / EtOAc) to give N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine(4) (228 mg, 96%) was obtained as a pink solid.

[0201] TLC: R f 0.28 (2:1 hexanes / EtOAc). Mp: 143.2-144.6℃. 1H NMR (400 MHz, DMSO-d6): δ 7.80 (dd, J = 5.0, 1.6 Hz, 1H), 6.98 (dd, J = 7.5, 1.6 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.77-6.63 (m, 2H), 6.01 (s, 1H), 4.24 (td, J = 5.5, 3.9 Hz, 4H), 3.36 (s, 2H). 13 C NMR (100 MHz, CDCl3): δ 146.5, 143.8, 139.1, 138.9, 135.4, 130.7, 123.6, 117.5, 116.8, 113.1, 108.8, 64.7, 64.4. HRMS (ESI) m / z calcd for C 13 H 14 N3O2 + ([M + H] + ) 244.1081, found 244.1081.

[0202] Manufacturing Example 3: Synthesis of imidazopyridine compound (6)

[0203]

[0204] N in a 10 mL oven-dried round-bottom flask with a side arm 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (4) (100 mg, 411 μmol), aldehyde 5 (493 μmol), and Na2S2O5 (156 mg, 822 μmol) were suspended in anhydrous DMF (2.00 mL) at room temperature. The reaction mixture was stirred in an oil bath overnight at 110 °C. Upon completion of the reaction, the reaction mixture was cooled to room temperature and concentrated using a rotary evaporator. The residue was diluted with cold water (50 mL) and stirred for 5 min. The mixture was extracted with CH2Cl2 (2 X 100 mL), and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (4:1 hexanes / EtOAc) to give imidazopyridine compound 6.

[0205]

[0206] Example 1: Synthesis of 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(4-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine (6a)

[0207]

[0208] Compound 6a (130 mg, 76%) was obtained as a white solid by the method of Manufacturing Example 3.

[0209] TLC: R f 0.18 (2:1 hexanes / EtOAc). Mp: 219.0-219.8℃. 1 H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 4.8, 1.5 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.24 (s, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.87-6.79 (m, 3H), 4.37-4.26 (m, 4H), 3.89-3.79 (m, 4H), 3.28-3.16 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 153.7, 152.1, 150.2, 144.2, 144.2, 144.1, 135.3, 130.6, 129.2, 126.7, 121.3, 120.2, 119.0, 118.3, 117.2, 114.4, 66.8, 64.5, 64.4, 48.2. HRMS (ESI) m / z calcd for C 24 H 23 N4O3 + ([M + H] + ) 415.1765, found 415.1765.

[0210]

[0211] Example 2: Synthesis of 7-[2-(3-phenoxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-1-ium (6b)

[0212]

[0213] Compound 6b (99.5 mg, 72%) was obtained as a white solid by the method of Manufacturing Example 3.

[0214] TLC: R f 0.25 (2:1 hexanes / EtOAc). Mp: 194.9-195.7℃. 1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 4.8, 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.48-7.44 (m, 1H), 7.38-7.35 (m, 1H), 7.35-7.32 (m, 1H), 7.32-7.30 (m, 1H), 7.30-7.27 (m, 1H), 7.23-7.20 (m, 1H), 7.13-7.10 (m, 1H), 7.10 - 7.05 (m, 1H), 6.97 (d, J = 21.3 Hz, 1H), 6.92 (ddd, J = 7.3, 2.1, 1.1 Hz, 2H), 6.89 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.5, 2.5 Hz, 1H), 4.41-4.14 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 157.3, 156.6, 152.8, 149.9, 144.9, 144.2, 144.1, 135.1, 131.4, 130.1, 129.9, 128.5, 127.5, 124.3, 123.6, 120.9, 120.6, 119.4, 119.2, 119.1, 118.3, 116.9, 64.4, 64.3. HRMS (ESI) m / z calcd for C 26 H 20 N3O3 + ([M + H] + ) 422.1499, found 422.1505.

[0215]

[0216] Example 3: Synthesis of 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-phenoxy-phenyl)-3H-imidazo[4,5-b]pyridine (6c)

[0217]

[0218] Compound 6c (149 mg, 86%) was obtained as a white solid by the method of Manufacturing Example 3.

[0219] TLC: R f0.22 (2:1 hexanes / EtOAc). MP: 181.6-182.5℃. 1 H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 4.8, 1.5 Hz, 1H), 8.13 (dd, J = 8.0, 1.5 Hz, 1H), 7.78 (dd, J = 7.6, 1.7 Hz, 1H), 7.35 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.28 (dd, J = 8.0, 4.8 Hz, 1H), 7.24-7.17 (m, 3H), 7.05 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.71 (td, J = 8.7, 1.8 Hz, 2H), 6.62-6.56 (m, 2H), 4.27-4.17 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 155.5, 155.4, 144.7, 143.8, 143.6, 135.3, 132.6, 131.7, 129.6, 128.9, 127.6, 123.9, 123.1, 121.6, 119.9, 119.4, 118.9, 117.5, 117.0, 116.4, 64.4, 64.3. HRMS (ESI) m / z calcd for C 26 H 19 N3NaO3 + ([M + Na] + ) 444.1319, found 444.1324.

[0220]

[0221] Example 4: Synthesis of 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6d)

[0222]

[0223] Compound 6d (122 mg, 82%) was obtained as a white solid by the method of Manufacturing Example 3.

[0224] TLC: R f 0.11 (2:1 hexanes / EtOAc). MP: 324.0-325.7℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.01 (s, 1H), 8.27 (dd, J = 4.8, 1.5 Hz, 1H), 8.12 (dd, J = 8.0, 1.5 Hz, 1H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.95-6.91 (m, 1H), 6.91-6.88 (m, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.15 (dd, J = 8.8, 2.4 Hz, 1H), 4.34 (td, J = 5.1, 3.7 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 160.4, 152.6, 148.7, 144.0, 143.74, 143.71, 132.2, 129.5, 128.6, 125.4, 121.0, 119.1, 117.7, 117.0, 107.0, 104.8, 103.2, 64.2, 64.1. HRMS (ESI) m / z calcd for C 20 H 16 N3O6 + ([M + H] + ) 362.1135, found 362.1137.

[0225]

[0226] Example 5: Synthesis of 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol (6e)

[0227]

[0228] Compound 6e (108 mg, 73%) was obtained as a white solid by the method of Manufacturing Example 3.

[0229] TLC: Rf 0.24 (1:1 hexane / EtOAc). Mp: 253.2-254.6℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.93 (s, 1H), 8.32 (dd, J = 4.8, 1.5 Hz, 1H), 8.17 (dd, J = 8.0, 1.5 Hz, 1H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.04 (d, J) = 2.4 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.86 (dd, J = 8.6, 2.4 Hz, 1H), 6.78-6.73 (m, 2H), 6.61 (dd, J = 2.1, 1.2 Hz, 1H), 4.37-4.27 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): δ 152.1, 150.4, 149.0, 148.6, 144.2, 143.7, 143.4, 132.8, 128.3, 126.3, 120.6, 119.3, 119.2, 117.5, 117.4, 116.7, 115.0, 114.4, 64.12, 64.09. HRMS (ESI) m / z calcd for C 20 H 16 N3O4 + ([M + H] + ) 362.1135, found 362.1141.

[0230]

[0231] Example 6: Synthesis of 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,2,3-triol (6f)

[0232]

[0233] Compound 6f (110 mg, 71%) was obtained as a white solid by the method of Manufacturing Example 3.

[0234] TLC: R f0.25 (1:1 hexane / EtOAc). Mp: 279.5-280.9℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 9.48 (s, 1H), 8.45 (s, 1H), 8.27 (dd, J = 4.8, 1.2 Hz, 1H), 8.14 (dd, J = 8.0, 1.2 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 8.0, 2.4 Hz, 1H), 6.41 (d, J = 8.8 Hz, 1H), 6.16 (d, J = 9.2 Hz, 1H), 4.36-4.32 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): δ 152.8, 148.9, 148.7, 148.5, 144.0, 143.8, 143.8, 133.3, 131.9, 128.6, 125.3, 121.2, 119.2, 118.6, 117.7, 117.2, 106.9, 104.9, 64.2, 64.1. HRMS (ESI) m / z calcd for C 20 H 16 N3O5 + ([M + H] + ) 378.1084, found 378.1090.

[0235]

[0236] Example 7: Synthesis of 5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,2,4-triol (6 g)

[0237]

[0238] Compound 6 g (113 mg, 73%) was obtained as a white solid by the method of Manufacturing Example 3.

[0239] TLC: R f0.23 (1:1 hexane / EtOAc). Mp: 316.2-317.3℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.67 (s, 1H), 8.39 (s, 1H), 8.25 (dd, J = 4.8, 1.2 Hz, 1H), 8.10 (dd, J = 8.0, 1.6 Hz, 1H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.89 (dd, J = 8.8, 2.8 Hz, 1H), 6.49 (s, 1H), 6.37 (s, 1H), 4.36-4.33 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): 153.3, 152.7, 149.7, 148.7, 144.0, 143.7, 143.6, 137.5, 132.2, 128.5, 125.2, 121.0, 119.1, 117.7, 117.0, 114.4, 103.8, 103.0, 64.2, 64.1. HRMS (ESI) m / z calcd for C 20 H 16 N3O5 + ([M + H] + ) 378.1084, found 378.1087.

[0240]

[0241] Example 8: Synthesis of {4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-phenyl}-dimethyl-amine (6h)

[0242]

[0243] Compound 6h (97.9 mg, 64%) was obtained as a white solid by the method of Manufacturing Example 3.

[0244] TLC: R f 0.19 (2:1 hexanes / EtOAc). Mp: 194.9-195.7℃. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (dd, J = 4.8, 1.5 Hz, 1H), 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.51-7.41 (m, 2H), 7.28 (dd, J = 7.9, 4.8 Hz, 1H), 7.01 (d, J = 0.8 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.81 (dd, J = 8.5, 2.5 Hz, 1H), 6.72-6.64 (m, 2H), 4.38-4.27 (m, 4H), 2.95 (s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ 153.5, 151.0, 149.9, 143.6, 142.8, 134.7, 129.9, 129.0, 125.8, 121.2, 118.6, 117.6, 117.1, 116.1, 111.2, 64.1, 64.1, 39.6. HRMS (ESI) m / z calcd for C 22 H 21 N4O2 + ([M + H] + ) 373.1659, found 373.1662.

[0245]

[0246] Example 9: Synthesis of 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-4-nitro-phenol (6i)

[0247]

[0248] Compound 6i (70.0 mg, 44%) was obtained as a white solid by the method of Manufacturing Example 3.

[0249] TLC: R f 0.17 (1:1 hexane / EtOAc). Mp: 199.9-201.1℃. 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 4.8, 1.5 Hz, 1H), 8.05 (dd, J = 8.0, 1.4 Hz, 1H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.91 (dd, J = 8.5, 2.5 Hz, 1H), 6.72 (dd, J = 8.7, 2.8 Hz, 1H), 6.39 (d, J = 2.7) Hz, 1H), 4.36 (h, J = 3.7 Hz, 4H). 13 C NMR (100 MHz, CDCl3) δ 153.3, 152.2, 149.2, 145.1, 144.8, 144.5, 137.4, 132.5, 128.9, 126.2, 121.4, 120.8, 119.5, 118.8, 118.6, 117.5, 114.0, 111.9, 64.5, 64.4. HRMS (ESI) m / z calcd for C 20 H 15 N4O5 + ([M + H] + ) 391.1037, found 391.1043.

[0250]

[0251] Example 10: Synthesis of {5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-furan-2-yl}-methanol (6j)

[0252]

[0253] Compound 6j (43.2 mg, 30%) was obtained as a white solid by the method of Manufacturing Example 3.

[0254] TLC: R f 0.11 (1:1 hexane / EtOAc). Mp: 218.5-219.8℃. 1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 4.8, 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.30-7.27 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.5, 2.5 Hz, 1H), 6.32 (dt, J = 3.5, 0.6 Hz, 1H), 6.12 (d, J = 3.5 Hz, 1H), 4.69 (s, 2H), 4.35 (ttd, J) = 7.1, 3.3, 1.5 Hz, 4H). 13 C NMR (100 MHz, CDCl3) δ 157.0, 149.8, 145.3, 145.1(2C), 144.5, 143.6, 135.1, 127.8, 127.5, 121.5, 119.4, 118.6, 117.6, 114.6, 109.6, 64.6, 64.4, 57.6. HRMS (ESI) m / z calcd for C 19 H 16 N3O4 + ([M + H] + ) 350.1135, found 350.1144.

[0255]

[0256] Example 11: Synthesis of 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(3-nitro-4-piperidin-1-yl-phenyl)-3H-imidazo[4,5-b]pyridine (6k)

[0257]

[0258] Compound 6k (121 mg, 64%) was obtained as a white solid by the method of Manufacturing Example 3.

[0259] TLC: R f 0.22 (2:1 hexanes / EtOAc). Mp: 177.9-178.9℃. 1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 8.8, 2.3 Hz, 1H), 7.28 (dd, J = 8.1, 4.8 Hz, 1H), 7.03 (d, J = 3.9 Hz, 1H), 7.01 (d, J = 4.2 Hz, 1H), 6.95 (dd, J = 2.5, 0.3 Hz, 1H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 4.33 (td, J = 5.1, 3.6 Hz, 4H), 3.22 - 3.00 (m, 4H), 1.76-1.68 (m, 4H), 1.65-1.60 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 150.8, 149.7, 146.5, 144.02, 143.98, 143.7, 139.4, 134.4, 133.4, 128.1, 126.9, 126.7, 121.2, 120.4, 120.0, 119.1, 117.8, 117.2, 64.2, 64.1, 51.4, 25.2, 23.3. HRMS (ESI) m / z calcd for C 25 H 24 N5O4 + ([M + H] + ) 458.1823, found 458.1825.

[0260]

[0261] Example 12: Synthesis of 4-chloro-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-phenol (6l)

[0262]

[0263] Compound 6l (162 mg, 99%) was obtained as a white solid by the method of Manufacturing Example 3.

[0264] TLC: R f0.22 (2:1 hexanes / EtOAc). Mp: 221.5-222.7℃. 1 H NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 4.8, 1.5 Hz, 1H), 8.06 (dd, J = 8.0, 1.5 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 7.12 (dd, J = 2.5, 0.8 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.81 (dd, J = 2.5, 0.7 Hz, 1H), 4.41-4.30 (m, 4H), 2.32 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 155.8, 150.7, 148.5, 145.0, 144.4, 143.8, 132.0, 131.6, 128.5, 128.0, 126.3, 124.8, 121.24, 121.22, 119.7, 117.9, 117.3, 113.1, 64.2, 64.1, 15.9. HRMS (ESI) m / z calcd for C 21 H 17 ClN3O3 + ([M + H] + ) 394.0953, found 394.0957.

[0265]

[0266] Example 13: Synthesis of 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(3-morpholin-4-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine (6m)

[0267]

[0268] Compound 6m (13.8 mg, 20%) was obtained as a white solid by the method of Manufacturing Example 3.

[0269] TLC: R f 0.25 (2:1 hexanes / EtOAc). MP: 144.6-146.0℃.1 H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 4.8, 1.5 Hz, 1H), 8.13 (dd, J = 8.0, 1.5 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 8.0, 4.8 Hz, 1H), 6.96 (d, J = 2.7 Hz, 1H), 6.94 (d, J = 3.4 Hz, 1H), 6.80 (dd, J = 8.6, 2.4 Hz, 1H), 4.30 (tt, J = 5.1, 2.5 Hz, 4H), 3.70 - 3.62 (m, 4H), 3.45 (s, 2H), 2.35 (t, J = 4.6 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 152.9, 149.5, 144.1, 143.6, 143.5, 137.8, 134.5, 130.7, 129.7, 129.5, 128.43 128.38, 127.9, 126.9, 121.1, 119.1, 117.5, 117.1, 66.1, 64.1, 64.1, 62.0, 52.9. HRMS (ESI) m / z calcd for C 25 H 25 N4O3 + ([M + H] + ) 429.1921, found 429.1924.

[0270]

[0271] Example 14: Synthesis of 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(4-morpholin-4-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine(6n)

[0272]

[0273] Compound 6n (102 mg, 98%) was obtained as a white solid by the method of Manufacturing Example 3.

[0274] TLC: Rf 0.11 (1:1 hexane / EtOAc). MP: 162.2-163.5℃. 1 H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 4.8, 1.5 Hz, 1H), 8.12 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.30-7.27 (m, 1H), 6.99 - 6.94 (m, 2H), 6.84-6.79 (m, 1H), 4.36-4.29 (m, 4H), 3.74-3.66 (m, 4H), 3.51 (s, 2H), 2.50-2.39 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 144.7, 144.25, 144.21, 140.1, 135.2, 129.4(2C), 129.2(2C), 128.8, 128.7, 127.4, 121.2, 119.2, 118.3, 117.1, 67.1, 64.5, 64.4, 63.1, 53.7. HRMS (ESI) m / z calcd for C 25 H 25 N4O3 + ([M + H] + ) 429.1921, found 429.1923.

[0275]

[0276] Example 15: Synthesis of 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-5-hydroxymethyl-2-methyl-pyridin-3-ol (6o)

[0277]

[0278] Compound 6o (126 mg, 79%) was obtained as a white solid by the method of Manufacturing Example 3.

[0279] TLC: R f 0.10 (EtOAc only). MP: 174.0-175.8℃. 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J = 4.8, 1.5 Hz, 1H), 8.16 (s, 1H), 8.13 (dd, J = 8.1, 1.5 Hz, 1H), 7.37 (dd, J = 8.1, 4.8 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.73 (dd, J = 8.6, 2.5 Hz, 1H), 4.33-4.26 (m, 4H), 4.24 (d, J = 4.6 Hz, 2H), 2.54 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 149.6, 149.2, 149.1, 147.8, 145.6, 144.3, 143.8, 140.3, 133.6, 133.3, 127.0, 126.9, 122.5, 119.7, 119.6, 117.9, 115.9, 64.4, 64.3, 61.1, 19.5. HRMS (ESI) m / z calcd for C 21 H 19 N4O4 + ([M + H] + ) 391.1401, found 391.1402.

[0280]

[0281] Example 16: Synthesis of 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-furan-2-yl-vinyl)-3H-imidazo[4,5-b]pyridine(6p)

[0282]

[0283] Compound 6p (136 mg, 96%) was obtained as a white solid by the method of Manufacturing Example 3.

[0284] TLC: R f 0.11 (2:1 hexanes / EtOAc). Mp: 216.5-217.6℃. 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J = 4.8, 1.5 Hz, 1H), 8.03 (dd, J = 8.0, 1.4 Hz, 1H), 7.76 (d, J = 15.7 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.26-7.21 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 8.5, 2.5 Hz, 1H), 6.79 (d, J = 15.7 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 6.45 (dd, J = 3.4, 1.8 Hz, 1H), 4.39-4.32 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 152.3, 152.2, 149.5, 144.6, 144.4, 144.3, 144.0, 135.6, 127.2, 126.5, 124.8, 121.2, 119.3, 118.3, 117.3, 113.3, 112.4, 111.8, 64.5, 64.4. HRMS (ESI) m / z calcd for C 20 H 16 N3O3 + ([M + H] + ) 346.1186, found 346.1188.

[0285]

[0286] Example 17: Synthesis of 2,4-dichloro-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6q)

[0287]

[0288] Compound 6q (16.0 mg, 9%) was obtained as a white solid by the method of Manufacturing Example 3.

[0289] TLC: R f 0.34 (1:1 hexane / EtOAc). Mp: 279.2-280.6℃. 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 4.8, 1.5 Hz, 1H), 8.05 (dd, J = 8.0, 1.5 Hz, 1H), 7.33 (dd, J = 8.0, 4.8 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.93-6.88 (m, 2H), 4.37 (td, J = 5.4, 3.7 Hz, 4H). 13 C NMR (100 MHz, CDCl3) δ 156.6, 150.8, 150.6, 148.9, 145.6, 145.4, 144.9, 131.7, 127.9, 126.2, 126.1, 121.2, 119.9, 119.1, 117.4, 110.5, 109.9, 106.2, 64.6, 64.5. HRMS (ESI) m / z calcd for C 20 H 14 Cl2N3O4 + ([M + H] + ) 430.0356, found 430.0362.

[0290]

[0291] Example 18: Synthesis of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-methoxy-2-nitrophenyl)-3H-imidazo[4,5-b]pyridine(6r)

[0292]

[0293] According to the method of Manufacturing Example 3, N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (351 mg, 1.44 mmol), 4-methoxy-2-nitrobenzaldehyde (306 mg, 1.69 mmol) and Na2S2O5 (548 mg, 2.88 mmol) were used to obtain compound 6r (345 mg, 59%) as a light brown solid.

[0294] TLC R f 0.50 (1:3 hexane / EtOAc). 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 4.8, 1.5 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.20 (dd, J = 8.6, 2.6 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.71 (dd, J = 8.6, 2.5 Hz, 1H), 4.30-4.21 (m, 4H), 3.92 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 161.4, 150.5, 149.7, 148.5, 145.4, 144.2, 144.0, 134.1, 133.8, 127.6, 126.8, 120.6, 119.5, 119.2, 118.0, 117.0, 116.7, 110.2, 64.3, 64.3, 56.2. HRMS (ESI) m / z calcd for C 21 H 17 N4O5 + ([M + H] + ) 405.1193, found 405.1194.

[0295]

[0296] Example 19: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxybenzonitrile (6s)

[0297]

[0298] According to the method of Manufacturing Example 3, N 2Compound 6s (371 mg, 58%) was obtained as a light brown solid using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (407 mg, 1.67 mmol), 2-formyl-5-methoxybenzonitrile (402 mg, 2.50 mmol) and Na2S2O5 (599 mg, 3.15 mmol).

[0299] TLC R f 0.13 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 4.8, 1.5 Hz, 1H), 8.21 (dd, J = 8.0, 1.5 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 7.07 (dd, J = 8.8, 2.6 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 8.6, 2.5 Hz, 1H), 4.33-4.24 (m, 4H), 3.87 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 160.4, 150.0, 148.9, 145.5, 144.1, 144.0, 134.7, 132.7, 128.1, 127.5, 125.2, 120.8, 119.5, 118.9, 118.6, 118.0, 117.3, 116.9, 114.5, 64.3, 64.3, 55.9. HRMS (ESI) m / z calcd for C 22 H 17 N4O3 + ([M + H] + ) 385.1295, found 385.1299.

[0300]

[0301] Example 20: Synthesis of 3-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (6t)

[0302]

[0303] According to the method of Manufacturing Example 3, N 2 Compound 6t (88 mg, 58%) was obtained as an orange oil using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (108 mg, 442 μmol), 2-aminonicotinaldehyde (83.5 mg, 684 μmol) and Na2S2O5 (170 mg, 894 μmol).

[0304] TLC R f 0.25 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 4.8, 1.5 Hz, 1H), 8.10-8.03 (m, 2H), 7.28 (dd, J = 8.0, 4.8 Hz, 1H), 7.23 (dd, J = 7.8, 1.8 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.80 (dd, J = 8.6, 2.5 Hz, 1H), 6.70 (brs, 2H), 6.42 (dd, J = 7.8, 4.8 Hz, 1H), 4.35-4.27 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 157.9, 151.3, 149.9, 149.0, 144.1, 143.6, 143.5, 138.2, 133.9, 128.3, 126.6, 120.9, 119.0, 117.5, 116.9, 111.2, 106.4, 64.12, 64.07. HRMS (ESI) m / z calcd for C 19 H 16 N5O2 + ([M + H] + ) 346.1299, found 346.1300.

[0305]

[0306] Example 21: Synthesis of 5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (6u)

[0307]

[0308] According to the method of Manufacturing Example 3, N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (50.1 mg, 206 μmol), 6-aminonicotinaldehyde (36.2 mg, 296 μmol) and Na2S2O5 (76.4 mg, 402 μmol) were used to obtain compound 6u (13.0 mg, 18%) as a white solid.

[0309] TLC R f 0.45 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J = 4.8, 1.5 Hz, 1H), 8.09 (dd, J = 2.4, 0.8 Hz, 1H), 8.07 (dd, J = 8.0, 1.5 Hz, 1H), 7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.85 (dd, J = 8.5, 2.5 Hz, 1H), 6.47 (brs, 2H), 6.42 (dd, J = 8.8, 0.8 Hz, 1H), 4.37-4.28 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 160.3, 152.1, 149.7, 148.9, 143.7, 143.6, 143.2, 137.2, 134.7, 128.6, 126.0, 121.1, 118.8, 117.6, 117.1, 113.5, 107.2, 64.14, 64.09. HRMS (ESI) m / z calcd for C 19 H 16 N5O2 + ([M + H] + ) 346.1299, found 346.1298.

[0310]

[0311] Example 22: Synthesis of 6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-3-ol (6v)

[0312]

[0313] According to the method of Manufacturing Example 3, N 2 Compound 6v (23.1 mg, 16%) was obtained as a white solid using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (99.8 mg, 410 μmol), 5-hydroxypicolinaldehyde (76.9 mg, 625 μmol) and Na2S2O5 (161 mg, 844 μmol).

[0314] TLC R f 0.18 (10:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 10.54 (brs, 1H), 8.30 (dd, J = 4.7, 1.5 Hz, 1H), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.35 (dd, J = 8.0, 4.7 Hz, 1H), 7.27 (dd, J = 8.7, 2.6 Hz, 1H), 6.94-6.85 (m, 2H), 6.73 (dd, J = 8.6, 2.4 Hz, 1H), 4.34-4.26 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 154.5, 151.7, 149.5, 144.2, 143.0, 143.0, 139.6, 137.2, 134.3, 129.3, 127.0, 125.9, 122.6, 120.8, 119.1, 116.8, 116.7, 64.11, 64.06. HRMS (ESI) m / z calcd for C 19 H 15 N4O3 + ([M + H] + ) 347.1139, found 347.1141

[0315]

[0316] Example 23: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-nitrophenol (6w)

[0317]

[0318] According to the method of Manufacturing Example 3, N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (334 mg, 1.22 mmol), 2-hydroxy-4-nitrobenzaldehyde (307 mg, 1.84 mmol) and Na2S2O5 (446 mg, 2.35 mmol) were used to obtain compound 6w (110 mg, 23%) as a yellow solid.

[0319] TLC R f 0.35 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 13.76 (s, 1H), 8.48 (dd, J = 4.8, 1.5 Hz, 1H), 8.13 (dd, J = 8.1, 1.5 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 8.9, 2.4 Hz, 1H), 7.37 (dd, J = 8.1, 4.8 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 4.43-4.33 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 160.8, 150.2, 149.4, 148.9, 146.6, 145.4, 144.9, 132.0, 128.3, 128.0, 127.0, 121.1, 120.3, 119.1, 117.34, 117.25, 113.4, 113.0, 64.53, 64.45. HRMS (ESI) m / z calcd for C 20 H 15 N4O5 + ([M + H] + ) 391.1037, found 391.1038.

[0320]

[0321] Example 24: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxyphenol (6x)

[0322]

[0323] According to the method of Manufacturing Example 3, N 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (56.7 mg, 233 μmol), 2-hydroxy-4-methoxybenzaldehyde (54.0 mg, 355 μmol) and Na2S2O5 (89.6 mg, 471 μmol) were used to obtain compound 6x (57.1 mg, 65%) as a white solid.

[0324] TLC R f 0.50 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.29 (dd, J = 4.8, 1.5 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.92 (dd, J = 8.6, 2.4 Hz, 1H), 6.53 (d, J = 2.6 Hz, 1H), 6.36 (dd, J = 8.9, 2.6 Hz, 1H), 4.39-4.29 (m, 4H), 3.75 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.9, 162.1, 152.4, 148.9, 144.9, 144.7, 144.6, 131.8, 129.0, 128.6, 125.5, 121.3, 119.5, 118.7, 117.4, 106.6, 104.8, 102.0, 64.5, 64.3, 55.4. HRMS (ESI) m / z calcd for C 21 H 18 N3O4 + ([M + H] + ) 376.1292, found 376.1294.

[0325]

[0326] Example 25: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-ethoxyphenol (6y)

[0327]

[0328] According to the method of Manufacturing Example 3, N 2 Compound 6y (127 mg, 57%) was obtained as a white solid using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (139 mg, 573 μmol) and Na2S2O5 (219 mg, 1.15 μmol).

[0329] TLC R f 0.70 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 13.57 (s, 1H), 8.34 (dd, J = 4.8, 1.5 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 6.89 (dd, J = 8.5, 2.4 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.20 (dd, J = 9.0, 2.6 Hz, 1H), 4.41-4.31 (m, 4H), 4.04 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.4, 162.2, 152.4, 148.8, 144.9, 144.7, 144.6, 131.6, 129.0, 128.6, 125.5, 121.3, 119.5, 118.8, 117.4, 107.1, 104.6, 102.5, 64.5, 64.4, 63.7, 14.8. HRMS (ESI) m / z calcd for C 22 H 20 N3O4+ ([M + H] + ) 390.1448, found 390.1457.

[0330]

[0331] Example 26: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-propoxyphenol (6z)

[0332]

[0333] According to the method of Manufacturing Example 3, N 2 Compound 6z (120 mg, 94%) was obtained as a white solid using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (77.1 mg, 317 μmol) and Na2S2O5 (123 mg, 645 μmol).

[0334] TLC R f 0.25 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 13.45 (s, 1H), 8.35 (dd, J = 4.8, 1.5 Hz, 1H), 8.02 (dd, J = 8.0, 1.5 Hz, 1H), 7.28 (dd, J = 8.0, 4.8 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 6.89 (dd, J = 8.5, 2.4 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 6.21 (dd, J = 9.0, 2.6 Hz, 1H), 4.41-4.30 (m, 4H), 3.92 (t, J = 6.6 Hz, 2H), 1.86-1.73 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.6, 162.3, 152.7, 149.0, 144.9, 144.69, 144.65, 132.0, 128.9, 128.8, 125.5, 121.4, 119.5, 118.8, 117.5, 107.1, 104.8, 102.6, 69.7, 64.5, 64.4, 22.6, 10.6. HRMS (ESI) m / z calcd for C 23 H 22 N3O4 + ([M + H] + ) 404.1605, found 404.1609.

[0335]

[0336] Example 27: Synthesis of 5-butoxy-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol (6aa)

[0337]

[0338] According to the method of Manufacturing Example 3, N 2 Compound 6aa (163 mg, 88%) was obtained as a white solid using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (108 mg, 445 μmol) and Na2S2O5 (163 mg, 857 μmol).

[0339] TLC R f 0.43 (1:1 hexane / EtOAc). 1H NMR (400 MHz, CDCl3) δ 13.56 (s, 1H), 8.34 (dd, J = 4.9, 1.5 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.31-7.23 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 6.89 (dd, J = 8.5, 2.4 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.20 (dd, J = 9.0, 2.6 Hz, 1H), 4.40-4.31 (m, 4H), 3.96 (t, J = 6.5 Hz, 2H), 1.81-1.69 (m, 2H), 1.51-1.43 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 164.5, 161.6, 150.1, 146.6, 146.1, 145.4, 144.7, 130.5, 129.6, 126.4, 124.8, 121.5, 120.8, 118.9, 117.0, 108.7, 102.9, 101.3, 68.2, 64.5, 64.4, 31.2, 19.3, 14.0. HRMS (ESI) m / z calcd for C 24 H 24 N3O4 + ([M + H] + ) 418.1761, found 418.1765.

[0340]

[0341] Example 28: Synthesis of 2-(2,4-dibutoxyphenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridine (6ab)

[0342]

[0343] According to the method of Manufacturing Example 3, N 2Compound 6ab (14.4 mg, 7%) was obtained as an orange sticky oil using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (108 mg, 445 μmol) and Na2S2O5 (163 mg, 857 μmol).

[0344] TLC R f 0.38 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 8.09 (dd, J = 8.0, 1.5 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.30-7.14 (m, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.71 (dd, J = 8.6, 2.4 Hz, 1H), 6.54 (dd, J = 8.4, 2.2 Hz, 1H), 6.34 (d, J = 2.2 Hz, 1H), 4.34-4.18 (m, 4H), 3.98 (t, J = 6.5 Hz, 2H), 3.63 (t, J = 7.0 Hz, 2H), 1.89-1.71 (m, 2H), 1.59-1.39 (m, 4H), 1.29-1.15 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 163.2, 158.3, 152.2, 147.7, 145.2, 143.7, 143.6, 133.4, 132.8, 128.3, 126.5, 119.8, 119.6, 117.5, 117.4, 116.0, 105.8, 99.9, 68.2, 68.1, 64.5, 64.4, 31.4, 30.8, 19.3, 19.1, 14.0, 13.9. HRMS (ESI) m / z calcd for C 28 H 32 N3O4 + ([M + H] +) 474.2387, found 474.2392.

[0345]

[0346] Example 29: Synthesis of 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6ac)

[0347]

[0348] According to the method of Manufacturing Example 3, N 2 Compound 6ac (12.4 mg, 23%) was obtained as a white solid using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (35.1 mg, 144 μmol), 2,4-dihydroxy- 5-methylbenzaldehyde (28.9 mg, 190 μmol) and Na2S2O5 (56.8 mg, 299 μmol).

[0349] TLC R f 0.38 (1:1 X 2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.95 (s, 1H), 8.26 (dd, J = 4.8, 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.91 (dd, J = 8.6, 2.4 Hz, 1H), 6.73 (s, 1H), 6.40 (s, 1H), 4.38-4.29 (m, 4H), 1.83 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 190.7, 161.0, 151.0, 149.2, 145.2, 144.10, 144.07, 137.2, 135.2, 132.9, 127.9, 125.0, 120.8, 120.4, 119.4, 118.1, 116.8, 112.1, 64.39, 64.35, 55.8. HRMS (ESI) m / z calcd for C 21 H 18 N3O4 + ([M + H] + ) 376.1292, found 376.1293.

[0350]

[0351] Example 30: Synthesis of 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-ethylbenzene-1,3-diol (6ad)

[0352]

[0353] According to the method of Manufacturing Example 3, N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (121 mg, 499 μmol), 5-ethyl-2, 4-dihydroxybenzaldehyde (106 mg, 635 μmol) and Na2S2O5 (179 mg, 941 μmol) were used to obtain compound 6ad (111 mg, 57%) as a white solid.

[0354] TLC R f 0.30 (1:1 X 2 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 9.98 (s, 1H), 8.26 (dd, J = 4.8, 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 6.96 (dd, J = 8.5, 2.5 Hz, 1H), 6.77 (s, 1H), 6.41 (s, 1H), 4.37-4.27 (m, 4H), 2.25 (q, J = 7.5 Hz, 2H), 0.81 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 158.7, 158.5, 152.8, 148.7, 144.1, 143.9, 143.7, 132.0, 128.8, 127.6, 125.2, 121.4, 120.7, 119.2, 117.8, 117.3, 103.7, 102.7, 64.3, 64.2, 21.0, 12.8. HRMS (ESI) m / z calcd for C 22 H 20 N3O4 + ([M + H] + ) 390.1448, found 390.1452.

[0355]

[0356] Example 31: Synthesis of 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-isopropylbenzene-1,3-diol (6ae)

[0357]

[0358] According to the method of Manufacturing Example 3, N 2Compound 6ae (21.4 mg, 11%) was obtained as a white solid using -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (116 mg, 477 μmol), 2,4-dihydroxy-5-isopropylbenzaldehyde (118 mg, 652 μmol) and Na2S2O5 (173 mg, 912 μmol).

[0359] TLC R f 0.35 (1:1 X 2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.01 (s, 1H), 8.26 (dd, J = 4.8, 1.5 Hz, 1H), 8.12 (dd, J = 8.0, 1.5 Hz, 1H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.99 (dd, J = 8.5, 2.5 Hz, 1H), 6.83 (s, 1H), 6.41 (s, 1H), 4.37-4.27 (m, 4H), 2.95 (septet, J = 6.8 Hz, 1H), 0.82 (d, J = 6.8 Hz, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 158.7, 158.1, 152.8, 148.7, 144.3, 144.1, 143.7, 131.9, 128.9, 125.5, 125.4, 125.1, 121.5, 119.2, 117.9, 117.4, 103.4, 102.8, 64.3, 64.2, 25.0, 22.2. HRMS (ESI) m / z calcd for C 23 H 22 N3O4 + ([M + H] + ) 404.1605, found 404.1604.

[0360]

[0361] Example 32: Synthesis of 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methoxybenzene-1,3-diol (6af)

[0362]

[0363] According to the method of Manufacturing Example 3, N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (94.4 mg, 388 μmol), 2,4-dihydroxy- 5-methoxybenzaldehyde (93.8 mg, 558 μmol) and Na2S2O5 (147 mg, 773 μmol) were used to obtain compound 6af (109 mg, 72%) as a white solid.

[0364] TLC R f 0.13 (1:1 X 2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.82 (s, 1H), 8.27 (dd, J = 4.8, 1.5 Hz, 1H), 8.12 (dd, J = 8.0, 1.5 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 8.5, 2.5 Hz, 1H), 6.56 (s, 1H), 6.42 (s, 1H), 4.36-4.28 (m, 4H), 3.31 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 154.7, 152.4, 150.7, 148.7, 144.2, 143.9, 143.8, 140.3, 132.0, 128.7, 125.2, 121.6, 119.2, 117.8, 117.5, 111.0, 104.2, 102.3, 64.3, 64.2, 55.1. HRMS (ESI) m / z calcd for C 21 H 18 N3O5 + ([M + H]+ ) 392.1241, found 392.1243.

[0365]

[0366] Example 33: Synthesis of 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-iodobenzene-1,3-diol (6ag)

[0367]

[0368] According to the method of Manufacturing Example 3, N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (593.2 mg, 2.44 mmol), 2,4-dihydroxy-5-iodobenzaldehyde (968.7 mg, 3.67 mmol) and Na2S2O5 (696.8 mg, 3.67 mmol) were used, and compound 6ag (441 mg, 37%) was obtained as a pale yellow solid.

[0369] TLC R f 0.50 (1:1 X 2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 10.85 (s, 1H), 8.30 (dd, J = 4.8, 1.5 Hz, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.32 (s, 1H), 7.08 (d, J = 2.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.94 (dd, J = 8.5, 2.5 Hz, 1H), 6.49 (s, 1H), 4.38-4.28 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 159.9, 159.5, 151.2, 148.5, 144.1, 144.0, 143.7, 138.6, 132.3, 128.3, 125.8, 120.9, 119.2, 117.6, 116.9, 108.0, 102.8, 72.0, 64.2, 64.2. HRMS (ESI) m / z calcd for C 20 H 15 IN3O4 + ([M + H] + ) 488.0102, found 488.0101.

[0370]

[0371] Example 34: Synthesis of 4-bromo-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1, 3-diol (6ah)

[0372]

[0373] According to the method of Manufacturing Example 3, N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (151 mg, 622 μmol), 5-bromo-2, 4-dihydroxybenzaldehyde (159 mg, 731 μmol) and Na2S2O5 (265 mg, 1.39 mmol) were used to obtain compound 6ah (110 mg, 40%) as a beige solid.

[0374] TLC R f 0.33 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.79 (s, 1H), 8.29 (dd, J = 4.8, 1.5 Hz, 1H), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.92 (dd, J = 8.6, 2.4 Hz, 1H), 6.54 (s, 1H), 4.37-4.27 (m, 4H). 13 C NMR (100 MHz, DMSO) δ 158.9, 156.9, 151.3, 148.5, 144.1, 144.0, 143.7, 132.6, 132.5, 128.3, 125.9, 120.9, 119.3, 117.7, 116.9, 107.2, 103.9, 98.7, 64.2, 64.2. HRMS (ESI) m / z calcd for C 20 H 15 BrN3O4 + ([M + H] + ) 440.0240, found 440.0241.

[0375]

[0376] Example 35: Synthesis of 4-chloro-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ai)

[0377]

[0378] According to the method of Manufacturing Example 3, N 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (40.0 mg, 101 μmol), 5-chloro-2,4-dihydroxybenzaldehyde (21.0 mg, 121 μmol) and Na2S2O5 (20.0 mg, 101 μmol) were used to obtain compound 6ai (23.2 mg, 58%) as a pale yellow solid.

[0379] TLC: R f 0.55 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (brs, 1H), 10.74 (brs, 1H), 8.30 (dd, J = 4.8, 1.5 Hz, 1H), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 7.04 (s, 1H), 6.92 (dd, J = 8.6, 2.4 Hz, 1H), 6.55 (s, 1H), 4.35-4.28 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 158.2, 155.9, 151.4, 148.5, 144.1, 144.0, 143.6, 132.5, 129.6, 128.2, 125.9, 120.9, 119.2, 117.6, 116.9, 110.1, 106.5, 104.1, 64.2, 64.1. HRMS (ESI) m / z calcd for C 20 H 15 ClN3O4 + ([M + H] + ) 396.0746, found 396.0746.

[0380]

[0381] Examples 36 to 46 below were synthesized based on the following reaction scheme 2.

[0382] [Reaction Formula 2]

[0383]

[0384]

[0385] Example 36: Synthesis of 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-3-nitrophenol (6aj)

[0386]

[0387] 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-methoxy-2-nitrophenyl)-3H-imidazo[4,5-b]pyridine6r (60.6 mg, 150 μmol) was dissolved in anhydrous CH2Cl2 (1.2 mL) in a 2 mL oven-dried round-bottom flask with a side arm. BBr3 solution (600 μL, 600 μmol, 1 M in CH2Cl2) was slowly added at 0 °C, and the reaction mixture was stirred at room temperature for 22 h. Upon completion of the reaction, 25% aqueous ammonia was added until the pH reached 10 and stirred for 2 h. The reaction mixture was acidified to pH 5 with 10% aqueous HCl. The aqueous layer was extracted with CH2Cl2 (2 X 10 mL), and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (200:1 → 50:1 CH2Cl2 / MeOH) to give compound 6aj (19.6 mg, 33%) as a beige-white solid.

[0388] TLC R f 0.38 (80:1 X 2 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.35 (dd, J = 4.8, 1.5 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.38 (dd, J) = 8.0, 4.8 Hz, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.5, 2.5 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.72 (dd, J = 8.8, 2.5 Hz, 1H), 4.31-4.22 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 159.4, 150.4, 149.6, 148.4, 144.3, 143.5, 143.3, 134.4, 133.9, 127.3, 127.0, 120.4, 120.3, 119.1, 117.4, 116.4, 115.3, 111.0, 64.1, 64.0. HRMS (ESI) m / z calcd for C 20 H 15 N4O5 + ([M + H] + ) 391.1037, found 391.1042.

[0389]

[0390] Example 37: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxyaniline (6ak)

[0391]

[0392] 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-methoxy-2-nitrophenyl)-3H-imidazo[4,5-b]pyridine6r (127 mg, 313 μmol) was dissolved in EtOH (6.0 mL) in a 100 mL oven-dried round-bottom flask with a side arm. 5% Pd / C (27.2 mg, 21 wt%) was added and stirred at room temperature under a hydrogen-filled balloon for 5 h. Upon completion of the reaction, the reaction mixture was filtered and filtered with Celite ® The residue was filtered through a plug and washed with EtOH (6 mL) and EtOAc (6 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (200:1→ 40:1 CH2Cl2 / MeOH) to give compound 6ak (91.3 mg, 78%) as a pale yellow solid.

[0393] TLC R f 0.63 (100:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (dd, J = 4.8, 1.5 Hz, 1H), 8.08 (dd, J = 8.0, 1.5 Hz, 1H), 7.31 (dd, J = 8.0, 4.8 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.75 (dd, J = 8.6, 2.5 Hz, 1H), 6.52 (brs, 2H), 6.35 (d, J = 2.5 Hz, 1H), 5.98 (dd, J = 8.8, 2.5 Hz, 1H), 4.35-4.26 (m, 4H), 3.69 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 161.1, 152.9, 150.5, 148.9, 143.4, 143.4, 143.3, 134.0, 131.5, 129.0, 125.7, 120.9, 118.7, 117.4, 116.9, 104.0, 102.4, 99.5, 64.1, 64.1, 54.8. HRMS (ESI) m / z calcd for C 21 H 19 N4O3 + ([M + H] + ) 375.1452, found 375.1453.

[0394]

[0395] Example 38: Synthesis of 3-amino-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol (6al)

[0396]

[0397] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxyaniline 6ak (54.2 mg, 145 μmol) was dissolved in anhydrous CH2Cl2 (1.5 mL) in a 5 mL oven-dried round-bottom flask with a side arm. BBr3 solution (2.00 mL, 2.0 mmol, 1 M in CH2Cl2) was slowly added at 0 °C, and the reaction mixture was stirred at room temperature for 48 h. Upon completion of the reaction, 25% aqueous ammonia was added until pH 10 and stirred for 1 h. The reaction mixture was acidified to pH 6 with 1 N aqueous HCl. The organic layers were extracted with CH2Cl2 (2 X 10 mL), and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (50:1 → 30:1 CH2Cl2 / MeOH) to obtain compound 6al (27.4 mg, 52%) as a beige white solid.

[0398] TLC R f 0.08 (80:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.22 (dd, J = 4.8, 1.5 Hz, 1H), 8.05 (dd, J = 8.0, 1.5 Hz, 1H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.5, 2.5 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.43 (brs, 2H), 6.20 (d, J = 2.4 Hz, 1H), 5.80 (dd, J = 8.7, 2.4 Hz, 1H), 4.35-4.26 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 159.5, 153.3, 150.6, 148.9, 143.4, 143.3, 143.1, 134.1, 131.6, 129.2, 125.5, 120.9, 118.7, 117.4, 116.9, 103.9, 102.8, 101.3, 64.11, 64.07. HRMS (EI) m / z calcd for C 20 H 16 N4O3 + ([M] + ) 360.1217, found 360.1218.

[0399]

[0400] Example 39: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-hydroxybenzonitrile (6am)

[0401]

[0402] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxybenzonitrile 6s (92.5 mg, 241 μmol) was dissolved in anhydrous CH2Cl2 (1.8 mL) in a 5 mL oven-dried round-bottom flask with a side arm. BBr3 solution (2.00 mL, 2.0 mmol, 1 M in CH2Cl2) was slowly added at 0 °C, and the reaction mixture was stirred at room temperature for 15 h. Upon completion of the reaction, 25% aqueous ammonia was added until the pH reached 10 and stirred for 1 h. The reaction mixture was acidified to pH 6 with 1 N aqueous HCl. Extracted with CH2Cl2 (2 X 30 mL), the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (35:1 CH2Cl2 / MeOH) to give compound 6am (41.4 mg, 46%) as an orange oil.

[0403] TLC R f0.09 (30:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.38 (dd, J = 4.8, 1.5 Hz, 1H), 8.23 ​​(dd, J = 8.0, 1.5 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.40 (dd, J) = 8.0, 4.8 Hz, 2H), 7.26 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.6, 2.5 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.74 (dd, J = 8.6, 2.5 Hz, 1H), 4.33-4.23 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 158.8, 150.4, 148.7, 144.7, 143.5, 143.3, 134.3, 133.1, 127.5, 127.3, 123.5, 120.7, 120.02, 119.98, 119.3, 117.34, 117.32, 116.8, 113.3, 64.09, 64.06. HRMS (ESI) m / z calcd for C 21 H 15 N4O3 + ([M + H] + ) 371.1139, found 371.1140.

[0404]

[0405] Example 40: Synthesis of 5-amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol (6ao)

[0406]

[0407] 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-nitrophenol 6w (400 mg, 1.03 mmol) was dissolved in EtOH (19.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. 5% Pd / C (82.2 mg, 21 wt%) was added and stirred at room temperature under a hydrogen-filled balloon for 4 h. Upon completion of the reaction, the reaction mixture was filtered and filtered using Celite ® The residue was filtered through a plug and washed with EtOH (20 mL) and EtOAc (20 mL). The filtrate was concentrated using a rotary evaporator to give compound 6ao (345 mg, 93%) as a pale yellow solid.

[0408] TLC R f 0.38 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 13.52 (s, 1H), 8.31 (dd, J = 4.8, 1.5 Hz, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.24 (dd, J = 8.0, 4.8 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 5.94 (dd, J = 8.7, 2.4 Hz, 1H), 4.40-4.30 (m, 4H), 3.90 (brs, 2H). 13 C NMR (100 MHz, CDCl3) δ 163.7, 162.2, 153.3, 150.3, 149.3, 144.8, 144.6, 144.2, 132.6, 129.2, 125.2, 121.5, 119.2, 118.7, 117.6, 106.3, 103.1, 102.6, 64.5, 64.4. HRMS (ESI) m / z calcd for C 20 H 17 N4O3+ ([M + H] + ) 361.1295, found 361.1296.

[0409]

[0410] Example 41: Synthesis of (2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(methylamino)phenol (6ap)

[0411]

[0412] 5-Amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol 6ao (101 mg, 279 μmol) and K2CO3 (40.4 mg, 292 μmol) were suspended in anhydrous DMF (2.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm. After stirring at 100 °C for 15 min, iodomethane (30.0 μL, 482 μmol) was slowly added. The reaction mixture was stirred at 100 °C for 30 min. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and washed with CH2Cl2 (20 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (2:1 hexanes / EtOAc) to give the monoalkylated compound 6ap (21.2 mg, 20%) as a yellow solid.

[0413] TLC R f 0.33 (1:1 hexane / EtOAc). 1H NMR (400 MHz, CDCl3) δ 13.59 (s, 1H), 8.29 (dd, J = 4.8, 1.5 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.23 (dd, J = 8.0, 4.8 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.89 (dd, J = 8.8, 2.4 Hz, 1H), 4.40-4.30 (m, 4H), 4.00 (brs, 1H), 2.84 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.4, 153.6, 152.6, 149.4, 144.7, 144.6, 143.9, 132.7, 129.3, 128.8, 125.0, 121.6, 119.1, 118.7, 117.6, 104.6, 101.7, 99.2, 64.5, 64.4, 30.3. HRMS (ESI) m / z calcd for C 21 H 19 N4O3 + ([M + H] + ) 375.1452, found 375.1453.

[0414]

[0415] Example 42: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(ethylamino)phenol (6aq)

[0416]

[0417] 5-Amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol 6ao (226 mg, 626 μmol) and K2CO3 (89.2 mg, 646 μmol) were suspended in anhydrous DMF (3.0 mL) in a 10 mL oven-dried round-bottom flask with a side arm and stirred in an oil bath at 100 °C for 15 min. After cooling to room temperature, 1-iodoethane (80.0 μL, 1.00 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred in an oil bath at 100 °C for 4 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and washed with CH2Cl2 (20 mL). The filtrate was concentrated using a rotary evaporator and the residue was purified by column chromatography (1.5:1 hexanes / EtOAc) to give the monoalkylated compound 6aq (84.5 mg, 35%) as a yellow solid.

[0418] TLC R f 0.50 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 13.56 (s, 1H), 8.29 (dd, J = 4.8, 1.5 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.23 (dd, J = 8.0, 4.8 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.87 (dd, J = 8.8, 2.4 Hz, 1H), 4.40-4.30 (m, 4H), 3.87 (brs, 1H), 3.17 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.4, 153.6, 151.7, 149.4, 144.7, 144.6, 143.8, 132.7, 129.3, 128.9, 125.0, 121.6, 119.1, 118.7, 117.6, 104.8, 101.6, 99.4, 64.5, 64.4, 38.0, 14.9. HRMS (ESI) m / z calcd for C 22 H 21 N4O3 + ([M + H] + ) 389.1608, found 389.1609.

[0419]

[0420] Example 43: Synthesis of 5-(diethylamino)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol)(6ar)

[0421]

[0422] 5-Amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol 6ao (226 mg, 626 μmol) and K2CO3 (89.2 mg, 646 μmol) were suspended in anhydrous DMF (3.0 mL) in a 10 mL oven-dried round-bottom flask with a side arm and stirred in an oil bath at 100 °C for 15 min. After cooling to room temperature, 1-iodoethane (80.0 μL, 1.00 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred in an oil bath at 100 °C for 4 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and washed with CH2Cl2 (20 mL). The filtrate was concentrated using a rotary evaporator and the residue was purified by column chromatography (1.5:1 hexanes / EtOAc) to give the dialkylated compound 6ar (40.8 mg, 16%) as a dark orange solid.

[0423] TLC R f0.55 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 13.40 (s, 1H), 8.27 (dd, J = 4.8, 1.5 Hz, 1H), 7.93 (dd, J = 7.9, 1.5 Hz, 1H), 7.21 (dd, J = 7.9, 4.8 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.5, 2.4 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.31 (d, J = 2.7 Hz, 1H), 5.96 (dd, J = 9.2, 2.7 Hz, 1H), 4.50-4.25 (m, 4H), 3.34 (q, J = 7.1 Hz, 4H), 1.16 (t, J = 7.1 Hz, 6H). HRMS (ESI) m / z calcd for C 24 H 25 N4O3 + ([M + H] + ) 417.1921.1608, found 417.1923.

[0424]

[0425] Example 44: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(propylamino)phenol (6as)

[0426]

[0427] 5-Amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol 6ao (82.8 mg, 230 μmol) and K2CO3 (35.5 mg, 257 μmol) were suspended in anhydrous DMF (2.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm and stirred in an oil bath at 100 °C for 15 min. After cooling to room temperature, 1-iodopropane (90.0 μL, 927 μmol) was slowly added to the reaction mixture. The reaction mixture was stirred in an oil bath at 100 °C for 2 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and washed with CH2Cl2 (20 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (2:1 hexanes / EtOAc) to give the monoalkylated compound 6as (43.0 mg, 47%) as a yellow solid.

[0428] TLC R f 0.45 (hexane / EtOAc 1:1). 1 H NMR (400 MHz, CDCl3) δ 13.57 (s, 1H), 8.28 (dd, J = 4.8, 1.5 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.22 (dd, J = 8.0, 4.8 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.87 (dd, J = 8.8, 2.4 Hz, 1H), 4.40-4.30 (m, 4H), 3.95 (brs, 1H), 3.10 (dd, J = 11.0, 6.9 Hz, 2H), 1.64 (dt, J = 14.5, 7.3 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.4, 153.6, 151.8, 149.4, 144.7, 144.6, 143.8, 132.7, 129.4, 128.9, 124.9, 121.6, 119.1, 118.7, 117.6, 104.8, 101.5, 99.4, 64.5, 64.4, 45.3, 22.7, 11.7. HRMS (ESI) m / z calcd for C 23 H 23 N4O3 + ([M + H] + ) 403.1765, found 403.1770.

[0429]

[0430] Example 45: Synthesis of 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(dipropylamino)phenol (6at)

[0431]

[0432] 5-Amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol 6ao (82.8 mg, 230 μmol) and K2CO3 (35.5 mg, 257 μmol) were suspended in anhydrous DMF (2.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm and stirred in an oil bath at 100 °C for 15 min. After cooling to room temperature, 1-iodopropane (90.0 μL, 927 μmol) was slowly added to the reaction mixture. The reaction mixture was stirred in an oil bath at 100 °C for 2 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and washed with CH2Cl2 (20 mL). The filtrate was concentrated using a rotary evaporator and the residue was purified by column chromatography (2:1 hexanes / EtOAc) to give the dialkylated compound 6at (3.1 mg, 3%) as a dark orange solid.

[0433] TLC R f0.50 (hexane / EtOAc 1:1). 1 H NMR (400 MHz, CDCl3) δ 13.51 (s, 1H), 8.27 (dd, J = 4.8, 1.5 Hz, 1H), 7.93 (dd, J = 7.9, 1.5 Hz, 1H), 7.21 (dd, J = 7.9, 4.8 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.5, 2.4 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 6.28 (d, J = 2.7 Hz, 1H), 5.93 (dd, J = 9.2, 2.7 Hz, 1H), 4.57-4.24 (m, 4H), 3.26-3.12 (m, 4H), 1.69-1.56 (m, 4H), 0.92 (t, J = 7.4 Hz, 6H).

[0434]

[0435] Example 46: Synthesis of 5-(butylamino)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol (6au)

[0436]

[0437] 5-Amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol 6ao (84.4 mg, 234 μmol) and K2CO3 (37.2 mg, 269 μmol) were suspended in anhydrous DMF (2.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm and stirred in an oil bath at 100 °C for 15 min. After cooling to room temperature, 1-iodobutane (90.0 μL, 786 μmol) was slowly added to the reaction mixture. The reaction mixture was stirred in an oil bath at 100 °C for 2 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and washed with CH2Cl2 (20 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (2:1 hexanes / EtOAc) to give compound 6au (39.9 mg, 41%) as a yellow solid.

[0438] TLC R f 0.50 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 13.58 (s, 1H), 8.28 (dd, J = 4.8, 1.5 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.22 (dd, J = 8.0, 4.8 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.5, 2.4 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.86 (dd, J = 8.9, 2.4 Hz, 1H), 4.40-4.31 (m, 4H), 3.92 (brs, 1H), 3.17-3.08 (m, 2H), 1.63-1.55 (m, 2H), 1.48-1.34 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.4, 153.6, 151.8, 149.4, 144.7, 144.6, 143.8, 132.7, 129.4, 128.9, 124.9, 121.6, 119.1, 118.7, 117.6, 104.8, 101.5, 99.4, 64.5, 64.4, 43.2, 31.6, 20.4, 14.0. HRMS (ESI) m / z calcd for C 24 H 25 N4O3 + ([M + H] + ) 417.1921, found 417.1929.

[0439]

[0440] Manufacturing Example 4: Synthesis of N-(benzo[d][1,3]dioxol-5-yl)-3-nitropyridin-2-amine (3c)

[0441]

[0442] In a 50 mL oven-dried round-bottom flask with a sidearm, 2-chloro-3-nitro-pyridine (500 mg, 3.16 mmol), benzo[d][1,3]dioxol-5-amine (2') (1.20 g, 3.78 mmol), and K2CO3 (872 mg, 6.31 mmol) were suspended in anhydrous i-PrOH (10.0 mL). The reaction mixture was stirred in an oil bath overnight at 80 °C. Upon completion of the reaction, the reaction mixture was cooled to room temperature and concentrated using a rotary evaporator. The resulting residue was then purified by column chromatography (1:1 hexanes / EtOAc) to give N-(benzo[d][1,3]dioxol-5-yl)-3-nitropyridin-2-amine (3c) (780 mg, 95%) as a white solid.

[0443] TLC R f 0.53 (2:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.51 (dd, J = 8.3, 1.8 Hz, 1H), 8.48 (dd, J = 4.5, 1.8 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.4, 2.2 Hz, 1H), 6.94 (dd, J = 8.3, 4.5 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.03 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 155.7, 150.4, 147.5, 144.6, 136.0, 132.8, 128.9, 117.0, 114.5, 108.3, 106.0, 101.7. HRMS (ESI) m / z calcd for C 12 H 10 N3O4 + ([M + H] + ) 260.0666, found 260.0666.

[0444]

[0445] Manufacturing Example 5: Synthesis of N2-(benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (4c)

[0446]

[0447] In a 50 mL oven-dried round-bottom flask with a side arm, N-(Benzo[d][1,3]dioxol-5-yl)-3-nitropyridin-2-amine (3c) (726 mg, 2.80 mmol) and Pd / C (77.0 mg) were suspended in EtOH (10.0 mL). The reaction mixture was stirred under a hydrogen-filled balloon at room temperature for 5 h. After the reaction was completed, the precipitate was filtered and washed with MeOH (10 mL). The filtrate was concentrated using a rotary evaporator, and the resulting residue was purified by column chromatography (1:2 hexanes / EtOAc) to yield N 2 -(Benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (4c) (640 mg, 99%) was obtained as a white solid.

[0448] TLC R f 0.52 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.45 (dd, J = 4.9, 1.6 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.4, 2.2 Hz, 1H), 6.86 (dd, J = 8.4, 2.2 Hz, 1H) 7.6, 1.7 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 7.6, 4.9 Hz, 1H), 5.93 (s, 2H), 5.00 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 147.3, 144.6, 141.2, 137.3, 134.8, 131.8, 119.8, 115.7, 111.4, 108.3, 101.6, 100.9. HRMS (ESI) m / z calcd for C 12 H 12 N3O2 + ([M + H] + ) 230.0924, found 230.0929.

[0449]

[0450] Example 47: Synthesis of 4-(3-(benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ca)

[0451]

[0452] N 2 -(Benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (4c, Preparation Example 5) was used and synthesized according to the method of Preparation Example 3 to obtain compound 6ca (47 mg, 31%) as a white solid.

[0453] TLC R f 0.48 (1:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.02 (s, 1H), 8.27 (dd, J = 4.8, 1.5 Hz, 1H), 8.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.94 (dd, J = 8.5, 1.8 Hz, 2H), 6.35 (d, J = 2.4 Hz, 1H), 6.21-6.11 (m, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 160.9, 160.4, 152.7, 148.7, 148.0, 147.8, 143.8, 132.2, 129.5, 129.2, 125.4, 121.9, 119.2, 109.2, 108.6, 107.1, 104.8, 103.2, 102.1. HRMS (ESI) m / z calcd for C 19 H 14 N3O4 + ([M + H] + ) 348.0979, found 348.0982.

[0454]

[0455] Example 48: Synthesis of 4-(3-(benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol (6cb)

[0456]

[0457] N 2 -(Benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (4c, Preparation Example 5) was used and synthesized according to the method of Preparation Example 3 to obtain compound 6cb (70 mg, 42%) as a white solid.

[0458] TLC R f 0.54 (1:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.79 (s, 1H), 8.29 (dd, J = 4.8, 1.5 Hz, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 8.2, 2.1 Hz, 1H), 6.51 (s, 1H), 6.17 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 158.2, 155.9, 151.5, 148.6, 147.8, 147.7, 144.1, 132.5, 129.6, 128.9, 126.0, 121.7, 119.2, 110.1, 109.1, 108.5, 106.5, 104.1, 102.1. HRMS (ESI) m / z calcd for C 19 H 13 ClN3O5 + ([M + H] + ) 382.0589, found 382.0592.

[0459]

[0460] Example 49: Synthesis of 4-(3-(benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6cc)

[0461]

[0462] N 2 -(Benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (4c, Preparation Example 5) was used and synthesized according to the method of Preparation Example 3 to obtain compound 6cc (84 mg, 53%) as a white solid.

[0463] TLC R f 0.49 (1:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.95 (s, 1H), 8.27 (dd, J = 4.8, 1.4 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.94 (dd, J = 8.2, 2.1 Hz, 1H), 6.78 (d, J = 0.9 Hz, 1H), 6.40 (s, 1H), 6.18 (s, 2H), 1.84 (d, J = 0.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 158.8, 158.3, 152.8, 148.7, 147.9, 147.7, 143.6, 132.3, 130.0, 129.4, 125.3, 121.9, 119.1, 114.8, 109.2, 108.5, 104.2, 102.7, 102.0, 15.5. HRMS (ESI) m / z calcd for C 20 H 16 N3O4 + ([M + H] + ) 362.1135, found 362.1137.

[0464]

[0465] Examples 50 to 55 below were synthesized based on the following reaction scheme 3.

[0466] [Reaction Formula 3]

[0467]

[0468]

[0469] Example 50: Synthesis of 5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-[1,1'-biphenyl]-2,3',4-triol (7a)

[0470]

[0471] N in a 10 mL oven-dried round-bottom flask with a side arm 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (4) (53.1 mg, 218 μmol), 3',4,6-trihydroxy-[1,1'-biphenyl]-3-carbaldehyde (5a) (45.3 mg, 197 μmol), and Na2S2O5 (55.0 mg, 289 μmol) were suspended in DMSO (0.5 mL). The reaction mixture was stirred in an oil bath at 130 °C for 3 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, dropped into ice water (25 mL), and stirred for 5 minutes. The precipitate was filtered and washed with water (10 mL). The filtered solid was purified by column chromatography (7:5:1.2 hexanes / EtOAc / MeOH) to obtain the desired compound 7a (65.7 mg, 74%) as a pale pink solid.

[0472] TLC R f 0.50 (1:1:0.5 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.26 (s, 1H), 9.27 (s, 1H), 8.28 (dd, J = 4.8, 1.5 Hz, 1H), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.07 (t, J = 8.5 Hz, 2H), 7.01 (s, 1H), 6.96 (dd, J = 8.5, 2.4 Hz, 1H), 6.74 (dd, J = 2.5, 1.6 Hz, 1H), 6.63 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 6.54 (s, 1H), 6.44 (dt, J = 8.0, 1.6, 1.0 Hz, 1H), 5.06-3.67 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 159.7, 157.9, 156.8, 152.4, 148.7, 144.4, 144.0, 143.9, 138.8, 132.0, 130.3, 128.7, 128.6, 125.4, 121.3, 119.4, 119.3, 119.0, 118.0, 117.3, 115.9, 113.3, 104.6, 103.7, 64.3, 64.2. HRMS (ESI) m / z calcd for C 26 H 20 N3O5 + ([M + H] + ) 454.1397, found 454.1397. HPLC (method A, l = 254 nm): 97.4%.

[0473]

[0474] Example 51: Synthesis of 3'-(benzyloxy)-5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-[1,1'-biphenyl]-2,4-diol (7b)

[0475]

[0476] N in a 5 mL oven-dried round-bottom flask with a side arm 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (4) (80.3 mg, 331 μmol), 4'-(benzyloxy)-4,6-dihydroxy-[1,1'-biphenyl]-3-carbaldehyde (5b) (86.1 mg, 269 μmol), and Na2S2O5 (177 mg, 928 μmol) were suspended in DMSO (1.5 mL). The reaction mixture was stirred in an oil bath at 130 °C for 0.5 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water (50 mL), and stirred for 5 minutes. The precipitate was filtered and washed with water (20 mL). The filtered solid was purified by column chromatography (99:1 → 19:1 CH2Cl2 / MeOH) to obtain the desired compound 7b (20.3 mg, 11%) as a beige solid.

[0477] TLC R f 0.43 (20:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, Acetone-d6) δ 13.23 (s, 1H), 9.03 (s, 1H), 8.29 (dd, J = 4.8, 1.5 Hz, 1H), 8.09 (dd, J = 8.0, 1.5 Hz, 1H), 7.51 (ddt, J = 7.4, 1.4, 0.6 Hz, 2H), 7.46-7.39 (m, 2H), 7.38-7.33 (m, 2H), 7.21-7.10 (m, 4H), 7.07 (s, 1H), 7.03 (dd, J = 8.5, 2.5 Hz, 1H), 6.99-6.91 (m, 2H), 6.62 (s, 1H), 5.15 (s, 2H), 4.44-4.34 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 159.1, 157.4, 156.5, 152.0, 148.3, 144.0, 143.6, 143.6, 136.8, 131.6, 129.7, 129.5, 129.1 (2C), 128.4, 128.1 (2C), 127.4, 127.2 (2C), 125.0, 121.1, 118.9, 118.6, 117.6, 117.1, 113.8 (2C), 104.2, 103.3, 68.8, 64.0, 63.9. HRMS (ESI) m / z calcd for C 33 H 25 N3O5 + ([M + H] + ) 544.1867, found 544.1867. HPLC (method A, l = 254 nm): 95.3%.

[0478]

[0479] Example 52: Synthesis of N-(5'-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-2',4'-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide (7c)

[0480]

[0481] A 5 mL oven-dried round-bottom flask with a side arm was charged with N-(5'-formyl-2',4'-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide (5c) (55.6 mg, 167 μmol), N 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (4) (40.3 mg, 166 μmol) and Na2S2O5 (87.6 mg, 461 μmol) were dissolved in DMSO (0.5 mL). The reaction mixture was stirred in an oil bath at 130 °C for 50 min. Upon completion of the reaction, the reaction mixture was cooled to room temperature, slowly added dropwise to ice water (10 mL), and stirred for 10 min. The precipitate was filtered and washed with water (20 mL) to obtain compound 7c (86.0 mg, 93%) as a pale brown solid.

[0482] TLC R f 0.18 (1:1 hexane:EtOAc). 1 H NMR (400 MHz, Acetone-d6) δ 13.20 (s, 1H), 9.54 (s, 1H), 9.13 (s, 1H), 8.31 (dd, J = 4.8, 1.5 Hz, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 8.05-7.98 (m, 2H), 7.86-7.78 (m, 2H), 7.61-7.50 (m, 3H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.28-7.13 (m, 5H), 7.06 (dd, J = 8.5, 2.5 Hz, 1H), 6.65 (s, 1H), 4.51-4.39 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 165.6, 159.7, 158.1, 152.4, 148.6, 144.5, 144.1, 144.1, 137.6, 135.0, 132.88, 131.9, 131.7, 130.1, 129.1, 128.9, 128.5 (2C), 128.5 (2C), 127.7 (2C), 125.4, 121.6, 120.1, 119.8 (2C), 119.4, 118.9, 118.1, 117.5, 104.6, 103.8, 64.5, 64.3. HRMS (ESI) m / z calcd for C 33 H 25 N4O5+ ([M + H] + ) 557.1819, found 557.1815. HPLC (method A, l = 254 nm): 94.9%.

[0483]

[0484] Example 53: Synthesis of 4-(6-chloropyridin-3-yl)-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (7d)

[0485]

[0486] N in a 4 mL vial 2 -(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (4) (29.8 mg, 110 μmol), 5-(6-chloropyridin-3-yl)-2,4-dihydroxybenzaldehyde (5d) (27.5 mg, 110 μmol), and Na2S2O5 (65.7 mg, 346 μmol) were suspended in DMSO (0.4 mL). The reaction mixture was stirred in an oil bath at 120 °C for 2 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water (20 mL), and stirred for 10 min. After the precipitate was filtered, the desired compound 7d (45.4 mg, 87%) was obtained as a beige solid.

[0487] TLC R f 0.13 (20:1 CH2Cl2 / MeOH) 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.65 (s, 1H), 8.31 (dd, J = 4.8, 1.5 Hz, 1H), 8.17 (dd, J = 8.0, 1.5 Hz, 1H), 8.08 (dd, J = 2.5, 0.7 Hz, 1H), 7.74 (dd, J = 8.3, 2.5 Hz, 1H), 7.48 (dd, J = 8.3, 0.7 Hz, 1H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.04 (s, 1H), 6.98 (dd, J = 8.5, 2.5 Hz, 1H), 6.59 (s, 1H), 4.42-4.27 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 160.4, 158.0, 152.0, 148.6 (2C), 147.9, 144.3, 144.1, 143.9, 139.2, 132.7, 132.1, 130.3, 128.6, 125.6, 123.4 (2C), 121.3, 119.3, 117.9, 117.3, 114.3, 105.5, 103.7, 64.3 (2C). HRMS (ESI) m / z calcd for C 25 H 16 ClN4O4 - ([M - H] - ) 471.0866, found 471.0871. HPLC (method A, l = 254 nm): 94.6%.

[0488]

[0489] Example 54: Synthesis of 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-(6-fluoropyridin-3-yl)benzene-1,3-diol (7e)

[0490]

[0491] N in a 4 mL vial 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pyridine-2,3-diamine (4) (17.1 mg, 70.0 μmol), 5-(6-fluoropyridin-3-yl)-2,4-dihydroxybenzaldehyde (5e) (16.8 mg, 72.0 μmol), and Na2S2O5 (41.5 mg, 218 μmol) were suspended in DMSO (0.4 mL). The reaction mixture was stirred in an oil bath at 120 °C for 1 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water (10 mL), and stirred for 10 min. After the precipitate was filtered, compound 7e (23.8 mg, 72%) was obtained as a beige solid.

[0492] TLC R f 0.25 (1:1 X 2 hexane / EtOAc) 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.59 (s, 1H), 8.30 (dd, J = 4.8, 1.5 Hz, 1H), 8.17 (dd, J = 8.0, 1.5 Hz, 1H), 7.98-7.77 (m, 3H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.20 (d, J = 2.5 Hz, 1H), 7.15 (ddd, J = 7.8, 3.0, 1.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.01 (s, 2H), 6.98 (dd, J = 8.5, 2.5 Hz, 1H), 6.59 (s, 1H), 4.51-3.94 (m, 5H). 13C NMR (100 MHz, DMSO-d6) δ 161.5 (d, J = 235.7 Hz), 160.3, 157.9, 152.1, 148.6, 146.0 (d, J = 15.1 Hz), 144.3, 144.1, 143.9, 141.7 (d, J = 7.8 Hz), 132.07, 131.72 (d, J = 4.5 Hz), 130.2, 128.6, 125.6, 121.4, 119.3, 117.9, 117.4, 114.6, 108.7 (d, J = 37.6 Hz), 105.3, 103.7, 64.3, 64.3. HRMS (ESI) m / z calcd for C 25 H 18 FN4O4 + ([M + H] + ) 457.1310, found 457.1307.

[0493]

[0494] Example 55: Synthesis of 4-(6-((cyclopropylmethyl)amino)pyridin-3-yl)-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (7k)

[0495]

[0496] 4-(6-Chloropyridin-3-yl)-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (7d) (83.6 mg, 177 μmol) was dissolved in cyclopropylmethylamine (0.5 mL) in a 1.0 mL microwave vial. The reaction mixture was irradiated by microwave at 200 °C, 200 W, and 4 bar for 13 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The residue was purified by column chromatography (2:1 → 1:2 hexanes / EtOAc) to give compound 7k (38.6 mg, 43%) as a pale yellow solid.

[0497] TLC R f0.43 (20:1 X 3 CH2Cl2 / MeOH) 1 H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.25 (s, 1H), 8.28 (dd, J = 4.8, 1.5 Hz, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.24-7.17 (m, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.96 (dd, J = 8.5, 2.5 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.56 (t, J = 5.7 Hz, 1H), 6.53 (s, 1H), 6.42 (dd, J = 8.7, 0.8 Hz, 1H), 4.42 (dd, J = 5.8, 2.4 Hz, 2H), 4.38 (dd, J = 5.8, 2.4 Hz, 2H), 3.17-3.09 (m, 2H), 1.06 (dddd, J = 13.1, 6.7, 3.2, 1.9 Hz, 1H), 0.49-0.38 (m, 2H), 0.25-0.17 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 159.3, 157.9, 157.4, 152.4, 148.6, 146.7, 144.5, 144.1, 143.9, 136.6, 131.9, 128.9, 128.8, 125.3, 121.5, 120.9, 119.3, 118.1, 117.5, 117.2, 107.0, 104.4, 103.6, 64.3, 45.2, 11.0, 3.4. HRMS (ESI) m / z calcd for C 29 H 26 N5O4 + ([M + H] + ) 508.1979, found 508.1976. HPLC (method A, l = 254 nm): 95.1%

[0498] The structures of the compounds of Examples 1 to 55 are as shown in Table 1 below.

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505] <Experimental Example>

[0506] Experimental Example 1. Evaluation of BTK inhibitory activity

[0507] Evaluation of the BTK inhibitory activity of compounds according to the present invention was performed at Reaction Biology Corporation (www.reactionbiology.com, Malvern PA) using the 'HotSpot' analysis platform. BTK kinase inhibitory activity analysis was performed by analyzing the % enzyme activity at a single concentration and the IC at 10 concentrations. 50 was measured and analyzed. BTK kinase activity measurement was performed in the following series of steps. First, the substrate was prepared in a reaction buffer containing 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO. BTK kinase enzyme was introduced into this substrate solution and gently mixed. Then, the compound dissolved in 100% DMSO was accurately added to the reaction mixture using Acoustic technology (Echo550) capable of injecting nanoliter volumes. The reaction mixture was then incubated at room temperature for 20 minutes. To initiate the reaction 33P-ATP was added to the mixture. The reaction was allowed to proceed at room temperature for 2 h, and finally, kinase activity was detected using the P81 filter binding method, which quantifies substrate phosphorylation.

[0508] 1) % enzyme activity: BTK inhibitory activity was evaluated in single dose duplicate mode at a single concentration (10 μM), and the reaction was performed at 1 μM ATP.

[0509] 2) IC 50 : 10 dose IC in 3-fold serial dilutions starting at 100 μM, 30 μM, or 10 μM 50 The test was performed in mode 1. The reaction was performed at 10 μM ATP.

[0510] The results are shown in Table 2 below. In Table 2, ++++ indicates IC 50 < 100 nM, +++ is 100 nM ≤ IC 50 < 1 μM, and ++ is IC 50 ≥ 1 μM.

[0511] Example Compound #% Enzyme Activity IC 50BTKBTK Example 1 (6a) 95.81++ Example 2 (6b) 85.92++ Example 3 (6c) 62.44++ Example 4 (6d) 0.39++++ Example 5 (6e) 6.09+++ Example 6 (6f) 64.63++ Example 7 (6g) 23.38+++ Example 8 (6h) 84.54++ Example 9 (6i) 33.30++ Example 10 (6j) 85.02++ Example 11 (6k) 92.78++ Example 12 (6l) 107.23++ Example 13 (6m) 97.32++ Example 14 (6n) 110.03++ Example 15 (6o) 110.23++ Example 16(6p)90.45++Example 17(6q)37.41++Example 18(6r)103.70++Example 19(6s)99.94++Example 20(6t)104.87++Example 21(6u)86.18++Example 22(6v)85.83++Example 23(6w)81.30++Example 24(6x)55.07++Example 25(6y)75.01++Example 26(6z)87.89++Example 27(6aa)97.63++Example 28(6ab)96.81++Example 29(6ac)0.68++++Example 30(6ad)0.32++++Example 31(6ae)4.80+++Example 32(6af)0.27++++Example 33(6ag)0.65++++Example 34(6ah)10.10++Example 35(6ai)4.38++++Example 36(6aj)98.02++Example 37(6ak)105.84++Example 38(6al)103.71++Example 39(6am)95.76++Example 40(6ao)9.20++Example 41(6ap)2.62+++Example 42(6aq)2.12+++Example 43(6ar)67.70++Example 44(6as)4.70+++Example 45(6at)72.95++Example 46(6au)1079++Example 47(6ca)1.82+++Example 48(6cb)4.62+++Example 49(6cc)2.19++++Example 50(7a)7.96+++Example 51(7b)54.97++Example 52(7c)48.14++Example 53(7d)81.29++Example 54(7e)74.34++Example 55(7k)51.97++

[0512] According to Table 2 above, the imidazopyridine compounds according to the present invention were found to have excellent activity in inhibiting BTK.

[0513]

[0514] Experimental Example 2. Evaluation of the Biological Activity and Mechanism of Action of a Novel BTK Inhibitor

[0515] Test Example 2-1. Antibodies and Reagents

[0516] Fluo-3AM was purchased from Molecular Probes. AEBSF (Gold Biotechnology), Aprotinin, NaCl, NaHCO₃ (all Amresco), CaCl₂, DMSO, EGTA, FeCl₃, Glucose, KH₂PO₄, Na₂HPO₄, Na₄VO₄, Na₄P₂O7·10H2O, NaF, paraformaldehyde, prostaglandin E₁, sodium carboxymethyl cellulose, sodium citrate, Triton X-100, β-glycerophosphate (all Sigma-Aldrich), citric acid (Duksan), EDTA, KCl, Leupeptin, MgCl₂ (all USB), and HEPES (Thermo Scientific) were purchased from the respective manufacturers and used.

[0517] The antibodies used were as follows: anti-phospho-Btk(Tyr 551 ) antibody (Invitrogen), anti-Btk, anti-phospho-PLCγ₂(Tyr 753 ), anti-PLCγ₂, (all Santa Cruz Biotechnology), and anti-β-actin antibodies (Abfrontier) were purchased from the respective manufacturers and used.

[0518] Test Example 2-2. Human Platelet Isolation

[0519] Blood samples were collected from healthy, drug-naive volunteers using vacutainers anticoagulated with acid / citrate / dextrose (22.0 g sodium citrate, 24.5 g dextrose, 7.3 g citric acid / L). Platelet-rich plasma was centrifuged at 150 g for 15 min, followed by an additional centrifugation at 300 g for 10 min to concentrate platelets. The platelet pellet was suspended in a washing buffer containing Tyrode's HEPES buffer (10 mM HEPES, 129 mM NaCl, 0.8 mM KH₂PO₄, 8.9 mM NaCo₃, 2.8 mM KCl, 0.8 mM MgCl₂, 5.6 mM glucose), and 2 mM EDTA, 10% acid citrate dextrose solution, and 1 μM PGE₁ were added, followed by centrifugation again. Finally, 5 × 10 platelets were suspended in Tyrode's HEPES buffer. 8 Resuspended at a concentration of 100 cells / mL.

[0520] Test Example 2-3. Platelet Aggregation Analysis (Light Transmission Aggregometry)

[0521] Washed platelets suspended in Tyrode's HEPES buffer were pretreated with 1 mM CaCl₂ for 2 min, and then the agonist, Collagen-related peptide-XL (CRP-XL, Triple Helix Peptides), was added. Platelet aggregation was measured using a four-channel platelet aggregation analyzer (Chrono-Log) with continuous stirring at 1000 rpm at 37°C.

[0522] Candidate BTK inhibitors with potential as antiplatelet agents were selected by evaluating their aggregation inhibition ability in washed platelets treated with CRP-XL, which is capable of platelet activation through the Glycoprotein VI (GPVI) receptor of platelets, as shown in Tables 3 and 4 below.

[0523] Specifically, Table 3 shows the human washed platelet (5×10 8 (dog / mL) were pretreated with candidate BTK inhibitor drugs for 5 minutes and treated with CRP-XL as an agonist for 2 minutes. Afterwards, IC 50 When calculating the values, 16 candidate drugs with significant potential for use as antiplatelet agents were selected. Table 4 also shows the IC 50 Candidate BTK inhibitors with values ​​higher than 10 μM were selected, and all values ​​were performed as (n = 3). In Tables 3 and 4, ++++ indicates IC 50 < 100 nM, +++ is 100 nM ≤ IC 50 < 1 μM, and ++ is IC 50 ≥ 1 μM.

[0524] Example Compound #IC 50 BTKPlatelet Example 46d++++++Example 76g++++Example 176q++++Example 296ac+++++++Example 306ad+++++++Example 316ae++++++Example 326af+++++++Example 336ag+++++++Example 346ah++++Example 356ai++++++Example 416ap+++++Example 426aq+++++Example 446as+++++Example 476ca+++++Example 496cc+++++++

[0525] Example Compound #IC 50BTK Platelet Example 16a++++ Example 26b++++ Example 36c++++ Example 56e++++ Example 66f++++ Example 86h++++ Example 96i++++ Example 106j++++ Example 116k++++ Example 126l++++ Example 136m++++ Example 146n++++ Example 156o++++ Example 166p++++ Example 186r++++ Example 196s++++ Example 206t++++ Example 216u++++ Example 226v++++ Example 236w++++ Example 246x++++ Example 256y++++ Example 266z++++ Example 276aa++++Example 286ab++++Example 366aj++++Example 376ak++++Example 386al++++Example 396am++++Example 406ao++++Example 436ar++++Example 456at++++Example 466au++++Example 486cb+++++

[0526] According to Table 3, the washed platelet aggregation inhibition ability of the compounds according to the examples is IC 50 As a result of evaluation, the compound of Example 30 (6ad) was 1.74 × 10 -7 M showed the lowest value and the most potent BTK inhibitory activity. According to Table 4, IC 50 A group of BTK inhibitor candidates confirmed to have a value of 10 μM or higher can be identified.

[0527] Also, IC for CRP-XL of the compound of Example 30 (6ad), which confirmed strong BTK inhibitory activity in platelet aggregation ability test 50 (M) was measured and the results are shown in Figure 1. According to the platelet aggregation analysis graph in Figure 1, the compound of Example 30 (6ad) showed an excellent effect in inhibiting platelet aggregation in a concentration-dependent manner. This suggests that it is a candidate substance that can be utilized as an antiplatelet agent through inhibition of BTK function of platelets.

[0528]

[0529] Test Example 2-4. Western Blot Analysis

[0530] After platelet stimulation, the cells were lysed in cell lysis buffer (20 mM HEPES [pH 7.0], 150 mM NaCl, 1% Triton X-100, 10% glycerol, 1 mM EDTA, 2 mM EGTA, 20 mM β-glycerophosphate, 1 mM Na₃VO₄, 1 mg / mL leupeptin, 1 mg / mL aprotinin, 1 mM AEBSF). Cell debris was removed by centrifugation at 12,500 × g for 10 min at 4 °C, and the supernatant was used for Western blot and immunoprecipitation analysis. The degree of phosphorylation of the GPVI platelet activation signaling pathway inhibited by the compound of Example 30 (6ad) was analyzed using 30 μg of protein for Western blot analysis and 300 μg of protein for immunoprecipitation analysis, and the results are shown in Figures 2a to 2c.

[0531] According to Figures 2a to 2c, the phosphorylation level of the GPVI platelet activation signaling pathway due to the action of Ibrutinib, a positive control, together with the compound according to Example 30 (6ad) was confirmed by Western blot. When human platelets are activated by the GPVI signaling pathway, ITAM (immunoreceptor tyrosine-base activation motif) present together with the GPVI receptor is phosphorylated by SFK proteins such as LYN or FYN. Then, PLCγ2 is gathered with other proteins in LAT by the action of SYK protein, forming a signalsosome, and platelet activation becomes possible through secondary messengers and calcium ion regulation downstream. BTK is Tyr 551 and Tyr 223 It is activated through stepwise phosphorylation of Tyr 551 Phosphorylation of Tyr facilitates access of ATP and substrates to the active site. 223Upon phosphorylation, full activation is induced through the interaction between the SH₃-SH₂ domains. The compound according to Example 30 (6ad) binds to Tyr of BTK 223 Selectively phosphorylate Tyr of PLCγ2, downstream of BTK 753 The possibility of preventing platelet hyperactivation was confirmed through the degree of phosphorylation.

[0532] The compound according to Example 30 (6ad) was found to have higher selectivity for BTK than LYN, another off-target, in terms of BTK inhibition.

[0533] Therefore, the compound of Example 30 (6ad) inhibits Tyr of BTK in the GPVI signaling pathway in platelets. 223 By selectively inhibiting phosphorylation, it was confirmed to block phosphorylation of the downstream signal PLCγ2 and prevent platelet hyperactivation. Alternatively, the compound of Example 30 (6ad) is evaluated as an antiplatelet agent candidate with high selectivity for BTK and limited off-target effects, such as LYN, and thus has a low potential for side effects.

[0534]

[0535] Test Example 2-5. Analysis of intracytoplasmic calcium concentration

[0536] Washed platelets suspended in PBS were pretreated with 1 μM Fluo-3AM for 10 min at 37°C, protected from light. This was followed by an additional 2 min pretreatment with 1 mM CaCl₂. Fluorescently stained platelets were stimulated with CRP-XL (Triple Helix Peptides), and the fluorescence (emission: 525 nm, excitation: 488 nm) of Fluo-3AM was measured using a spectrofluorometer (JASCO) while shaking at 800 rpm at 37°C.

[0537] Calcium ion signaling, one of the platelet activation mechanisms, was evaluated. Acalabrutinib, a clinically used BTK inhibitor, was used as a positive control. Fluo-3 AM is a cell-permeable fluorescent dye that emits fluorescence when bound to calcium ions in living cells, allowing the concentration of intracellular calcium ions to be determined. The results are shown in Fig. 3. Specifically, washed human platelets were pretreated with Fluo-3 AM for 10 minutes and RSP1141 / DMSO for 10 minutes under stirring at 800 rpm, and then pretreated with CRP-XL for an additional 2 minutes. The fluorescence was measured using a spectrofluorometer. A significant difference was observed compared to the CRP-XL alone treatment group.

[0538] According to Fig. 3, the fluorescence intensity of Fluo-3 AM of washed platelets pretreated with Acalabrutinib, a positive control, decreased in a concentration-dependent manner under conditions treated with CRP-XL, an agent that promotes platelet activation. In addition, the compound according to Example 30 (6ad) showed a concentration-dependent decrease in the fluorescence intensity of Fluo-3 AM, similar to the positive control Acalabrutinib, and almost completely reduced the calcium ion concentration inside the platelets even at a lower concentration of 1 μM compared to Acalabrutinib, suggesting that it can surpass the efficacy of Acalabrutinib, a positive control. In addition, it was confirmed that the compound according to Example 30 (6ad) can have an advantage as a reversible inhibitor while showing an effect similar to Acalabrutinib, an irreversible positive control as an antiplatelet agent.

[0539] Therefore, the compound of Example 30 (6ad) effectively and concentration-dependently reduces intracellular calcium concentration when treated with CRP-XL, a platelet activation stimulator, and in particular, it showed an effect equivalent to or greater than that of the positive control, Acalabrutinib, even at a low concentration of 1 μM. This suggests that the compound is a promising candidate as a reversible BTK inhibitor that exerts antiplatelet effects while having a low potential for side effects.

[0540]

[0541] The specification omits detailed descriptions of matters that would be readily apparent and inferred by those skilled in the art. Furthermore, various modifications, other than the specific examples described herein, are possible without altering the technical spirit or essential configuration of the invention. Therefore, the present invention may be practiced in ways other than those specifically described and exemplified herein, as will be readily apparent to those skilled in the art.

Claims

A compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, Is or And, Is , , C3-C8 heteroaryl containing an unsubstituted or substituted nitrogen or oxygen atom or unsubstituted or substituted C2-C5 alkenyl-(C3-C8 heteroaryl containing a nitrogen or oxygen atom), wherein the substitution is at least one or more of halogen, C1-C3 alkyl, -OH, C1-C3 alkylene-OH, -NH2, -NO2 or -CN; R1 is -NR a R b , unsubstituted or substituted -O-phenyl, unsubstituted or substituted C3-C8heterocycloalkyl containing nitrogen or oxygen atoms, or unsubstituted or substituted -(C1-C3alkylene)-(C3-C8heterocycloalkyl containing nitrogen or oxygen atoms), wherein substitution is substitution with at least one or more halogen, C1-C3alkyl, -OH, -NH2, -NO2 or -CN; R2 is -C1-C8alkoxy, -C1-C5haloalkoxy, unsubstituted or substituted C3-C8heterocycloalkyl, unsubstituted or substituted C3-C8heteroaryl, -NR a R b , -OH, -NO2 or -CN; R3 is halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C1-C5 haloalkoxy, unsubstituted or substituted C3-C8 heterocycloalkyl, unsubstituted or substituted C3-C8 heteroaryl, -NR a R b , -OH, -NO2 or -CN; R4 is halogen, -C1-C8 alkyl, -C1-C8 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C8 heterocycloalkyl, unsubstituted or substituted C3-C8 heteroaryl, -OH, -NO2 or -CN, R a and R b may be the same or different, and each independently represents hydrogen or C1-C8 alkyl; m is 0 or 1; n and p are each independently 1 or 2. In the first paragraph, Is , , , , a C3-C8 heteroaryl containing an unsubstituted or substituted nitrogen or oxygen atom or an unsubstituted or substituted C2-C5 alkenyl-(C3-C8 heteroaryl containing a nitrogen or oxygen atom), an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In the first paragraph, Is , , , , , , , , , , unsubstituted or substituted pyridine, unsubstituted or substituted furan, or unsubstituted or substituted -C2-C5 alkenyl-furan, wherein substitution is substitution with at least one halogen, C1-C3 alkyl, -OH, C1-C3 alkylene-OH, -NH2, -NO2 or -CN, a compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof. In the first paragraph, A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is -NH2, -NH-CH3, -NH-CH2CH3, -N-(CH3)2, -N-(CH2CH3)2, unsubstituted or substituted -O-phenyl, unsubstituted or substituted pyrrolidine, unsubstituted or substituted piperidine, unsubstituted or substituted piperazine, unsubstituted or substituted tetrahydrofuran, unsubstituted or substituted morpholine, unsubstituted or substituted C1-C3 alkylene-pyrrolidine, unsubstituted or substituted C1-C3 alkylene-piperidine, unsubstituted or substituted C1-C3 alkylene-piperazine, unsubstituted or substituted C1-C3 alkylene-tetrahydrofuran, unsubstituted or substituted C1-C3 alkylene-morpholine. In the first paragraph, R2 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentoxy, unsubstituted or substituted C3-C5 heterocycloalkyl, unsubstituted or substituted C3-C5 heteroaryl, -NH2, -NH-(C1-C5 alkyl), -N-(C1-C5 alkyl)2, -OH, -NO2 or -CN; A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is chloro (Cl), fluorine (F), methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentoxy, unsubstituted or substituted C3-C5 heterocycloalkyl, unsubstituted or substituted C3-C5 heteroaryl, -NH2, -NH-(C1-C5 alkyl), -N-(C1-C5 alkyl)2, -OH, -NO2, or -CN. In the first paragraph, R4 is halogen, -C1-C6 alkyl, -C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C5 heterocycloalkyl, unsubstituted or substituted C3-C5 heteroaryl, -OH, -NO2 or -CN, The above substitution is at least one or more of halogen, C1-C3 alkyl, -OH, -O-phenyl, -O-(C3-C8 heteroaryl), -O-(C1-C3 alkylene)-phenyl, -O-(C1-C3 alkylene)-(C3-C8 heteroaryl), -NHC(=O)-phenyl, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)-(C3-C8 heteroaryl), -NH-(C1-C3 alkyl), -NH-(C3-C8 cycloalkyl), -NH-(C3-C8 heteroaryl), NH-phenyl, -NH-(C1-C3 alkylene)-phenyl, -NH-(C1-C3 alkylene)-(C3-C8 cycloalkyl), -C(=O)O-(C1-C3 alkyl), -C(=O)NH-phenyl, A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with -C(=O)NH-(C1-C3 alkylene)-phenyl. In the first paragraph, R4 is chloro (Cl), bromine (Br), iodo (I), methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, unsubstituted or substituted phenyl, unsubstituted or substituted tetrahydrofuran, unsubstituted or substituted tetrahydrothiophene, unsubstituted or substituted pyrrolidine, unsubstituted or substituted piperidine, unsubstituted or substituted piperazine, unsubstituted or substituted furan, unsubstituted or substituted thiophene, unsubstituted or substituted pyrrole, unsubstituted or substituted pyridine, unsubstituted or substituted pyrimidine, -OH, -NO2 or -CN, wherein said substitution is at least one or more of halogen, C1-C3 alkyl, -OH, -O-phenyl, -O-(C3-C8 heteroaryl), -O-(C1-C3 alkylene)-phenyl, -O-(C1-C3 alkylene)-(C3-C8 heteroaryl), -NHC(=O)-phenyl, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)-(C3-C8 heteroaryl), -NH-(C1-C3 alkyl), -NH-(C3-C8 cycloalkyl), -NH-(C3-C8 heteroaryl), NH-phenyl, -NH-(C1-C3 alkylene)-phenyl, -NH-(C1-C3 alkylene)-(C3-C8 cycloalkyl), -C(=O)O-(C1-C3 alkyl), -C(=O)NH-phenyl, A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with -C(=O)NH-(C1-C3 alkylene)-phenyl. In the first paragraph, Is , , , , , , , , , , , , , , , , , , , , , , , , , , , , and is one selected from the group consisting of, Here R a and R b may be the same or different, and each independently represents hydrogen or C1-C6 alkyl, R5 is C1-C6 alkyl, R6 to R 10 may be the same or different, and each independently represents halogen, C1-C6 alkyl or C1-C6 alkoxy, R 11 is phenyl or -(C1-C3alkylene)-phenyl, R 12 is phenyl or -C3-C8heteroaryl, R 13 is halogen or -C1-C3 alkyl, R 14 A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is C3-C8 cycloalkyl or -(C1-C3 alkylene)-(C3-C8 cycloalkyl). In the first paragraph, the compound represented by the chemical formula 1 is any one selected from the group consisting of the compounds described below, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(4-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine; 7-[2-(3-phenoxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-1-ium; 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-phenoxy-phenyl)-3H-imidazo[4,5-b]pyridine; 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol; 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,2,3-triol; 5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,2,4-triol; {4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-phenyl}-dimethyl-amine; 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-4-nitro-phenol; {5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-furan-2-yl}- methanol; 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(3-nitro-4-piperidin-1-yl-phenyl)-3H-imidazo[4,5-b] pyridine; 4-Chloro-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-phenol; 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(3-morpholin-4-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine; 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(4-morpholin-4-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine; 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-5-hydroxymethyl-2-methyl-pyridin-3-ol; 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-furan-2-yl-vinyl)-3H-imidazo[4,5-b]pyridine; 2,4-Dichloro-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene- 1,3-diol; 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-methoxy-2-nitrophenyl)-3H-imidazo[4,5-b]pyridine; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxybenzonitrile; 3-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine; 5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine; 6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-3-ol; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-nitrophenol; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxyphenol; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-ethoxyphenol; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-propoxyphenol; 5-Butoxy-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol; 2-(2,4-dibutoxyphenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridine; 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3 -diol; 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-ethylbenzene-1,3 -diol; 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-isopropylbenzene-1,3 -diol; 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methoxybenzene-1,3 -diol; 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-iodobenzene-1,3 -diol; 4-Bromo-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1, 3-diol; 4-chloro-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-3-nitrophenol; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-methoxyaniline; 3-amino-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-hydroxybenzonitrile; 5-amino-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol; (2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(methylamino)phenol; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(ethylamino)phenol; 5-(Diethylamino)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol); 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(propylamino)phenol; 2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(dipropylamino)phenol; 5-(Butylamino)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol; 4-(3-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol; 4-(3-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol; 5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-[1,1'-biphenyl]-2,3',4-triol; 3'-(Benzyloxy)-5-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)- [1,1'-biphenyl]-2,4-diol; N-(5'-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-2',4'-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide; 4-(6-chloropyridin-3-yl)-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-(6-fluoropyridin-3-yl)benzene-1,3-diol; and 4-(6-((cyclopropylmethyl)amino)pyridin-3-yl)-6-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3H-imidazo[4, 5-b]pyridin-2-yl)benzene-1,3-diol. A pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, comprising a compound according to any one of claims 1 to 9, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, wherein the Bruton's tyrosine kinase (BTK)-mediated disease is an autoimmune disease, cancer, or vascular disease. In claim 10, the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodine thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, autonomic dysfunction, asthma, chronic spontaneous urticaria, A pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase-mediated disease, wherein the disease is any one selected from the group consisting of pemphigus, systemic lupus erythematosus, hidradenitis, dermatosis, immunoglobulin G4-related disease, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia. A pharmaceutical composition for the prevention or treatment of a Bruton's tyrosine kinase-mediated disease, wherein the cancer is a B-cell malignancy in claim 10. A pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase-mediated disease, wherein the vascular-related disease is any one selected from the group consisting of acute myocardial infarction, stroke, coronary artery disease, peripheral vascular disease, deep vein thrombosis, pulmonary embolism, and thromboembolism. A pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase-mediated disease, wherein the pharmaceutical composition exhibits inhibitory activity against Bruton's tyrosine kinase (BTK) in claim 10. A method for preventing or treating a Bruton's tyrosine kinase-mediated disease, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 9, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A method for preventing or treating a Bruton's tyrosine kinase (BTK)-mediated disease, wherein the above-mentioned Bruton's tyrosine kinase (BTK)-mediated disease is an autoimmune disease, cancer, or vascular disease. In claim 15, the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodine thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, autonomic dysfunction, asthma, chronic spontaneous urticaria, Any one selected from the group consisting of pemphigus, systemic lupus erythematosus, hidradenitis, dermatosis, immunoglobulin G4-related disease, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia, The above cancer is a B-cell malignancy, A method for preventing or treating a Bruton's tyrosine kinase-mediated disease, wherein the vascular-related disease is any one selected from the group consisting of acute myocardial infarction, stroke, coronary artery disease, peripheral vascular disease, deep vein thrombosis, pulmonary embolism, and thromboembolism. Use of a compound according to any one of claims 1 to 9, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of Bruton's tyrosine kinase-mediated diseases, The above Bruton's tyrosine kinase (BTK) mediated disease is an autoimmune disease, cancer or vascular disease. In claim 16, the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodine thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, autonomic dysfunction, asthma, chronic spontaneous urticaria, Any one selected from the group consisting of pemphigus, systemic lupus erythematosus, hidradenitis, dermatosis, immunoglobulin G4-related disease, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia, The above cancer is a B-cell malignancy, The above vascular-related disease is any one selected from the group consisting of acute myocardial infarction, stroke, coronary artery disease, peripheral vascular disease, deep vein thrombosis, pulmonary embolism, and thromboembolism. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of Bruton's tyrosine kinase-mediated diseases, A pharmaceutical composition, wherein the above Bruton's tyrosine kinase (BTK) mediated disease is an autoimmune disease, cancer or vascular disease. In claim 19, the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodine thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, autonomic dysfunction, asthma, chronic spontaneous urticaria, Any one selected from the group consisting of pemphigus, systemic lupus erythematosus, hidradenitis, dermatosis, immunoglobulin G4-related disease, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia, The above cancer is a B-cell malignancy, A pharmaceutical composition, wherein the vascular-related disease is any one selected from the group consisting of acute myocardial infarction, stroke, coronary artery disease, peripheral vascular disease, deep vein thrombosis, pulmonary embolism, and thromboembolism.

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