Novel imidazopyridine derivatives and uses thereof

Abstract

The present disclosure provides a novel imidazopyridine compound, an optical isomer thereof, or pharmaceutically acceptable salts 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 preventing or treating BTK-mediated diseases such as autoimmune diseases or cancer.

Description

Novel imidazopyridine derivatives and uses thereof

[0001] The present invention relates to a novel imidazopyridine derivative 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, a more important goal is to develop noncovalent inhibitors that can achieve sufficiently high exposure, low clearance, and sustained 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] In the present invention, the term “C1-C 10“Alkyl” means C1-C, such as 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, nonyl, decyl, etc. 10 refers to a straight or branched chain saturated hydrocarbon. Preferred alkyl groups contain about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the chain. Side chain means one or more lower alkyl groups, such as methyl, ethyl or propyl, attached to the linear alkyl chain. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents, which may be the same or different.

[0016] In the present invention, the term “C1-C5 alkoxy” refers to straight-chain and branched-chain alkoxy having 1 to 5 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.

[0017] 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.

[0018] 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 polycyclic heteroaryl such as imidazo[2,1-b]thiazole, but is not limited thereto. In addition, the heteroaryl may be substituted or unsubstituted, and when substituted, C1-C3 alkyl, -NH2, or -NHC(=O)O-(C1-C5 alkyl) may be substituted. In addition, the polycyclic heteroaryl group, if the polycyclic heteroaryl group is bonded to the parent structure through an aromatic ring, a non-aromatic ring (e.g., cycloalkyl,may include cycloalkenyl, heterocycloalkyl, heterocycloalkenyl).

[0019] 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, 3-Oxa-8-azabicyclo[3.2.1]octan-yl, hexahydro-2H-furo[3,2-b]pyrrole, azetidin-3-one, etc., but are not limited thereto. In addition, the heterocycloalkyl may be substituted or unsubstituted, and when substituted, C1-C3 alkyl, -NH2, or -NHC(=O)O-(C1-C5 alkyl) may be substituted. When nitrogen is present in the 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. In addition, when sulfur is present in the 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.Additionally, one ring of the polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl) if the polycyclic heterocycloalkyl group is attached to the parent structure via a non-aromatic carbon or nitrogen atom.

[0020] 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.

[0021] 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.

[0022] Novel imidazopyridine compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof

[0023] 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:

[0024] [Chemical Formula 1]

[0025]

[0026] In the above chemical formula 1,

[0027] R1 is -OH, -C1-C 10 Alkyl, -C1-C5 alkoxy, -C1-C5 haloalkoxy, -NHC(=O)-(C1-C5 alkyl), -NHC(=O)O-(C1-C5 alkyl), -C(=O)NH2, -NR a Rb , unsubstituted or substituted -O-phenyl, unsubstituted or substituted C3-C8heterocycloalkyl containing one or more nitrogen atoms, or unsubstituted or substituted -(C1-C3alkyl)-(C3-C8heterocycloalkyl containing one or more nitrogen atoms), wherein substitution is substitution with at least one C1-C3alkyl, -NH2, or -NHC(=O)O-(C1-C5alkyl);

[0028] R a and R b is hydrogen or C1-C5 alkyl;

[0029] R2 is -OH, -C1-C5alkoxy, or halogen;

[0030] n is an integer from 0 to 3;

[0031] Is or C3-C8 heteroaryl containing unsubstituted or substituted nitrogen or oxygen atoms, wherein the substitution is at least one C1-C3 alkyl;

[0032] R3 is halogen, -OH, -C1-C5 alkyl, -C1-C5 alkoxy, -C1-C5 haloalkoxy, -NO2 or -NH2;

[0033] R4 is hydrogen, -OH, or -C1-C5alkoxy;

[0034] R5 is halogen, -C1-C5 alkyl, or -C1-C5 alkoxy;

[0035] m is an integer from 0 to 3.

[0036]

[0037] Specifically, C1-C mentioned in R1 to R5 above 10 Alkyl, C1-C5 alkoxy, C1-C5 haloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heteroaryl can be selected from the specific substituents mentioned below:

[0038] C1-C above 10Alkyl may be straight-chain or branched, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl.

[0039] The above C1-C5 alkoxy may be straight-chain or branched methoxy, ethoxy, propoxy, butoxy, or pentyloxy.

[0040] 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.

[0041] The above C3-C8 heterocycloalkyl may contain one or more nitrogen atoms, and may be azetidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, or hexahydro-2H-furo[3,2-b]pyrrole.

[0042] The above C3-C8 heteroaryl may contain a nitrogen or oxygen atom, and may be furanyl, thiazolyl, oxazolyl, pyranyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridonyl, pyrimidinyl, benzopyrrolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisooxazolyl, benzoxazolyl, isoindolyl, indolyl, indazolyl, benzothiadiazolyl, quinazolinyl, quinoxalinyl, or benzodioxozolyl.

[0043]

[0044] Specifically, R1 is -OH, -C1-C5 alkyl, -C1-C3 alkoxy, -C1-C5 haloalkoxy, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)O-(C1-C5 alkyl), -C(=O)NH2, -NR a R b, unsubstituted or substituted -O-phenyl, unsubstituted or substituted C3-C6 heterocycloalkyl containing one or more nitrogen atoms, or unsubstituted or substituted -(C1-C3 alkyl)-(C3-C6 heterocycloalkyl containing one or more nitrogen atoms), wherein substitution is substitution with at least one C1-C3 alkyl, -NH2, or -NHC(=O)O-(C1-C5 alkyl); R a and R b may be hydrogen or C1-C3 alkyl.

[0045] More specifically, the R1 is -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)O-(C1-C5 alkyl), -C(=O)NH2, -NH2, -NH-CH3, -N-(CH3)2, unsubstituted or substituted -O-phenyl, unsubstituted or substituted pyrrolidine, unsubstituted or substituted piperidine, unsubstituted or substituted piperazine, unsubstituted or substituted morpholine, unsubstituted or substituted thiomorpholine, unsubstituted or substituted -(C1-C3 alkyl)-pyrrolidine, unsubstituted or substituted -(C1-C3 alkyl)-piperidine, -(C1-C3 alkyl)-piperazine, unsubstituted or substituted -(C1-C3 alkyl)-morpholine or unsubstituted or substituted -(C1-C3 alkyl)-thiomorpholine, wherein the substitution may be substitution with at least one or more C1-C3 alkyl, -NH2, or -NHC(=O)O-(C1-C5 alkyl).

[0046] More specifically, the R1 is -OH, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -NHC(=O)-CH3, -NHC(=O)-CH2CH3, -NHC(=O)O-(C(CH3)3), -C(=O)NH2, -NH2, -N-(CH3)2, unsubstituted or substituted , unsubstituted or substituted , unsubstituted or substituted or unsubstituted or substituted , wherein the substitution may be with at least one C1-C3 alkyl, -NH2, or -NHC(=O)O-(C1-C5 alkyl).

[0047] More specifically, the R1 is -OH, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, -NHC(=O)-CH3, -NHC(=O)-CH2CH3, -NHC(=O)O-(C(CH3)3), -C(=O)NH2, -NH2, -N-(CH3)2, , , , or It could be.

[0048]

[0049] The compound represented by the above chemical formula 1 may be a compound represented by the following chemical formulas 1-1 to 1-4:

[0050] [Chemical Formula 1-1]

[0051]

[0052] [Chemical Formula 1-2]

[0053]

[0054] [Chemical Formula 1-3]

[0055]

[0056] [Chemical Formula 1-4]

[0057] .

[0058] In the above chemical formulas 1-1 to 1-4, R1, R2 and is as described above in the chemical formula 1.

[0059]

[0060] Specifically Is , unsubstituted or substituted furan or unsubstituted or substituted pyridine, wherein the substitution is at least one C1-C3 alkyl;

[0061] R3 is chloro (Cl), fluorine (F), -OH, -C1-C3 alkyl, -C1-C3 alkoxy, or -NO2;

[0062] R4 is hydrogen (H), -OH, or -C1-C3alkoxy;

[0063] R5 is chloro (Cl), fluorine (F), -C1-C3 alkyl, or -C1-C3 alkoxy;

[0064] m can be an integer from 0 to 2.

[0065] More specifically Is , , unsubstituted or substituted furan or unsubstituted or substituted pyridine, wherein the substitution may be at least one C1-C3 alkyl.

[0066] More specifically Is , , , , unsubstituted or substituted furan or unsubstituted or substituted pyridine, wherein the substitution may be at least one C1-C3 alkyl.

[0067] According to a specific example of the present invention, the above Is , , , , unsubstituted furan, unsubstituted pyridine, or C1-C3 alkyl substituted pyridine.

[0068]

[0069] The compound represented by the above chemical formula 1 may be a compound represented by the following chemical formula 2 or 3:

[0070] [Chemical Formula 2]

[0071]

[0072] [Chemical Formula 3]

[0073] .

[0074] In the above chemical formula 2 or 3, R1 to R5, n and m are as described above in the above chemical formula 1.

[0075] may be unsubstituted or substituted, and may be furan or pyridine. Here, substitution is substitution with C1-C3 alkyl.

[0076]

[0077] The compound represented by the above chemical formula 2 may be a compound represented by the following chemical formulas 2-1 to 2-3:

[0078] [Chemical Formula 2-1]

[0079]

[0080] [Chemical Formula 2-2]

[0081]

[0082] [Chemical Formula 2-3]

[0083] .

[0084] In the above chemical formulas 2-1 to 2-3, R1 to R5, n and m are as described above in the above chemical formula 1.

[0085]

[0086] 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:

[0087] 4-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol (6a);

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

[0089] 2-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,4-diol (6c);

[0090] 2-(2,5-dimethoxyphenyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine(6d);

[0091] 2-(4-fluorophenyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine(6e);

[0092] 2-(Furan-2-yl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine(6f);

[0093] 3-(4-methoxyphenyl)-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine (6g);

[0094] 3-(4-methoxyphenyl)-2-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridine(6h);

[0095] 3-(4-methoxyphenyl)-2-(6-methylpyridin-2-yl)-3H-imidazo[4,5-b]pyridine(6i);

[0096] 4-chloro-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6j);

[0097] 2,4-Dichloro-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6k);

[0098] 3-(4-methoxyphenyl)-2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridine(6l);

[0099] 4-Ethyl-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6m);

[0100] 4-chloro-6-(3-(4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6n);

[0101] 4-chloro-6-(3-(4-(morpholinomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6o);

[0102] 4-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6aa);

[0103] 4-chloro-6-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6ab);

[0104] 4-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol(6ac);

[0105] 4-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6ba);

[0106] 4-chloro-6-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6bb);

[0107] 4-Methyl-6-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6bc);

[0108] 4-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6da);

[0109] 4-chloro-6-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6db);

[0110] 4-Methyl-6-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6dc);

[0111] 4-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6ea);

[0112] 4-chloro-6-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6eb);

[0113] 4-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol(6ec);

[0114] 4-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6fa);

[0115] 4-chloro-6-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6fb);

[0116] 4-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol(6fc);

[0117] 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6ga);

[0118] 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol(6gb);

[0119] 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6 gc);

[0120] N-(4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide(6ha);

[0121] N-(4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide(6hb);

[0122] N-(4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide(6hc);

[0123] 4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide (6ia);

[0124] 4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide (6ib);

[0125] 4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide(6ic);

[0126] tert-Butyl (4-(4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate (6ja);

[0127] tert-Butyl (4-(4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate (6jb);

[0128] tert-Butyl (4-(4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate (6jc);

[0129] 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6ka);

[0130] 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol (6 kb);

[0131] 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol(6kc);

[0132] 4-[3-(4-Dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol(6la);

[0133] 4-Chloro-6-[3-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6 lb);

[0134] 4-[3-(4-Dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol(6lc);

[0135] 4-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6ma);

[0136] 4-chloro-6-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6mb);

[0137] 4-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol(6mc);

[0138] 4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6na);

[0139] 4-chloro-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol(6nb);

[0140] 4-Methyl-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol hydrochloride (6nc);

[0141] {4-[2-(2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6oa);

[0142] {4-[2-(5-chloro-2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6ob);

[0143] {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester(6oc);

[0144] {3-[2-(4-Hydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6ra);

[0145] {3-[2-(5-chloro-2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6rb);

[0146] {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6rc);

[0147] 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol(6qa);

[0148] 4-[3-(4-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol trifluoroacetic acid salt (6pb);

[0149] 4-[3-(4-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol(6qb);

[0150] 4-[3-(4-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol trifluoroacetic acid salt (6pc);

[0151] 4-[3-(4-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol (6qc);

[0152] 4-[3-(3-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol trifluoroacetic acid salt (6sa);

[0153] 4-[3-(3-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol(6ta);

[0154] 4-[3-(3-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol(6tb); and

[0155] 4-[3-(3-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol(6tc).

[0156] 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.

[0157]

[0158] pharmaceutical composition

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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 chemical formula 1 as 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 or cancer.

[0164] 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 an autoimmune disease or cancer.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] The compound of the present invention exhibits inhibitory activity against Bruton's tyrosine kinase (BTK) enzyme, and thus can be used to treat BTK-mediated diseases such as autoimmune diseases or cancer.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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 or cancer.

[0189] 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 or cancer.

[0190] 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 or cancer.

[0191] 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 or cancer.

[0192] The novel compound according to the present invention can be usefully utilized as a pharmaceutical composition for preventing or treating BTK-mediated diseases such as autoimmune diseases or cancer by effectively inhibiting the enzymatic activity of Bruton's tyrosine kinase (BTK).

[0193] 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 different forms, 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.

[0194] The reagents and solvents mentioned below were purchased from Korea Fisher Scientific Co., Ltd., Sejin CI Co., Ltd., etc., unless otherwise specified.

[0195] 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.

[0196] 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.

[0197] Flash chromatography was performed on E. Merck 230-400 mesh silica gel 60.

[0198] 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.

[0199] NMR spectra were recorded using an Agilent (Santa Clara, CA, USA) Unity 400 instrument or a Bruker (Switchen, Fallanden) AvANCE NEO Nanobay 400 MHz NMR 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).

[0200] High-resolution mass spectra (HRMS) were obtained using electrospray ionization (ESI, TOF), electron ionization (EI, magnetic sector), chemical ionization (CI, magnetic sector), or fast atom bombardment (FAB, magnetic sector) on an Agilent 6230 TOF LC / MS (Agilent Technologies, Santa Clara, CA, USA) installed at the Ewha Womans University Drug Discovery Research Center.

[0201] <Example>

[0202] Examples 1 to 13 below were synthesized based on the following reaction scheme 1.

[0203] [Reaction Formula 1]

[0204]

[0205] Manufacturing Example 1: Synthesis of N-(4-methoxyphenyl)-3-nitropyridin-2-amine (3)

[0206]

[0207] 2-Chloro-3-nitropyridine (1) (100 mg, 637 μmol) and K2CO3 (177 mg, 1.27 mmol) were dissolved in 2-propanol (2.0 mL) in a 10 mL oven-dried round-bottom flask with a side arm. p-Anisidine (2) (119 mg, 956 μmol) was slowly added to the stirred solution. The reaction mixture was stirred at room temperature under reflux in an oil bath for 26 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and washed sequentially with saturated aqueous NaHCO3 (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. The residue was purified by column chromatography (6:1 hexane / EtOAc) to give N-(4-methoxyphenyl)-3-nitropyridin-2-amine (3) (148 mg, 95%) as a white solid.

[0208] TLC: R f 0.55 (3:1 hexanes / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 9.97 (brs, 1H), 8.51 (dd, J = 8.4, 1.8 Hz, 1H), 8.44 (dd, J = 4.4, 1.8 Hz, 1H), 7.49 (d, J = 9.2 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 6.78 (dd, J = 8.4, 4.4 Hz, 1H), 3.83 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 157.3, 155.7, 151.0, 135.7, 130.7, 128.4, 125.0, 114.4, 113.5, 55.7. HRMS (ESI) m / z calcd for C 12 H 12 N3O3 + ([M + H] + ) 246.0873, found 246.0874.

[0209]

[0210] Manufacturing Example 2: Synthesis of N2-(4-methoxyphenyl)pyridine-2,3-diamine (4)

[0211]

[0212] In a 50 mL oven-dried round-bottom flask with a sidearm, N-(4-methoxyphenyl)-3-nitropyridin-2-amine (3) (150 mg, 612 μmol) was dissolved in concentrated HCl (1.7 mL). Tin(II) chloride hydrate (423 mg, 1.84 mmol) was added and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was poured into ice-water (10 mL) and diluted with EtOAc (30 mL). The mixture was basified to pH 10 with 1 N aqueous NaOH solution. The aqueous layer was then extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (90:1 → 30:1 CH2Cl2 / MeOH) to obtain N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (115 mg, 87%) as a white solid.

[0213] TLC: R f 0.30 (3:1 hexanes / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 5.0, 1.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.97 (dd, J = 7.5, 1.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.70 (dd, J = 7.5, 5.0 Hz, 1H), 6.08 (brs, 1H), 3.79 (s, 3H), 3.35 (brs, 2H). 13C NMR (100 MHz, CDCl3) δ 155.1, 147.0, 139.3, 134.6, 130.2, 123.5, 121.3, 116.5, 114.5, 55.7. HRMS (ESI) m / z calcd for C 12 H 14 N3O + ([M + H] + ) 216.1131, found 216.1135.

[0214]

[0215] Example 1: Synthesis of 4-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol (6a)

[0216]

[0217] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (100 mg, 465 μmol), 4-hydroxybenzaldehyde (73.0 mg, 581 μmol), and Na2S2O5 (91.1 mg, 465 μmol) were suspended in anhydrous DMF (2.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 6 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (10 mL) to precipitate the product. The precipitate was filtered and washed further with cold water (20 mL). The collected solid was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give compound 6a (139 mg, 95%) as a pale yellow solid.

[0218] TLC: R f 0.45 (10:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.24 (dd, J = 4.8, 1.5 Hz, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 7.48-7.37 (m, 2H), 7.37-7.20 (m, 3H), 7.18-6.97 (m, 2H), 6.85-6.67 (m, 2H), 3.83 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.2, 159.1, 153.3, 149.8, 143.4, 134.6, 130.8, 129.4, 128.3, 126.4, 120.2, 118.9, 115.3, 114.7, 55.5. HRMS (ESI) m / z calcd for C 19 H 16 N3O2 + ([M + H] + ) 318.1237, found 318.1239.

[0219]

[0220] Example 2: Synthesis of 4-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6b)

[0221]

[0222] In a 10 mL oven-dried round-bottomed flask with a side arm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (100 mg, 465 μmol), 2,4-dihydroxybenzaldehyde (82.0 mg, 581 μmol), and Na2S2O5 (91.1 mg, 465 μmol) were suspended in anhydrous DMF (2.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 6 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (10 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (20 mL). The collected solid was purified by column chromatography (50:1 CH2Cl2 / MeOH) to give compound 6b (138 mg, 89%) as a pale yellow solid.

[0223] TLC: R f 0.10 (50:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.01 (s, 1H), 8.26 (dd, J = 4.8, 1.5 Hz, 1H), 8.13 (dd, J = 8.0, 1.5 Hz, 1H), 7.45-7.38 (m, 2H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.20-7.05 (m, 2H), 6.87 (d, J = 8.8 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 6.12 (dd, J = 8.8, 2.4 Hz, 1H), 3.86 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 160.4, 159.5, 152.7, 148.7, 143.8, 132.2, 129.5, 129.3, 128.2, 125.4, 119.1, 114.8, 107.0, 104.8, 103.2, 55.5. HRMS (ESI) m / z calcd for C 19 H 16 N3O3 + ([M + H] +) 334.1186, found 334.1189.

[0224]

[0225] Example 3: Synthesis of 2-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,4-diol (6c)

[0226]

[0227] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (100 mg, 465 μmol), 2,5-dihydroxybenzaldehyde (82.0 mg, 581 μmol), and Na2S2O5 (91.1 mg, 465 μmol) were suspended in anhydrous DMF (2.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 4 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (10 mL) to precipitate the product. The precipitate was filtered and washed further with cold water (20 mL). The collected solid was purified by column chromatography (50:1 CH2Cl2 / MeOH) to give compound 6c (143 mg, 93%) as a pale yellow solid.

[0228] TLC: R f 0.10 (50:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.91 (s, 1H), 8.32 (dd, J = 4.8, 1.5 Hz, 1H), 8.19 (dd, J = 8.0, 1.5 Hz, 1H), 7.42-7.32 (m, 3H), 7.13-7.01 (m, 2H), 6.79-6.70 (m, 2H), 6.63-6.54 (m, 1H), 3.84 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 159.2, 152.2, 150.3, 149.0, 148.7, 144.3, 132.9, 128.9, 128.1, 126.3, 119.3, 119.2, 117.4, 115.1, 114.6, 114.4, 55.4. HRMS (ESI) m / z calcd for C 19 H 16 N3O3 + ([M + H] + ) 334.1186, found 334.1189.

[0229]

[0230] Example 4: Synthesis of 2-(2,5-dimethoxyphenyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine (6d)

[0231]

[0232] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (100 mg, 465 μmol), 2,5-dimethoxybenzaldehyde (98.5 mg, 581 μmol), and Na2S2O5 (91.1 mg, 465 μmol) were suspended in anhydrous DMF (2.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 4 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (10 mL) to precipitate the product. The precipitate was filtered and washed further with cold water (20 mL). The collected solid was purified by column chromatography (100:1 CH2Cl2 / MeOH) to give compound 6d (128 mg, 76%) as a pale yellow solid.

[0233] TLC: R f 0.10 (100:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 4.8, 1.5 Hz, 1H), 8.17 (dd, J = 8.0, 1.5 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.26-7.19 (m, 2H), 7.18 (d, J = 3.2 Hz, 1H), 7.02 (dd, J = 9.0, 3.2 Hz, 1H), 6.99-6.94 (m, 2H), 6.89 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.32 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 158.6, 152.8, 152.1, 150.8, 148.5, 144.0, 134.5, 128.0, 127.9, 127.0, 120.0, 118.7, 116.9, 116.9, 113.8, 112.6, 55.5, 55.4 (2C). HRMS (ESI) m / z calcd for C 21 H 20 N3O3 + ([M + H] + ) 362.1499, found 362.1502.

[0234]

[0235] Example 5: Synthesis of 2-(4-fluorophenyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine (6e)

[0236]

[0237] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (50.0 mg, 232 μmol), 4-fluorobenzaldehyde (25.0 μL, 290 μmol), and Na2S2O5 (45.6 mg, 232 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 8 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and washed further with cold water (10 mL). The collected solid was purified by column chromatography (50:1 CH2Cl2 / MeOH) to give compound 6e (68.0 mg, 92%) as a pale yellow solid.

[0238] TLC: R f 0.10 (50:1 CH2Cl2 / MeOH). 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), 7.67-7.58 (m, 2H), 7.31-7.25 (m, 3H), 7.08-6.98 (m, 4H), 3.87 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.1, 162.6, 159.9, 151.3 (d, J C-F = 270.3 Hz), 144.8, 135.2, 131.6 (d, J C-F = 8.5 Hz), 129.0, 128.2, 127.4, 126.1, 119.3, 115.8 (d, J C-F = 21.8 Hz), 115.2, 55.7. HRMS (ESI) m / z calcd for C 19 H 15 FN3O + ([M + H] + ) 320.1194, found 320.1196.

[0239]

[0240] Example 6: Synthesis of 2-(furan-2-yl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine (6f)

[0241]

[0242] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (50.0 mg, 232 μmol), 2-furaldehyde (32.0 μL, 290 μmol), and Na2S2O5 (45.6 mg, 232 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 6 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (10 mL). The collected solid was purified by column chromatography (50:1 CH2Cl2 / MeOH) to give compound 6f (41.2 mg, 61%) as a pale yellow solid.

[0243] TLC: R f 0.10 (50:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J = 4.8, 1.5 Hz, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.94-7.82 (m, 1H), 7.55-7.39 (m, 2H), 7.35 (dd, J) = 8.0, 4.8 Hz, 1H), 7.24-7.11 (m, 2H), 6.59 (dd, J = 3.6, 1.8 Hz, 1H), 6.28 (dd, J = 3.6, 0.8 Hz, 1H), 3.87 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 159.8, 149.4, 145.6, 144.8, 144.3, 143.9, 134.5, 129.7, 127.4, 126.9, 119.1, 114.8, 113.4, 112.1, 55.5. HRMS (ESI) m / z calcd for C 17 H 14 N3O2 + ([M + H] + ) 292.1081, found 292.1084.

[0244]

[0245] Example 7: Synthesis of 3-(4-methoxyphenyl)-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine (6 g)

[0246]

[0247] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (50.0 mg, 232 μmol), 4-nitrobenzaldehyde (45.0 mg, 290 μmol), and Na2S2O5 (45.6 mg, 232 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 2 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and washed further with cold water (10 mL). The collected solid was purified by column chromatography (60:1 CH2Cl2 / MeOH) to give compound 6 g (44.5 mg, 55%) as a pale yellow solid.

[0248] TLC: R f 0.10 (60:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 8.39 (dd, J = 4.8, 1.5 Hz, 1H), 8.30-8.15 (m, 3H), 7.89-7.78 (m, 2H), 7.47-7.34 (m, 3H), 7.15-7.07 (m, 2H), 3.84 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.4, 150.8, 149.5, 147. 9, 145.1, 135.8, 134.5, 130.4, 129.4, 127.7, 127.4, 123.6, 119.5, 114.8, 55.5. HRMS (ESI) m / z calcd for C 19 H 15 N4O3 + ([M + H] + ) 347.1139, found 347.1142.

[0249]

[0250] Example 8: Synthesis of 3-(4-methoxyphenyl)-2-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridine(6h)

[0251]

[0252] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (50.0 mg, 232 μmol), picolinaldehyde (28.0 μL, 290 μmol), and Na2S2O5 (45.6 mg, 232 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 3 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (10 mL). The collected solid was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give compound 6h (39.8 mg, 57%) as a pale yellow solid.

[0253] TLC: Rf 0.10 (30:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (dd, J = 2.3, 0.9 Hz, 1H), 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 8.24 (dd, J = 8.0, 1.5 Hz, 1H), 7.92 (dt, J = 8.0, 2.3, 1.6 Hz, 1H), 7.48-7.44 (m, 1H), 7.44-7.37 (m, 3H), 7.15-7.06 (m, 2H), 3.84 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.9, 151.1, 151.0, 150.0, 145.1, 136.9, 135.0, 130.0, 127.8, 128.0, 126.4, 124.0, 119.7, 115.2, 56.0. HRMS (ESI) m / z calcd for C 18 H 15 N3O + ([M + H] + ) 303.1240, found 303.1240.

[0254]

[0255] Example 9: Synthesis of 3-(4-methoxyphenyl)-2-(6-methylpyridin-2-yl)-3H-imidazo[4,5-b]pyridine (6i)

[0256]

[0257] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (50.0 mg, 232 μmol), 6-methylpicolinaldehyde (29.0 mg, 290 μmol), and Na2S2O5 (45.6 mg, 232 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 2 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (10 mL). The collected solid was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give compound 6i (49.7 mg, 57%) as a pale yellow solid.

[0258] TLC: R f 0.10 (30:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (dd, J = 4.8, 1.5 Hz, 1H), 8.22 (dd, J = 8.0, 1.5 Hz, 1H), 7.92 (dt, J = 7.8, 0.8 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.39 (dd, J = 8.0, 4.8 Hz, 1H), 7.34-7.23 (m, 3H), 7.09-6.95 (m, 2H), 3.82 (s, 3H), 2.19 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.8, 157.0, 151.4, 149.6, 148.0, 144.8, 137.1, 134.2, 129.2, 129.0, 127.5, 123.8, 121.5, 119.2, 113.7, 55.4, 23.7. HRMS (ESI) m / z calcd for C 19 H 17 N4O + ([M + H] + ) 317.1397, found 317.1399.

[0259]

[0260] Example 10: Synthesis of 4-chloro-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6j)

[0261]

[0262] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (100 mg, 465 μmol), 5-chloro-2,4-dihydroxybenzaldehyde (100 mg, 581 μmol), and Na2S2O5 (91.1 mg, 465 μmol) were suspended in anhydrous DMF (2.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 3 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (10 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (20 mL). The collected solid was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give 6j (136 mg, 80%) as a pale yellow solid.

[0263] TLC: R f 0.10 (30:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 10.73 (s, 1H), 8.30 (dd, J = 4.8, 1.5 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.52-7.39 (m, 2H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.19-7.07 (m, 2H), 7.02 (s, 1H), 6.54 (s, 1H), 3.85 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 159.5, 158.2, 155.8, 151.5, 148.6, 144.1, 132.5, 129.5, 129.2, 127.9, 125.9, 119.2, 114.7, 110.1, 106.6, 104.1, 55.6. HRMS (ESI) m / z calcd for C 19 H 15 ClN3O3 + ([M + H] + ) 368.0796, found 368.0799.

[0264]

[0265] Example 11: Synthesis of 2,4-dichloro-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6k)

[0266]

[0267] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (50.0 mg, 232 μmol), 3,5-dichloro-2,4-dihydroxybenzaldehyde (60.1 mg, 290 μmol), and Na2S2O5 (45.6 mg, 232 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 23 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (10 mL). The collected solid was purified by column chromatography (40:1 CH2Cl2 / MeOH) to obtain compound 6k (43.0 mg, 46%) as a pale yellow solid.

[0268] TLC: R f 0.10 (40:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H), 10.77 (s, 1H), 8.33 (dd, J = 4.8, 1.5 Hz, 1H), 8.22 (dd, J = 8.0, 1.5 Hz, 1H), 7.61-7.47 (m, 2H), 7.42 (dd, J = 8.0, 4.8 Hz, 1H), 7.27-7.10 (m, 2H), 6.86 (s, 1H), 3.88 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 160.1, 155.4, 152.0, 150.6, 148.6, 144.8, 131.3, 129.6, 127.5, 126.1, 125.9, 119.7, 115.2, 111.2, 110.4, 105.9, 55.7. HRMS (ESI) m / z calcd for C 19 H 14 Cl2N3O3 + ([M + H] + ) 402.0407, found 402.0407.

[0269]

[0270] Example 12: Synthesis of 3-(4-methoxyphenyl)-2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridine (6l)

[0271]

[0272] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (50.0 mg, 232 μmol), isonicotinaldehyde (28.2 μL, 290 μmol), and Na2S2O5 (45.6 mg, 232 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 12 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (10 mL). The collected solid was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give compound 6l (43.5 mg, 62%) as a pale yellow solid.

[0273] TLC: R f 0.10 (30:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, CDCl3) δ 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 8.45 (dd, J = 4.8, 1.5 Hz, 1H), 8.19 (dd, J = 8.1, 1.5 Hz, 0H), 7.52 (dd, J = 4.8, 1.6) Hz, 1H), 7.34 (dd, J = 8.1, 4.8 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.06 (d, J = 9.1 Hz, 1H), 3.89 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 160.3, 150.6, 150.2, 150.0, 145.9, 137.3, 135.6, 129.0, 128.2, 127.6, 123.4, 119.7, 115.4, 55.75. HRMS (ESI) m / z calcd for C 18 H 15 N4O + ([M + H] + ) 303.1240, found 303.1246.

[0274]

[0275] Example 13: Synthesis of 4-ethyl-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6m)

[0276]

[0277] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-methoxyphenyl)pyridine-2,3-diamine (4) (50.0 mg, 232 μmol), 5-ethyl-2,4-dihydroxybenzaldehyde (48.2 mg, 290 μmol), and Na2S2O5 (45.6 mg, 232 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 19 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (10 mL). The collected solid was purified by column chromatography (3:1 hexanes / EtOAc) to give compound 6m (68.3 mg, 81%) as a pale yellow solid.

[0278] TLC: R f 0.28 (3:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (brs, 1H), 9.96 (brs, 1H), 8.26 (dd, J = 4.8, 1.4 Hz, 1H), 8.12 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 (d, J = 8.8) Hz, 2H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.73 (s, 1H), 6.41 (s, 1H), 3.86 (s, 3H), 2.21 (q, J = 7.5 Hz, 2H), 0.76 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 159.7, 158.6, 158.5, 152.9, 148.7, 143.7, 132.1, 129.6, 128.5, 127.8, 125.2, 120.7, 119.1, 114.9, 103.8, 102.7, 55.6, 21.2, 12.9. HRMS (ESI) m / z calcd for C 21 H 20 N3O3 + ([M + H] + ) 362.1499, found 362.1502.

[0279]

[0280] Examples 14 and 15 below were synthesized based on the following reaction scheme 2.

[0281] [Reaction Formula 2]

[0282]

[0283] Example 14: Synthesis of 4-chloro-6-(3-(4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6n)

[0284] Step 1: Synthesis of N-(4-morpholinophenyl)-3-nitropyridin-2-amine (3n)

[0285]

[0286] 2-Chloro-3-nitropyridine (1) (200 mg, 1.25 mmol) and K2CO3 (347 mg, 2.50 mmol) were dissolved in 2-propanol (4 mL) in a 10 mL oven-dried round-bottom flask with a side arm at room temperature. 4-Morpholinoaniline (2n, Scheme 2) (273 mg, 1.50 mmol) was slowly added to the stirred solution. The reaction mixture was stirred under reflux in an oil bath for 17 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo. The resulting residue was diluted with EtOAc (200 mL) and washed sequentially with saturated aqueous NaHCO3 solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (8:1 hexanes / EtOAc) to give compound 3n (376 mg, 100%) as a white solid.

[0287] TLC: R f 0.33 (8:1 hexanes / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 9.99 (brs, 1H), 8.51 (dd, J = 8.3, 1.8 Hz, 1H), 8.45 (ddd, J = 4.5, 1.8, 0.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.77 (dd, J = 8.3, 4.5 Hz, 1H), 3.95-3.82 (m, 4H), 3.23-3.11 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 155.7, 150.9, 149.0, 135.7, 130.2, 128.4, 124.5, 116.3, 113.5, 67.0, 49.7. HRMS (ESI) m / z calcd for C 15 H 17 N4O3 + ([M + H] +) 301.1295, found 301.1297.

[0288] Step 2: Synthesis of N2-(4-morpholinophenyl)pyridine-2,3-diamine(4n)

[0289]

[0290] Compound 3n (375 mg, 1.25 mmol) was dissolved in EtOH (6.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. 5% Pd / C (50.0 mg, 13 wt%) was added and stirred at room temperature for 4 h under a hydrogen-filled balloon. 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 (10 mL). The filtrate was concentrated using a rotary evaporator. The residue was purified by column chromatography (40:1 CH2Cl2 / MeOH) to give compound 4n (291 mg, 86%) as a pink solid.

[0291] TLC: R f 0.15 (40:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 4.9, 1.6 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 6.97 (dd, J = 7.6, 1.6 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 6.70 (dd, J = 7.6, 4.9 Hz, 1H), 6.08 (brs, 1H), 3.93-3.80 (m, 4H), 3.35 (brs, 2H), 3.14-3.03 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 150.4, 146.8, 139.3, 134.5, 130.3, 123.6, 120.8, 117.3, 116.5, 67.2, 50.5. HRMS (ESI) m / z calcd for C 15 H 18 N4O + ([M + H] +) 271.1553, found 271.1559.

[0292] Step 3: Synthesis of 4-chloro-6-(3-(4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6n)

[0293]

[0294] In a 10 mL oven-dried round-bottom flask with a sidearm, N2-(4-morpholinophenyl)pyridine-2,3-diamine(4n) (50.0 mg, 185 μmol), 5-chloro-2,4-dihydroxybenzaldehyde (40 mg, 231 μmol), and Na2S2O5 (36.3 mg, 185 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred in an oil bath at 110 °C for 19 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (10 mL). The collected solid was purified by column chromatography (60:1 → 20:1 CH2Cl2 / MeOH) to obtain compound 6n (74.2 mg, 95%) as a pale yellow solid.

[0295] TLC: R f 0.20 (20:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, CDCl3) δ 13.62 (brs, 1H), 8.38 (dd, J = 4.8, 1.5 Hz, 1H), 8.03 (dd, J = 8.0, 1.5 Hz, 1H), 7.35-7.27 (m, 3H), 7.11 (d, J = 9.0 Hz, 2H), 6.93 (s, 1H), 6.74 (s, 1H), 5.66 (brs, 1H), 3.98-3.86 (m, 4H), 3.36-3.24 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 158.4, 155.9, 151.5, 151.3, 148.7, 144.1, 132.4, 129.4, 128.5, 126.1, 125.8, 119.2, 115.3, 110.1, 106.4, 104.1, 66.0, 48.1. HRMS (ESI) m / z calcd for C 22 H 20 ClN4O3 + ([M + H] + ) 423.1218, found 423.1220.

[0296]

[0297] Example 15: Synthesis of 4-chloro-6-(3-(4-(morpholinomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6o)

[0298] Step 1: Synthesis of N-(4-(morpholinomethyl)phenyl)-3-nitropyridin-2-amine (3o)

[0299]

[0300] 2-Chloro-3-nitropyridine (1) (200 mg, 1.25 mmol) and K2CO3 (173 mg, 1.25 mmol) were suspended in 2-propanol (6 mL) in a 50 mL oven-dried round-bottom flask with a side arm at room temperature. 4-(morpholinomethyl)aniline (2o, Scheme 2) (120 mg, 624 μmol) was slowly added to the stirred solution. The reaction mixture was stirred under reflux in an oil bath for 29 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo. The resulting residue was diluted with EtOAc (100 mL) and washed sequentially with saturated aqueous NaHCO3 solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (2:1 → 1:1 hexanes / EtOAc) to obtain compound 3o (129 mg, 66%) as a white solid.

[0301] TLC: R f 0.33 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 10.11 (brs, 1H), 8.53 (dd, J = 8.4, 1.8 Hz, 1H), 8.48 (dd, J = 4.4, 1.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.83 (dd, J = 8.4, 4.4 Hz, 1H), 3.82-3.60 (m, 4H), 3.50 (s, 2H), 2.55-2.39 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 155.4, 150.4, 137.0, 135.7, 134.5, 129.9, 128.8, 122.5, 114.0, 67.2, 63.1, 53.8. HRMS (ESI) m / z calcd for C 16 H 18 N4O3 + ([M + H]+ ) 315.1452, found 315.1452.

[0302] Step 2: Synthesis of N2-(4-(morpholinomethyl)phenyl)pyridine-2,3-diamine (4o)

[0303]

[0304] Compound 3o (98.0 mg, 313 μmol) was dissolved in concentrated HCl (2.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. Tin (II) chloride dihydrate (360 mg, 1.56 mmol) was added and 90 o C for 1 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into cold water (10 mL), and diluted with EtOAc (30 mL). The mixture was basified to pH 9 with saturated aqueous NaHCO3 solution, and the aqueous layer was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (20:1 CH2Cl2 / MeOH) to give compound 4o (71.7 mg, 81%) as a white solid.

[0305] TLC: R f 0.10 (20:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 4.9, 1.6 Hz, 1H), 7.04 (dd, J = 7.6, 1.6 Hz, 1H), 6.79 (dd, J = 7.6, 4.9 Hz, 1H), 6.22 (brs, 1H), 3.77-3.68 (m, 4H), 3.47 (s, 2H), 3.43 (brs, 2H), 2.46 (t, J = 4.7 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 145.9, 140.6, 139.3, 131.1, 130.5, 130.2, 123.8, 118.3, 117.4, 67.1, 63.2, 53.7. HRMS (ESI) m / z calcd for C 16 H 21 N4O + ([M + H] + ) 285.1710, found 285.1711.

[0306] Step 3: Synthesis of 4-chloro-6-(3-(4-(morpholinomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6o)

[0307]

[0308] Compound 4o (42.2 mg, 149 μmol), 5-chloro-2,4-dihydroxybenzaldehyde (31.0 mg, 179 μmol), and Na2S2O5 (30.0 mg, 149 μmol) were suspended in anhydrous DMF (1.5 mL) in a 10 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred in an oil bath at 110 °C for 14 h. Upon completion of the reaction, the reaction mixture was concentrated using a rotary evaporator. The resulting residue was then diluted with cold water (5 mL) to precipitate the product. The precipitate was filtered and further washed with cold water (10 mL). The collected solid was purified by column chromatography (60:1 → 20:1 CH2Cl2 / MeOH) to give compound 6o (36.4 mg, 56%) as a pale yellow solid.

[0309] TLC: R f 0.20 (20:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.78 (s, 1H), 8.31 (dd, J = 4.8, 1.5 Hz, 1H), 8.18 (dd, J = 8.0, 1.5 Hz, 1H), 7.61-7.49 (m, 2H), 7.49-7.42 (m, 2H), 7.39 (dd, J = 8.0, 4.8 Hz, 1H), 6.86 (s, 1H), 6.53 (s, 1H), 3.67-3.52 (m, 6H), 2.42 (t, J = 4.7 Hz, 4H). 13 C NMR (100 MHz, CDCl3) δ 161.2, 154.3, 151.4, 148.8, 145.1, 140.5, 134.4, 132.4, 131.3, 128.3, 127.8, 126.2, 119.7, 110.2, 106.2, 105.2, 67.2, 63.0, 53.7. HRMS (ESI) m / z calcd for C 23 H 22 ClN4O3 + ([M + H] + ) 437.1375, found 437.1382.

[0310]

[0311] Examples 16 to 69 below were synthesized based on the following reaction scheme 3.

[0312] [Reaction Formula 3]

[0313]

[0314] Manufacturing Example 3: Synthesis of amino nitrile pyridine (3')

[0315] Manufacturing Example 3-1: Synthesis method 1 of amino nitrile pyridine (3')

[0316]

[0317] In a 50 mL oven-dried round-bottom flask with a sidearm, 2-chloro-3-nitro-pyridine (1) (500 mg, 3.16 mmol), substituted aniline (2', Scheme 3) (3.78 mmol), and K2CO3 (872 mg, 6.31 mmol) were suspended in anhydrous i-PrOH (10.0 mL). The reaction mixture was stirred overnight in an oil bath 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 amino nitrile pyridine 3' as a red solid.

[0318] Manufacturing Example 3-2: Synthesis method 2 of amino nitrile pyridine (3')

[0319]

[0320] In a 50 mL oven-dried round-bottom flask with a sidearm, 2-chloro-3-nitro-pyridine (1) (500 mg, 3.16 mmol), substituted aniline (2', Scheme 3) (3.16 mmol), Pd2(dba)3 (231 mg, 252 μmol), Xantphos (310 mg, 536 μmol), and K3PO4 (1.34 g, 6.31 mmol) were suspended in anhydrous 1,4-dioxane (14.3 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 (4:1 hexanes / EtOAc) to give amino nitrile pyridine 3' as a red solid.

[0321] Manufacturing Example 4: Synthesis of pyridine-2,3-diamine (4')

[0322] Manufacturing Example 4-1: Synthesis method 1 of pyridine-2,3-diamine (4')

[0323]

[0324] Compound 3' (770 mg, 2.80 mmol) and Pd / C (77.0 mg) were suspended in EtOH (10.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred at room temperature under a hydrogen-filled balloon for 5 h. Upon completion of the reaction, 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 give compound 4' as a pink solid.

[0325] Manufacturing Example 4-2: Synthesis method 2 of pyridine-2,3-diamine (4')

[0326]

[0327] Compound 3' (781 mg, 1.85 mmol), Fe powder (620 mg, 11.1 mmol), and NH4Cl (890 mg, 16.6 mmol) were suspended in MeOH (5.0 mL) and H2O (5.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred at 90 °C overnight. Upon completion of the reaction, the reaction mixture was basified to pH = 11 with K2CO3 and extracted with CH2Cl2 (500 mL). The extracted organic layers were combined, dried over anhydrous MgSO4, and concentrated using a rotary evaporator. The resulting residue was then purified by column chromatography (3:1 hexanes / EtOAc) to give compound 4' (543 mg, 75%) as a pink solid.

[0328] Manufacturing Example 5: Synthesis of compounds 6aa, 6ba, 6da-6ta, 6ab, 6bb, 6db-6tb and 6ac, 6bc, 6dc-6tc

[0329]

[0330] Compound 4' (100 mg, 408 μmol), aldehyde 5'ac (489 μmol, Scheme 3), and Na2S2O5 (155 mg, 816 μmol) were suspended in anhydrous DMF (2.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred overnight at 110 °C in an oil bath. 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 compounds 6aa, 6ba, 6da-6ta, 6ab, 6bb, 6db-6tb, and 6ac, 6bc, 6dc-6tc as ivory solids.

[0331]

[0332] Example 16: Synthesis of 4-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6aa)

[0333] Step 1: Synthesis of N-(3,4-dimethoxyphenyl)-3-nitropyridin-2-amine (3'a)

[0334]

[0335] Compound 3'a (777 mg, 89%) was obtained as a red solid using the method of Manufacturing Example 3-1.

[0336] TLC R f 0.48 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.52 (dd, J = 8.3, 1.8 Hz, 1H), 8.46 (dd, J = 4.5, 1.9 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.6, 2.5 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.79 (dd, J = 8.4, 4.5 Hz, 1H), 3.90 (d, J = 2.3 Hz, 6H). 13C NMR (100 MHz, DMSO-d6) δ 155.8, 150.4, 149.0, 146.4, 136.0, 131.9, 128.8, 115.9, 114.4, 112.2, 108.9, 56.2, 56.0. HRMS (ESI) m / z calcd for C 13 H 14 N3O4 + ([M + H] + ) 276.0979, found 279.0981.

[0337] Step 2: Synthesis of N2-(3,4-dimethoxyphenyl)pyridine-2,3-diamine (4'a)

[0338]

[0339] Compound 4'a (610 mg, 89%) was obtained as a pink solid using the method of Manufacturing Example 4-1.

[0340] TLC R f 0.50 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.46 (dd, J = 4.9, 1.7 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.7, 2.5 Hz, 1H), 6.88-6.79 (m, 2H), 6.56 (dd, J = 7.5, 4.9 Hz, 1H), 5.00 (s, 2H), 3.74 (s, 3H), 3.71 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 149.1, 144.8, 143.4, 136.6, 134.9, 131.8, 119.7, 115.4, 113.1, 110.8, 104.8, 56.5, 55.8. HRMS (ESI) m / z calcd for C 13 H 16 N3O2 + ([M + H] + ) 246.1243, found 246.1239.

[0341] Step 3: Synthesis of 4-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6aa)

[0342]

[0343] Compound 6aa (119 mg, 80%) was obtained as a white solid using the method of Preparation Example 5.

[0344] TLC R f 0.49 (1:2 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 9.99 (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), 7.15 (d, J = 5.9 Hz, 1H), 7.14 (s, 1H), 7.04 (dd, J = 8.5, 2.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.14 (dd, J = 8.8, 2.4 Hz, 1H), 3.87 (s, 3H), 3.70 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 160.6, 152.7, 149.3, 149.2, 148.8, 143.8, 132.0, 129.4, 128.2, 125.4, 120.4, 119.2, 112.0, 111.9, 107.0, 104.7, 103.2, 55.8, 55.7. HRMS (ESI) m / z calcd for C 20 H 18 H3O4 + ([M + H] + ) 364.1292, found 364.1297.

[0345]

[0346] Example 17: Synthesis of 4-chloro-6-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ab)

[0347]

[0348] Compound 6ab (25 mg, 15%) was obtained as a white solid using the method of Preparation Example 5.

[0349] TLC R f 0.50 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.76 (s, 1H), 8.31 (dd, J = 4.7, 1.5 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.04 (dd, J = 8.4, 2.3 Hz, 1H), 7.02 (s, 1H), 6.54 (s, 1H), 3.85 (s, 3H), 3.69 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 158.5, 156.0, 151.5, 149.3, 149.2, 148.6, 144.1, 132.3, 129.4, 127.9, 125.8, 120.3, 119.2, 112.0, 111.9, 110.1, 106.2, 104.1, 55.9, 55.8. HRMS (ESI) m / z calcd for C 20 H 17 ClN3O4 + ([M + H] + ) 398.0902, found 398.0902.

[0350]

[0351] Example 18: Synthesis of 4-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6ac)

[0352]

[0353] Using the method of Preparation Example 5, compound 6ac (110 mg, 72%) was obtained as a white solid.

[0354] TLC R f 0.48 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.94 (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), 7.15 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 1.2 Hz, 1H), 7.02 (dd, J = 8.4, 2.4 Hz, 1H), 6.73 (d, J = 0.9 Hz, 1H), 6.40 (s, 1H), 3.86 (s, 3H), 3.69 (s, 3H), 1.78 (d, J = 0.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.3, 159.0, 153.3, 149.8, 149.8, 149.2, 144.2, 132.7, 130.4, 128.8, 125.7, 121.0, 119.6, 115.2, 112.7, 112.4, 104.7, 103.1, 56.4, 56.3, 16.0. HRMS (ESI) m / z calcd for C 21 H 20 N3O4 + ([M + H] + ) 378.1448, found 378.1451.

[0355]

[0356] Example 19: Synthesis of 4-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ba)

[0357] Step 1: Synthesis of 3-nitro-N-(3,4,5-trimethoxyphenyl)pyridin-2-amine (3'b)

[0358]

[0359] Compound 3'b (615 mg, 64%) was obtained as a red solid using the method of Manufacturing Example 3-1.

[0360] TLC R f 0.49 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.54 (dd, J = 8.3, 1.8 Hz, 1H), 8.49 (dd, J = 4.5, 1.8 Hz, 1H), 6.91 (s, 2H), 6.84 (dd, J = 8.4, 4.5) Hz, 1H), 3.89 (s, 6H), 3.86 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 155.8, 150.4, 149.0, 146.4, 136.0, 131.9, 128.8, 115.9, 114.4, 112.2, 108.9, 56.2, 56.0. HRMS (ESI) m / z calcd for C 14 H 16 N3O5 + ([M + H] + ) 306.1084, found 306.1086.

[0361] Step 2: Synthesis of N2-(3,4,5-trimethoxyphenyl)pyridine-2,3-diamine (4'b)

[0362]

[0363] Compound 4'b (473 mg, 88%) was obtained as a pink solid using the method of Manufacturing Example 4-1.

[0364] TLC R f 0.51 (EtOAc only). 1H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.51 (dd, J = 4.8, 1.6 Hz, 1H), 7.08 (s, 2H), 6.89 (dd, J = 7.6, 1.7 Hz, 1H), 6.60 (dd, J = 7.6, 4.9) Hz, 1H), 5.03 (s, 2H), 3.75 (s, 6H), 3.61 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 153.1, 144.1, 138.8, 134.7, 132.2, 131.8, 120.0, 115.9, 96.60, 60.6, 56.1. HRMS (ESI) m / z calcd for C 14 H 18 N3O3 + ([M + H] + ) 276.1343, found 276.1347.

[0365] Step 3: Synthesis of 4-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ba)

[0366]

[0367] Using the method of Preparation Example 5, compound 6ba (105 mg, 74%) was obtained as a white solid.

[0368] TLC R f 0.49 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.06 (s, 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), 6.89 (d, J = 4.8 Hz, 3H), 6.36 (d, J = 2.4 Hz, 1H), 6.16 (dd, J = 8.9, 2.4 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 6H). 13C NMR (100 MHz, DMSO-d6) δ 160.9, 160.6, 153.4, 152.5, 148.6, 143.8, 137.9, 132.1, 131.3, 129.4, 125.4, 119.2, 107.0, 106.1, 104.8, 103.2, 60.2, 56.2. HRMS (ESI) m / z calcd for C 21 H 20 N3O5 + ([M + H] + ) 394.1397, found 394.1400.

[0369]

[0370] Example 20: Synthesis of 4-chloro-6-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6bb)

[0371]

[0372] Using the method of Manufacturing Example 5, compound 6bb (80 mg, 52%) was obtained as a white solid.

[0373] TLC R f 0.50 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.77 (s, 1H), 8.35 (dd, J = 4.7, 1.5 Hz, 1H), 8.19 (dd, J = 8.0, 1.5 Hz, 1H), 7.40 (dd, J = 8.0, 4.8 Hz, 1H), 6.99 (s, 1H), 6.93 (s, 2H), 6.57 (s, 1H), 3.77 (s, 3H), 3.72 (s, 6H). 13C NMR (100 MHz, DMSO-d6) δ 158.7, 156.0, 153.4, 151.3, 148.4, 144.2, 138.2, 132.2, 130.8, 129.3, 125.8, 119.3, 110.1, 106.2, 106.1, 104.1, 60.3, 56.3. HRMS (ESI) m / z calcd for C 21 H 19 ClN3O5 + ([M + H] + ) 428.1008, found 428.1008.

[0374]

[0375] Example 21: Synthesis of 4-methyl-6-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6bc)

[0376]

[0377] Using the method of Preparation Example 5, compound 6bc (92 mg, 62%) was obtained as a white solid.

[0378] TLC R f 0.39 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.02 (s, 1H), 8.29 (dd, J = 4.8, 1.5 Hz, 1H), 8.13 (dd, J = 8.0, 1.5 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 6.91 (s, 2H), 6.69 (d, J = 0.9 Hz, 1H), 6.40 (s, 1H), 3.77 (s, 3H), 3.72 (s, 6H), 1.80 (d, J = 0.8 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 158.9, 158.7, 153.5, 152.6, 148.6, 143.7, 138.2, 132.1, 131.4, 129.8, 125.3, 119.1, 114.7, 106.4, 104.0, 102.6, 60.4, 56.4, 15.5. HRMS (ESI) m / z calcd for C 22 H 22 N3O5 + ([M + H] + ) 408.1554, found 408.1557.

[0379]

[0380] Example 22: Synthesis of 4-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6da)

[0381] Step 1: Synthesis of 3-nitro-N-(4-(trifluoromethoxy)phenyl)pyridin-2-amine (3'd)

[0382]

[0383] Compound 3'd (232 mg, 24%) was obtained as a white solid using the method of Manufacturing Example 3-1.

[0384] TLC R f 0.65 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.56 (dd, J = 8.3, 1.8 Hz, 1H), 8.52 (dd, J = 4.5, 1.8 Hz, 1H), 7.81-7.73 (m, 2H), 7.42-7.30 (m, 2H), 7.04 (dd, J = 8.3, 4.5 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ155.3, 149.7, 144.7, 138.2, 136.1, 129.6, 124.8, 121.8, 120.6 (d, J = 255.7 Hz), 115.4. HRMS (ESI) m / z calcd for C12 H9F3N3O3 + ([M + H] + ) 300.0591, found 300.0592.

[0385] Step 2: Synthesis of N2-(4-(trifluoromethoxy)phenyl)pyridine-2,3-diamine (4'd)

[0386]

[0387] Compound 4'd (194 mg, 98%) was obtained as a white solid using the method of Manufacturing Example 4-1.

[0388] TLC R f 0.50 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.77-7.65 (m, 2H), 7.50 (dd, J = 4.8, 1.7 Hz, 1H), 7.26-7.15 (m, 2H), 6.92 (dd, J = 7.6, 1.6 Hz, 1H), 6.66 (dd, J = 7.6, 4.8 Hz, 1H), 5.08 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 143.6, 142.1, 141.5, 134.7, 132.6, 121.8, 120.8 (d, J = 254.7 Hz), 120.4, 119.2, 116.8. HRMS (ESI) m / z calcd for C 12 H 11 F3N3O3 + ([M + H] + ) 270.0849, found 270.0849.

[0389] Step 3: Synthesis of 4-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6da)

[0390]

[0391] Using the method of Preparation Example 5, compound 6da (54 mg, 37%) was obtained as a white solid.

[0392] TLC R f 0.48 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.92 (s, 1H), 8.29 (dd, J = 4.8, 1.5 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.64-7.59 (m, 2H), 7.56 (dd, J = 9.3, 1.0 Hz, 2H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 6.20 (dd, J = 8.6, 2.4 Hz, 1H) . 13 C NMR (100 MHz, DMSO-d6) δ 161.3, 159.6, 153.1, 148.8, 148.4 (d, J = 1.9 Hz), 144.2, 135.3, 133.6, 131.0, 130.2, 126.5, 122.4, 124.60-116.46 (m), 119.8, 107.6, 106.2, 103.4. HRMS (ESI) m / z calcd for C 19 H 13 F3N3O3 + ([M + H] + ) 388.0904, found 388.0905.

[0393]

[0394] Example 23: Synthesis of 4-chloro-6-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6db)

[0395]

[0396] Using the method of Manufacturing Example 5, compound 6db (62 mg, 21%) was obtained as a white solid.

[0397] TLC R f 0.45 (2:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.72 (s, 1H), 8.31 (dd, J = 4.8, 1.5 Hz, 1H), 8.18 (dd, J = 8.0, 1.5 Hz, 1H), 7.65-7.60 (m, 2H), 7.60-7.55 (m, 2H), 7.39 (dd, J = 8.0, 4.8 Hz, 1H), 7.11 (s, 1H), 6.48 (s, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 157.07, 155.94, 151.41, 148.25, 147.97 (d, J = 1.8 Hz), 144.08, 134.58, 133.37, 130.47, 129.52, 126.44, 121.96, 120.06 (q, J = 256.8 Hz), 119.34, 110.29, 107.37, 103.89. HRMS (ESI) m / z calcd for C 19 H 12 ClF3N3O3 + ([M + H] + ) 422.0514, found 422.0515.

[0398]

[0399] Example 24: Synthesis of 4-methyl-6-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6dc)

[0400]

[0401] Using the method of Preparation Example 5, compound 6dc (41 mg, 28%) was obtained as a white solid.

[0402] TLC R f 0.49 (2:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.95 (s, 1H), 8.28 (dd, J = 4.8, 1.5 Hz, 1H), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.66-7.56 (m, 4H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 6.73 (s, 1H), 6.36 (s, 1H), 1.94-1.56 (m, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 158.8, 157.3, 152.7, 148.4, 148.0 (d, J = 1.8 Hz), 143.7, 135.0, 133.0, 130.7, 129.9, 125.8, 122.1, 120.07 (d, J = 256.8 Hz), 119.3, 115.0, 104.8, 102.5, 15.2. HRMS (ESI) m / z calcd for C 20 H 15 F3N3O3 + ([M + H] + ) 402.1060, found 402.1068

[0403]

[0404] Example 25: Synthesis of 4-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ea)

[0405] Step 1: Synthesis of 2-methoxy-5-((3-nitropyridin-2-yl)amino)phenol (3'e)

[0406]

[0407] Compound 3'e (602 mg, 73%) was obtained as a red solid using the method of Manufacturing Example 3-2.

[0408] TLC R f 0.63 (3:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.13 (s, 1H), 8.57 (dd, J = 8.3, 1.8 Hz, 1H), 8.54 (dd, J = 4.5, 1.8 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 9.0, 2.8 Hz, 1H), 7.00-6.93 (m, 2H), 3.83 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 155.6, 152.5, 150.1, 148.4, 136.0, 132.2, 129.0, 119.7, 118.7, 114.7, 113.5, 56.5. HRMS (ESI) m / z calcd for C 12 H 12 N3O4 + ([M + H] + ) 262.0822, found 262.0823.

[0409] Step 2: Synthesis of 5-((3-aminopyridin-2-yl)amino)-2-methoxyphenol (4'e)

[0410]

[0411] Compound 4'e (605 mg, 91%) was obtained as a white solid using the method of Manufacturing Example 4-1.

[0412] TLC R f 0.30 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.44 (dd, J = 4.8, 1.7 Hz, 1H), 7.39 (s, 1H), 7.21 (d, J = 2.5 Hz, 1H), 6.95 (dd, J = 8.7, 2.6 Hz, 1H), 6.83 (dd, J = 7.6, 1.7 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.54 (dd, J = 7.5, 4.8 Hz, 1H), 4.98 (s, 2H), 3.70 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 146.8, 144.8, 142.3, 136.6, 134.9, 131.7, 119.6, 115.3, 113.5, 109.9, 108.0, 56.7. HRMS (ESI) m / z calcd for C 12 H 14 N3O2 + ([M + H] + ) 232.1081, found 232.1087.

[0413] Step 3: Synthesis of 4-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ea)

[0414]

[0415] Using the method of Manufacturing Example 5, compound 6ea (61 mg, 41%) was obtained as a white solid.

[0416] TLC R f 0.23 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.99 (s, 1H), 9.51 (s, 1H), 8.26 (dd, J = 4.8, 1.5 Hz, 1H), 8.13 (dd, J = 8.0, 1.5 Hz, 1H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.3, 2.5 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.13 (dd, J = 8.8, 2.4 Hz, 1H), 3.87 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 161.3, 161.1, 153.0, 149.1, 148.8, 147.7, 144.2, 132.5, 129.8, 128.7, 125.8, 119.6, 119.4, 115.7, 112.9, 107.5, 105.0, 103.7, 56.2. HRMS (ESI) m / z calcd for C 19 H 16 N3O4 + ([M + H] + ) 350.1135, found 350.1137.

[0417]

[0418] Example 26: Synthesis of 4-chloro-6-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6eb)

[0419]

[0420] Compound 6eb (27 mg, 16%) was obtained as a white solid using the method of Preparation Example 5.

[0421] TLC R f 0.25 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.80 (s, 1H), 9.51 (s, 1H), 8.29 (dd,J= 4.8, 1.5 Hz, 1H), 8.14 (dd,J= 8.0, 1.5 Hz, 1H), 7.36 (dd,J= 8.0, 4.7 Hz, 1H), 7.10 (d,J= 8.6 Hz, 1H), 7.01 (s, 1H), 6.90 (d,J= 2.5 Hz, 1H), 6.85 (dd,J= 8.5, 2.5 Hz, 1H), 6.52 (s, 1H), 3.86 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 158.5, 155.9, 151.4, 148.5, 148.4, 147.2, 144.1, 132.3, 129.4, 127.9, 125.8, 119.2, 118.7, 115.1, 112.4, 110.1, 106.2, 104.1, 55.9. HRMS (ESI)m / zcalcd for C 19 H 15 ClN3O4 + ([M + H] + ) 384.0746, found 384.0745.

[0422]

[0423] Example 27: Synthesis of 4-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6ec)

[0424]

[0425] Using the method of Preparation Example 5, compound 6ec (104 mg, 66%) was obtained as a white solid.

[0426] TLC R f 0.25 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.96 (s, 1H), 9.49 (s, 1H), 8.25 (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), 7.11 (d,J= 8.3 Hz, 1H), 6.87 (d,J= 2.4 Hz, 1H), 6.86-6.82 (m, 1H), 6.74 (d,J= 0.9 Hz, 1H), 6.39 (s, 1H), 3.87 (s, 3H), 1.79 (d,J= 0.8 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 159.3, 159.1, 153.2, 149.1, 148.9, 147.7, 144.1, 132.6, 130.4, 128.9, 125.7, 119.5, 119.4, 115.8, 115.2, 112.9, 104.6, 103.2, 56.4, 16.0. HRMS (ESI)m / zcalcd for C 20 H 18 N3O4 + ([M + H] + ) 364.1292, found 364.1294.

[0427]

[0428] Example 28: Synthesis of 4-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6fa)

[0429] Step 1: Synthesis of N-(4-(difluoromethoxy)phenyl)-3-nitropyridin-2-amine (3'f)

[0430]

[0431] Compound 3'f (490 mg, 55%) was obtained as a white solid using the method of Manufacturing Example 3-1.

[0432] TLC R f 0.50 (4:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.54 (dd,J= 8.3, 1.8 Hz, 1H), 8.49 (dd,J= 4.5, 1.8 Hz, 1H), 7.72-7.59 (m, 2H), 7.24-7.13 (m, 3H), 7.07-6.92 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 155.5, 150.0, 147.6 (t,J= 3.2 Hz), 136.1, 129.3, 125.1(2C), 119.7, 116.96 (t,J= 257.7 Hz), 115.0. HRMS (ESI)m / zcalcd for C12 H 10 F2N3O3 + ([M + H] + ) 282.0685, found 282.0686.

[0433] Step 2: Synthesis of N2-(4-(difluoromethoxy)phenyl)pyridine-2,3-diamine (4'f)

[0434]

[0435] Compound 4'f (407 mg, 99%) was obtained as a white solid using the method of Manufacturing Example 4-1.

[0436] TLC R f 0.35 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.68-7.61 (m, 2H), 7.48 (dd,J= 4.9, 1.7 Hz, 1H), 7.26 (s, 1H), 7.10-7.02 (m, 2H), 6.92-6.87 (m, 1H), 6.62 (dd,J= 7.6, 4.8 Hz, 1H), 5.06 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 144.4 (t,J= 3.1 Hz), 144.0, 140.3, 134.7, 132.30, 120.2, 120.0, 119.7, 117.26 (t,J= 257.3 Hz), 116.3. HRMS (ESI)m / zcalcd for C 12 H 12 F2N3O + ([M + H] + ) 252.0943, found 252.0949.

[0437] Step 3: Synthesis of 4-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6fa)

[0438]

[0439] Using the method of Preparation Example 5, compound 6fa (91 mg, 62%) was obtained as a white solid.

[0440] TLC R f 0.53 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.95 (s, 1H), 8.28 (dd,J= 4.8, 1.5 Hz, 1H), 8.15 (dd,J= 8.0, 1.5 Hz, 1H), 7.58-7.52 (m, 2H), 7.40-7.33 (m, 3H), 7.19 (s, 1H), 6.92 (d,J= 8.7 Hz, 1H), 6.33 (d,J= 2.3 Hz, 1H), 6.17 (dd,J= 8.7, 2.4 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 160.9, 159.6, 152.7, 150.9 (t,J= 3.3 Hz), 148.5, 143.8, 132.8, 132.5, 130.1, 129.7, 125.8, 119.4, 119.2, 116.3 (t,J= 258.1 Hz), 107.1, 105.3, 103.1. HRMS (ESI)m / zcalcd for C 19 H 14 F2N3O3 + ([M + H] + ) 370.1003, found 370.0999.

[0441]

[0442] Example 29: Synthesis of 4-chloro-6-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6fb)

[0443]

[0444] Compound 6fb (52 mg, 32%) was obtained as a white solid using the method of Preparation Example 5.

[0445] TLC R f 0.57 (1:1 hexanes / EtOAc).1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 10.78 (s, 1H), 8.28 (dd,J= 4.8, 1.5 Hz, 1H), 8.15 (dd,J= 8.1, 1.5 Hz, 1H), 7.58-7.50 (m, 2H), 7.40-7.34 (m, 3H), 7.19 (s, 1H), 7.07 (s, 1H), 6.44 (s, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 157.9, 156.7, 152.0, 151.2 (t,J= 3.4 Hz), 148.9, 144.5, 133.6, 132.8, 130.6, 129.9, 126.7, 119.8, 119.7, 116.66 (t,J= 258.4 Hz), 110.8, 107.4, 104.5. HRMS (ESI)m / zcalcd for C 19 H 13 Cl F2N3O3 + ([M + H] + ) 404.0608, found 404.0608.

[0446]

[0447] Example 30: Synthesis of 4-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6fc)

[0448]

[0449] Using the method of Preparation Example 5, compound 6fc (109 mg, 71%) was obtained as a white solid.

[0450] TLC R f 0.39 (1:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.92 (s, 1H), 8.27 (dd,J= 4.8, 1.5 Hz, 1H), 8.14 (dd,J= 7.9, 1.5 Hz, 1H), 7.60-7.50 (m, 2H), 7.43-7.32 (m, 3H), 7.20 (s, 1H), 6.74 (d,J= 0.9 Hz, 1H), 6.37 (s, 1H), 1.83 (d,J= 0.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 159.3, 158.1, 153.3, 151.29 (t,J= 3.3 Hz), 149.0, 144.1, 133.3, 133.2, 131.0, 130.27, 126.1, 120.1, 119.6, 116.69 (t,J= 258.7 Hz), 115.4, 114.1, 105.2, 103.1, 15.8. HRMS (ESI)m / zcalcd for C 20 H 16 F2N3O3 + ([M + H] + ) 384.1154, found 384.1158.

[0451]

[0452] Example 31: Synthesis of 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ga)

[0453] Step 1: Synthesis of N-(4-(tert-butyl)phenyl)-3-nitropyridin-2-amine (3'g)

[0454]

[0455] Using the method of Manufacturing Example 3-1, compound 3'g (758 mg, 89%) was obtained as a white solid.

[0456] TLC R f 0.50 (10:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.54 (dd,J= 8.3, 1.8 Hz, 1H), 8.50 (dd,J= 4.5, 1.8 Hz, 1H), 7.54 (d,J= 8.7 Hz, 2H), 7.39 (d,J= 8.7 Hz, 2H), 7.02-6.92 (m, 1H), 1.30 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 155.7, 150.2, 147.2, 136.1, 136.0, 129.0, 125.7, 123.2, 114.7, 34.6, 31.7. HRMS (ESI)m / zcalcd for C 15 H 18 -N -3 O2 + ([M + H] + ) 272.1394, found 272.1394.

[0457] Step 2: Synthesis of N2-(4-(tert-butyl)phenyl)pyridine-2,3-diamine (4'g)

[0458]

[0459] Using the method of Manufacturing Example 4-1, compound 4'g (606 mg, 93%) was obtained as a white solid.

[0460] TLC R f 0.25 (5:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.56-7.49 (m, 2H), 7.46 (dd,J= 4.8, 1.7 Hz, 1H), 7.28-7.21 (m, 2H), 6.87 (dd,J= 7.5, 1.7 Hz, 1H), 6.58 (dd,J= 7.5, 4.8 Hz, 1H), 5.02 (s, 2H), 1.27 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 144.5, 142.7, 140.1, 134.8, 132.0, 125.4, 119.8, 118.7, 115.8, 34.2, 31.8. HRMS (ESI)m / zcalcd for C 15 H 20 N3 + ([M + H] + ) 242.1652, found 242.1653.

[0461] Step 3: Synthesis of 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ga)

[0462]

[0463] Using the method of Manufacturing Example 5, compound 6ga (141 mg, 95%) was obtained as a white solid.

[0464] TLC R f 0.40 (3:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.94 (s, 1H), 8.27 (dd,J= 4.7, 1.5 Hz, 1H), 8.15 (dd,J= 8.0, 1.5 Hz, 1H), 7.62-7.56 (m, 2H), 7.42-7.38 (m, 2H), 7.38-7.33 (m, 1H), 6.84 (d,J= 8.7 Hz, 1H), 6.34 (d,J= 2.4 Hz, 1H), 6.09 (dd,J= 8.8, 2.4 Hz, 1H), 1.36 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 160.1 152.6, 151.5, 148.6, 143.7, 133.1, 132.5, 129.7, 127.5, 126.4, 125.6, 119.2, 106.9, 105.1, 103.2, 34.6, 31.1. HRMS (ESI)m / zcalcd for C 22 H 22 N3O2 +([M + H] + ) 360.1707, found 360.1710.

[0465]

[0466] Example 32: Synthesis of 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol (6gb)

[0467]

[0468] Using the method of Preparation Example 5, compound 6gb (32 mg, 26%) was obtained as a white solid.

[0469] TLC R f 0.33 (3:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 10.75 (s, 1H), 8.30 (dd,J= 4.7, 1.5 Hz, 1H), 8.17 (dd,J= 8.0, 1.5 Hz, 1H), 7.65-7.58 (m, 2H), 7.45-7.40 (m, 2H), 7.38 (dd,J= 8.0, 4.8 Hz, 1H), 6.85 (s, 1H), 6.52 (s, 1H), 1.37 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 158.8, 156.4, 152.4, 151.8, 148.9, 144.6, 133.2, 132.9, 130.0, 128.0, 126.9, 126.4, 119.86 110.6, 106.7, 104.6, 35.1, 31.6. HRMS (ESI)m / zcalcd for C 22 H 21 ClN3O2 + ([M + H] + ) 394.1317, found 394.1320.

[0470]

[0471] Example 33: Synthesis of 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6 gc)

[0472]

[0473] Using the method of Manufacturing Example 5, compound 6gc (152 mg, 98%) was obtained as a white solid.

[0474] TLC R f 0.50 (3:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.96 (s, 1H), 8.26 (dd,J= 4.8, 1.5 Hz, 1H), 8.13 (dd,J= 8.0, 1.5 Hz, 1H), 7.67-7.59 (m, 2H), 7.45-7.40 (m, 2H), 7.36 (dd,J= 8.0, 4.8 Hz, 1H), 6.52 (d,J= 1.0 Hz, 1H), 6.39 (s, 1H), 1.72 (d,J= 0.8 Hz, 3H), 1.38 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 158.9, 158.6, 152.7, 152.0, 148.5, 143.7, 133.2, 132.2, 129.9, 127.8, 126.4, 125.3, 119.2, 114.6, 103.9, 102.7, 34.6, 31.1, 15.2. HRMS (ESI)m / zcalcd for C 23 H 24 N3O2 + ([M + H] + ) 374.1863, found 374.1865.

[0475]

[0476] Example 34: Synthesis of N-(4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide (6ha)

[0477] Step 1: Synthesis of N-(4-((3-nitropyridin-2-yl)amino)phenyl)acetamide (3'h)

[0478]

[0479] Compound 3'h (801 mg, 93%) was obtained as a white solid using the method of Manufacturing Example 3-2.

[0480] TLC R f 0.23 (1:2 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.93 (s, 1H), 8.53 (dd,J= 8.3, 1.8 Hz, 1H), 8.49 (dd,J= 4.5, 1.8 Hz, 1H), 7.62-7.50 (m, 4H), 6.96 (dd,J= 8.3, 4.5 Hz, 1H), 2.05 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 168.5, 155.7, 150.2, 136.3, 136.0, 133.8, 128.9, 123.9, 119.7, 114.6, 24.2. HRMS (ESI)m / zcalcd for C 13 H 13 N4O3 + ([M + H] + ) 273.0982, found 273.0983.

[0481] Step 2: Synthesis of N-(4-((3-aminopyridin-2-yl)amino)phenyl)acetamide (4'h)

[0482]

[0483] Compound 4'h (319 mg, 46%) was obtained as a white solid using the method of Manufacturing Example 4-1.

[0484] TLC R f 0.24 (EtOAc only). 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.62 (s, 1H), 7.58-7.51 (m, 2H), 7.46 (dd,J= 4.8, 1.6 Hz, 1H), 7.44-7.36 (m, 2H), 6.86 (dd,J= 7.5, 1.7 Hz, 1H), 6.57 (dd,J= 7.6, 4.9 Hz, 1H), 5.01 (s, 2H), 2.00 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 168.0, 144.4, 138.2, 134.8, 132.6, 132.0, 120.0, 119.8, 119.0, 115.7, 24.3. HRMS (ESI)m / zcalcd for C 13 H 15 N4O + ([M + H] + ) 243.1240, found 243.1244.

[0485] Step 3: Synthesis of N-(4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide (6ha)

[0486]

[0487] Using the method of Manufacturing Example 5, compound 6ha (137 mg, 93%) was obtained as a white solid.

[0488] TLC R f 0.48 (1:4 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.22 (s, 1H), 9.97 (s, 1H), 8.27 (dd,J= 4.8, 1.5 Hz, 1H), 8.14 (dd,J= 8.0, 1.5 Hz, 1H), 7.82-7.71 (m, 2H), 7.42-7.38 (m, 2H), 7.36 (dd,J= 8.0, 4.8 Hz, 1H), 6.87 (d,J= 8.7 Hz, 1H), 6.34 (d,J= 2.4 Hz, 1H), 6.13 (dd,J= 8.7, 2.4 Hz, 1H), 2.11 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 169.1, 161.3, 160.7, 153.11, 149.1, 144.3, 140.3, 132.8, 130.6, 130.1, 129.0, 126.0, 120.1, 119.7, 107.5, 105.3, 103.6, 24.6. HRMS (ESI)m / zcalcd for C 20 H 17 N4O3 + ([M + H] + ) 361.1295, found 361.1297.

[0489]

[0490] Example 35: Synthesis of N-(4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide (6hb)

[0491]

[0492] Compound 6hb (89 mg, 55%) was obtained as a white solid using the method of Manufacturing Example 5.

[0493] TLC R f 0.45 (EtOAc only). 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.78 (s, 1H), 10.21 (s, 1H), 8.29 (dd,J= 4.7, 1.5 Hz, 1H), 8.15 (dd,J= 8.0, 1.5 Hz, 1H), 7.80-7.71 (m, 2H), 7.43-7.39 (m, 2H), 7.37 (dd,J= 8.0, 4.8 Hz, 1H), 7.02 (s, 1H), 6.49 (s, 1H), 2.10 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 168.6, 158.1, 155.9, 151.4, 148.5, 144.1, 139.8, 132.6, 129.8, 129.7, 128.3, 126.0, 119.5, 119.2, 110.1, 106.6, 104.1, 24.1. HRMS (ESI)m / zcalcd for C 20 H 16 ClN4O3 + ([M + H] + ) 395.0905, found 395.0908.

[0494]

[0495] Example 36: Synthesis of N-(4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide (6hc)

[0496]

[0497] Using the method of Manufacturing Example 5, compound 6hc (139 mg, 90%) was obtained as a white solid.

[0498] TLC R f 0.32 (1:4 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.22 (s, 1H), 9.97 (s, 1H), 8.26 (dd,J= 4.7, 1.5 Hz, 1H), 8.12 (dd,J= 8.0, 1.5 Hz, 1H), 7.77 (d,J= 8.6 Hz, 2H), 7.42-7.37 (m, 2H), 7.35 (dd,J= 8.0, 4.8 Hz, 1H), 6.73 (d,J= 1.0 Hz, 1H), 6.38 (s, 1H), 2.11 (s, 3H), 1.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 168.6, 158.8, 158.2, 152.8, 148.6, 143.7, 139.8, 132.4, 130.3, 130.2, 128.5, 125.4, 119.6, 119.1, 114.8, 104.4, 102.6, 24.1, 15.5. HRMS (ESI)m / zcalcd for C 21 H 19 N4O3 + ([M + H] + ) 375.1452, found 375.1454.

[0499]

[0500] Example 37: Synthesis of 4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide (6ia)

[0501] Step 1: Synthesis of 4-((3-nitropyridin-2-yl)amino)benzamide (3'i)

[0502]

[0503] Compound 3'i (556 mg, 68%) was obtained as a white solid using the method of Manufacturing Example 3-2.

[0504] TLC R f 0.20 (1:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.59 (s, 1H), 8.58-8.55 (m, 1H), 7.94-7.85 (m, 2H), 7.84-7.74 (m, 2H), 7.28 (s, 2H), 7.10-7.05 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.8, 155.2, 149.3, 141.7, 136.1, 130.0, 129.7, 128.6, 121.6, 115.7. HRMS (ESI)m / zcalcd for C 12 H 11 N4O3 + ([M + H] + ) 259.0826, found 259.0825.

[0505] Step 2: Synthesis of 4-((3-aminopyridin-2-yl)amino)benzamide (4'i)

[0506]

[0507] Compound 4'i (243 mg, 68%) was obtained as a white solid using the method of Manufacturing Example 4-1.

[0508] TLC R f 0.20 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.81-7.74 (m, 2H), 7.71 (s, 1H), 7.69-7.62 (m, 2H), 7.55 (dd,J= 4.8, 1.7 Hz, 1H), 7.05 (s, 1H), 6.95 (dd,J= 7.7, 1.6 Hz, 1H), 6.70 (dd,J= 7.6, 4.8 Hz, 1H), 5.13 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 168.3, 145.6, 143.2, 134.8, 133.1, 128.7, 125.5, 120.7, 117.2, 116.9. HRMS (ESI)m / zcalcd for C 12 H 13N4O + ([M + H] + ) 229.1084, found 229.1084.

[0509] Step 3: Synthesis of 4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide (6ia)

[0510]

[0511] Compound 6ia (148 mg, 98%) was obtained as a white solid using the method of Preparation Example 5.

[0512] TLC R f 0.51 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.97 (s, 1H), 8.29 (dd,J= 4.8, 1.5 Hz, 1H), 8.17 (dd,J= 8.0, 1.5 Hz, 1H), 8.12 (s, 1H), 8.07-7.97 (m, 2H), 7.60-7.54 (m, 2H), 7.53 (d,J= 4.6 Hz, 1H), 7.39 (dd,J= 8.0, 4.8 Hz, 1H), 6.96 (d,J= 8.6 Hz, 1H), 6.32 (d,J= 2.4 Hz, 1H), 6.19 (dd,J= 8.7, 2.4 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.1 160.8 159.2, 152.6, 148.3, 143.8, 138.2, 134.2, 133.1, 130.4, 128.5, 127.4, 126.0, 119.3, 107.1, 105.6, 103.0. HRMS (ESI)m / zcalcd for C 19 H 15 N4O3 + ([M + H] + ) 347.1139, found 347.1140.

[0513]

[0514] Example 38: Synthesis of 4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide (6ib)

[0515]

[0516] Compound 6ib (34 mg, 20%) was obtained as a white solid using the method of Preparation Example 5.

[0517] TLC R f 0.52 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 10.70 (s, 1H), 8.32 (dd,J= 4.8, 1.5 Hz, 1H), 8.18 (dd,J= 8.0, 1.5 Hz, 1H), 8.10 (s, 1H), 8.06-7.95 (m, 2H), 7.58-7.53 (m, 2H), 7.51 (s, 1H), 7.40 (dd,J= 8.0, 4.8 Hz, 1H), 7.18 (s, 1H), 6.48 (s, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.0, 156.9, 155.9, 151.4, 148.2, 144.1, 137.9, 134.0, 133.5, 130.6, 128.4, 127.1, 126.5, 119.3, 110.2, 107.7, 103.8. HRMS (ESI)m / zcalcd for C 19 H 14 ClN4O3 + ([M + H] + ) 381.0749, found 381.0749.

[0518]

[0519] Example 39: Synthesis of 4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide (6ic)

[0520]

[0521] Using the method of Preparation Example 5, compound 6ic (42 mg, 26%) was obtained as a white solid.

[0522] TLC R f 0.42 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.89 (s, 1H), 8.29 (dd,J= 4.8, 1.5 Hz, 1H), 8.15 (dd,J= 8.0, 1.5 Hz, 1H), 8.11 (s, 1H), 8.06-7.99 (m, 2H), 7.58-7.52 (m, 2H), 7.52 (s, 1H), 7.38 (dd,J= 8.0, 4.8 Hz, 1H), 6.84 (d,J= 1.0 Hz, 1H), 6.36 (s, 1H), 1.86 (d,J= 0.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 167.7, 158.7, 157.0, 152.8, 148.3, 143.7, 138.3, 134.1, 133.2, 130.9, 128.4, 127.4, 125.9, 119.2, 115.0, 105.2, 102.5, 15.3. HRMS (ESI)m / zcalcd for C 20 H 17 N4O3 + ([M + H] + ) 359.1150, found 359.1150.

[0523]

[0524] Example 40: Synthesis of tert-butyl (4-(4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate (6ja)

[0525] Step 1: Synthesis of [4-(4-amino-phenoxy)-phenyl]-(3-nitro-pyridin-2-yl)-amine (3'j')

[0526]

[0527] Compound 3'j' (525 mg, 52%) was obtained as a white solid using the method of Manufacturing Example 3-2.

[0528] TLC R f 0.27 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.52 (dd,J= 8.3, 1.8 Hz, 1H), 8.47 (dd,J= 4.5, 1.8 Hz, 1H), 7.51 (d,J= 9.0 Hz, 2H), 6.94 (dd,J= 8.3, 4.5 Hz, 1H), 6.86 (d,J= 8.9 Hz, 2H), 6.78 (d,J= 8.7 Hz, 2H), 6.59 (d,J= 8.8 Hz, 2H), 4.97 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 156.2, 155.7, 150.4, 146.3, 145.9, 136.0, 132.8, 128.8, 125.4, 121.2, 117.1, 115.3, 114.5. HRMS (ESI)m / zcalcd for C 17 H 15 N4O3 + ([M + H] + ) 323.1139, found 323.1138.

[0529] Step 2: Synthesis of tert-butyl (4-(4-((3-nitropyridin-2-yl)amino)phenoxy)phenyl)carbamate (3'j)

[0530]

[0531] In a 50 mL oven-dried round-bottom flask with a sidearm, N-(4-(4-aminophenoxy)phenyl)-3-nitropyridin-2-amine (3'j') (525 mg, 1.63 mmol) was suspended in anhydrous DMF (3.0 mL). Then, Et3N (0.68 mL, 4.88 mmol) and Boc2O (0.45 mL, 1.95 mmol) were added dropwise. The reaction mixture was stirred at room temperature overnight. 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 (5:1 hexanes / EtOAc) to give compound 3'j (340 mg, 50%) as a red solid.

[0532] TLC R f 0.60 (4:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.34 (s, 1H), 8.54 (dd,J= 8.3, 1.8 Hz, 1H), 8.49 (dd,J= 4.6, 1.8 Hz, 1H), 7.63-7.55 (m, 2H), 7.47 (d,J= 8.9 Hz, 2H), 7.01-6.90 (m, 5H), 1.48 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 155.6, 154.6, 153.3, 151.6, 150.2, 136.0, 135.9, 133.8, 129.0, 125.4, 120.2, 119.8, 118.3, 114.7, 79.4, 28.6. HRMS (ESI)m / zcalcd for C 22 H 23 N4O5 + ([M + H] + ) 423.1663, found 423.1662.

[0533] Step 3: Synthesis of tert-butyl (4-(4-((3-aminopyridin-2-yl)amino)phenoxy)phenyl)carbamate (4'j)

[0534]

[0535] Compound 4'j (543 mg, 75%) was obtained as a pink solid using the method of Manufacturing Example 4-2.

[0536] TLC R f 0.20 (3:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.70 (s, 1H), 7.66-7.56 (m, 2H), 7.47 (dd,J= 4.8, 1.7 Hz, 1H), 7.42 (d,J= 8.6 Hz, 2H), 6.89 (dq,J= 7.7, 1.3 Hz, 5H), 6.60 (dd,J= 7.6, 4.8 Hz, 1H), 5.04 (s, 2H), 1.47 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 153.4, 152.9, 150.6, 144.3, 138.4, 135.1, 134.8, 132.0, 120.2, 120.2, 119.9, 119.2, 118.6, 115.9, 79.3, 28.6. HRMS (ESI)m / zcalcd for C 22 H 25 N4O3 + ([M + H] + ) 393.1921, found 393.1921.

[0537] Step 4: Synthesis of tert-butyl (4-(4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate (6ja)

[0538]

[0539] Using the method of Preparation Example 5, compound 6ja (113 mg, 87%) was obtained as a white solid.

[0540] TLC R f 0.39 (2:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.02 (s, 1H), 9.41 (s, 1H), 8.28 (dd,J= 4.8, 1.5 Hz, 1H), 8.14 (dd,J= 8.0, 1.5 Hz, 1H), 7.53 (d,J= 8.8 Hz, 2H), 7.48-7.40 (m, 2H), 7.36 (dd,J= 8.0, 4.8 Hz, 1H), 7.14-7.04 (m, 4H), 6.90 (d,J= 8.8 Hz, 1H), 6.34 (d,J= 2.4 Hz, 1H), 6.17 (dd,J= 8.8, 2.4 Hz, 1H), 1.48 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 160.1, 158.1, 152.9, 152.7, 150.0, 148.6, 143.8, 136.2, 132.4, 130.0, 129.8, 129.65, 125.60, 120.3, 119.8, 119.2, 117.9, 107.1, 105.0, 103.1, 79.0, 28.1. HRMS (ESI)m / zcalcd for C 29 H 27 N4O5 + ([M + H] + ) 511.1976, found 511.1977.

[0541]

[0542] Example 41: Synthesis of tert-butyl (4-(4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate (6jb)

[0543]

[0544] Using the method of Preparation Example 5, compound 6jb (78 mg, 56%) was obtained as a white solid.

[0545] TLC R f 0.41 (1:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 10.76 (s, 1H), 9.39 (s, 1H), 8.31 (dd,J= 4.7, 1.5 Hz, 1H), 8.17 (dd,J= 8.0, 1.5 Hz, 1H), 7.51 (d,J= 8.7 Hz, 2H), 7.49-7.43 (m, 2H), 7.38 (dd,J= 8.0, 4.8 Hz, 1H), 7.16-7.10 (m, 2H), 7.08-7.01 (m, 2H), 7.00 (s, 1H), 6.52 (d,J= 4.2 Hz, 1H), 1.48 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 158.1, 158.0, 155.9, 152.9, 151.5, 150.5, 148.4, 144.1, 136.0, 132.6, 130.0, 129.7, 129.6, 126.0, 119.8(2C), 119.3, 118.5, 110.2, 106.5, 104.1, 79.0, 28.1. HRMS (ESI)m / zcalcd for C 29 H 26 ClN4O5 + ([M + H] + ) 545.1586, found 545.1588.

[0546]

[0547] Example 42: Synthesis of tert-butyl (4-(4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate (6jc)

[0548]

[0549] Using the method of Preparation Example 5, compound 6jc (65 mg, 49%) was obtained as a white solid.

[0550] TLC R f 0.38 (2:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.90 (s, 1H), 9.34 (s, 1H), 8.22 (dd,J= 4.8, 1.5 Hz, 1H), 8.08 (dd,J= 8.0, 1.5 Hz, 1H), 7.47 (d,J= 8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.31 (dd,J= 8.0, 4.8 Hz, 1H), 7.03 (m, 2H), 7.04-6.93 (m, 2H), 6.67 (d,J= 1.0 Hz, 1H), 6.34 (s, 1H), 1.79 (d,J= 0.8 Hz, 3H), 1.43 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 158.8, 158.2, 158.0, 152.8, 152.8, 150.3, 148.6, 143.7, 136.0, 132.5, 130.3, 130.2, 129.8, 125.4, 119.9, 119.8, 119.2, 118.3, 114.9, 104.3, 102.7, 79.0, 28.1, 15.4. HRMS (ESI)m / zcalcd for C 30 H 29 N4O5 + ([M + H] + ) 525.2132, found 525.2133.

[0551]

[0552] Example 43: Synthesis of 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ka)

[0553]

[0554] Compound 6ja (50 mg, 98 μmol) was suspended in anhydrous CH2Cl2 (0.5 mL) in a 5 mL oven-dried round-bottom flask with a side arm. TFA (0.15 mL, 1.96 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3 X 10 mL), and the combined organic layers were dried over anhydrous MgSO4 and concentrated using a rotary evaporator. The resulting residue was then purified by column chromatography (2:1 hexanes / EtOAc) to give compound 6ka (34 mg, 84%) as a white solid.

[0555] TLC R f 0.20 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 9.99 (s, 1H), 8.27 (dd,J= 4.8, 1.5 Hz, 1H), 8.14 (dd,J= 8.0, 1.5 Hz, 1H), 7.44-7.38 (m, 2H), 7.36 (dd,J= 8.0, 4.8 Hz, 1H), 7.07-6.97 (m, 2H), 6.94-6.81 (m, 3H), 6.68-6.61 (m, 2H), 6.35 (d,J= 2.4 Hz, 1H), 6.16 (dd,J= 8.8, 2.4 Hz, 1H), 5.05 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 160.2, 159.4, 152.7, 148.7, 145.9, 144.9, 143.8, 132.3, 129.6, 129.5, 129.2, 125.5, 121.3, 119.2, 117.0, 115.0, 107.0, 104.9, 103.2. HRMS (ESI)m / zcalcd for C 24 H 19 N4O3 + ([M + H] +) 411.1452, found 411.1453.

[0556]

[0557] Example 44: Synthesis of 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol (6 kb)

[0558]

[0559] Compound 6jb (50 mg, 98 μmol) was suspended in anhydrous CH2Cl2 (0.5 mL) in a 5 mL oven-dried round-bottom flask with a side arm. TFA (0.15 mL, 1.96 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3 X 10 mL), and the combined organic layers were dried over anhydrous MgSO4 and concentrated using a rotary evaporator. The resulting residue was then purified by column chromatography (2:1 hexanes / EtOAc) to give compound 6kb (37 mg, 90%) as a white solid.

[0560] TLC R f 0.19 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 10.79 (s, 1H), 8.30 (dd,J= 4.8, 1.5 Hz, 1H), 8.16 (dd,J= 8.0, 1.5 Hz, 1H), 7.47-7.39 (m, 2H), 7.37 (dd,J= 8.0, 4.8 Hz, 1H), 7.09-7.00 (m, 2H), 6.97 (s, 1H), 6.87-6.80 (m, 2H), 6.66-6.57 (m, 2H), 6.51 (s, 1H), 5.03 (d,J=8.6 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 159.3, 158.2, 155.9, 151.5, 148.5, 145.8, 145.3, 144.1, 132.5, 129.6, 129.5, 129.0, 126.0, 120.9, 119.3, 117.4, 115.0, 110.2, 106.4, 104.1. HRMS (ESI)m / zcalcd for C 24 H 18 ClN4O3 + ([M + H] + ) 445.1062, found 445.1064.

[0561]

[0562] Example 45: Synthesis of 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6kc)

[0563]

[0564] Compound 6jc (50 mg, 98 μmol) was suspended in anhydrous CH2Cl2 (0.5 mL) in a 5 mL oven-dried round-bottom flask with a side arm. TFA (0.15 mL, 1.96 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3 X 10 mL), and the combined organic layers were dried over anhydrous MgSO4 and concentrated using a rotary evaporator. The resulting residue was then purified by column chromatography (2:1 hexanes / EtOAc) to give compound 6kc (31 mg, 78%) as a white solid.

[0565] TLC R f 0.20 (2:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.98 (s, 1H), 8.27 (dd,J= 4.8, 1.5 Hz, 1H), 8.13 (dd,J= 7.9, 1.5 Hz, 1H), 7.46-7.39 (m, 2H), 7.36 (dd,J= 8.0, 4.8 Hz, 1H), 7.09-7.02 (m, 2H), 6.91-6.81 (m, 2H), 6.70 (d,J= 1.0 Hz, 1H), 6.67-6.59 (m, 2H), 6.40 (s, 1H), 5.04 (d,J=8.7 Hz, 2H), 1.83 (d,J= 0.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.4, 158.8, 158.3, 152.8, 148.6, 145.7, 145.3, 143.7, 132.4, 130.0, 129.6, 129.5, 125.4, 121.0, 119.1, 117.3, 115.0, 114.8, 104.2, 102.7, 15.4. HRMS (ESI)m / zcalcd for C 25 H 21 N4O3 + ([M + H] + ) 425.1608, found 425.1609.

[0566]

[0567] Example 46: Synthesis of 4-[3-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6la)

[0568] Step 1: Synthesis of N,N-dimethyl-N'-(3-nitro-pyridin-2-yl)-benzene-1,4-diamine (3'l)

[0569]

[0570] Using the method of Manufacturing Example 3-2, compound 3'l (675 mg, 83%) was obtained as a white solid.

[0571] TLC R f 0.23 (6:1 hexanes / EtOAc).1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.49 (dd,J= 8.3, 1.8 Hz, 1H), 8.44 (dd,J= 4.4, 1.8 Hz, 1H), 7.43-7.36 (m, 2H), 6.88 (dd,J= 8.3, 4.4 Hz, 1H), 6.78-6.69 (m, 2H), 2.89 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 155.8, 151.2, 148.6, 135.5, 135.4, 129.0, 126.9, 124.9, 112.9, 40.82. HRMS (ESI)m / zcalcd for C 13 H 15 N4O2 + ([M + H] + ) 259.1190, found 259.1188.

[0572] Step 2: Synthesis of N2-(4-dimethylamino-phenyl)-pyridine-2,3-diamine (4'l)

[0573]

[0574] Using the method of Manufacturing Example 4-1, compound 4'l (417 mg, 72%) was obtained as a white solid.

[0575] TLC R f 0.25 (50:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 7.48-7.42 (m, 2H), 7.41 (dd,J= 4.8, 1.7 Hz, 1H), 7.38 (s, 1H), 6.81 (dd,J= 7.5, 1.7 Hz, 1H), 6.76-6.65 (m, 2H), 6.50 (dd,J= 7.5, 4.9 Hz, 1H), 4.94 (s, 2H), 2.82 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 150.7, 147.06, 139.0, 134.7, 131.3, 123.2, 121.8, 115.9, 114.1, 41.4. HRMS (ESI)m / zcalcd for C 13 H 17 N4 + ([M + H] + ) 229.1448, found 229.1448.

[0576] Step 3: Synthesis of 4-[3-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6la)

[0577]

[0578] Using the method of Preparation Example 5, compound 6la (128 mg, 85%) was obtained as a white solid.

[0579] TLC R f 0.40 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 10.05 (s, 1H), 8.26 (dd,J= 4.8, 1.5 Hz, 1H), 8.13 (dd,J= 7.9, 1.5 Hz, 1H), 7.35 (dd,J= 8.0, 4.8 Hz, 1H), 7.30-7.19 (m, 2H), 6.94 (d,J= 8.8 Hz, 1H), 6.92-6.81 (m, 2H), 6.36 (d,J= 2.4 Hz, 1H), 6.10 (dd,J= 8.8, 2.4 Hz, 1H), 3.02 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 161.3, 161.3, 153.3, 150.9, 149.4, 144.2, 132.4, 129.7, 129.1, 125.7, 124.1, 119.5, 112.9, 107.4, 105.1, 103.7, 40.5. HRMS (ESI)m / zcalcd for C 20 H 19 N4O2 +([M + H] + ) 347.1503, found 347.1506.

[0580]

[0581] Example 47: Synthesis of 4-chloro-6-[3-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6lb)

[0582]

[0583] Using the method of Preparation Example 5, compound 6lb (57 mg, 34%) was obtained as a yellow solid.

[0584] TLC R f 0.25 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.79 (s, 1H), 8.28 (dd,J= 4.8, 1.4 Hz, 1H), 8.14 (dd,J= 8.0, 1.5 Hz, 1H), 7.36 (dd,J= 8.0, 4.8 Hz, 1H), 7.32-7.20 (m, 2H), 7.03 (s, 1H), 6.92-6.82 (m, 2H), 6.53 (s, 1H), 3.00 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 159.2, 156.3, 152.1, 151.1, 149.2, 144.6, 132.6, 129.7, 129.0, 126.2, 123.8, 119.6, 113.0, 110.6, 106.7, 104.6, 40.6. HRMS (ESI)m / zcalcd for C 20 H 18 ClN4O2 + ([M + H] + ) 381.1113, found 381.1116.

[0585]

[0586] Example 48: Synthesis of 4-[3-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol (6lc)

[0587]

[0588] Using the method of Preparation Example 5, compound 6lc (44 mg, 28%) was obtained as a white solid.

[0589] TLC R f 0.35 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.95 (s, 1H), 8.25 (dd,J= 4.7, 1.5 Hz, 1H), 8.11 (dd,J= 8.0, 1.5 Hz, 1H), 7.34 (dd,J= 8.0, 4.8 Hz, 1H), 7.25 (d,J= 9.0 Hz, 2H), 6.89 (d,J= 9.0 Hz, 2H), 6.75 (d,J= 0.9 Hz, 1H), 6.40 (s, 1H), 3.01 (s, 6H), 1.77 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.2, 159.2, 153.5, 151.2, 149.4, 144.1, 132.5, 130.4, 129.1, 125.6, 124.3, 119.5, 115.1, 113.0, 104.6, 103.1, 40.6, 16.0. HRMS (ESI)m / zcalcd for C 21 H 21 N4O2 + ([M + H] + ) 361.1659, found 361.1661.

[0590]

[0591] Example 49: Synthesis of 4-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ma)

[0592] Step 1: Synthesis of 4-((3-nitropyridin-2-yl)amino)phenol (3'm)

[0593]

[0594] Using the method of Manufacturing Example 3-2, compound 3'm (521 mg, 71%) was obtained as a white solid.

[0595] TLC R f 0.25 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.36 (s, 1H), 8.50 (dd,J= 8.3, 1.8 Hz, 1H), 8.44 (dd,J= 4.5, 1.8 Hz, 1H), 7.46-7.23 (m, 2H), 6.89 (dd,J= 8.3, 4.5 Hz, 1H), 6.80-6.71 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 155.9, 155.0, 150.7, 136.0, 130.0, 128.4, 125.7, 115.6, 114.1. HRMS (ESI)m / zcalcd for C 11 H 10 N3O3 + ([M + H] + ) 232.0717, found 232.0719.

[0596] Step 2: Synthesis of 4-((3-aminopyridin-2-yl)amino)phenol (4'm)

[0597]

[0598] Compound 4'm (862 mg, 86%) was obtained as a white solid using the method of Manufacturing Example 4-1.

[0599] TLC R f 0.40 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.43-7.36 (m, 3H), 6.82 (dd,J= 7.5, 1.7 Hz, 1H), 6.72-6.62 (m, 2H), 6.51 (dd,J= 7.5, 4.9 Hz, 1H), 4.95 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 151.9, 145.3, 135.0, 134.3, 131.4, 121.3, 119.5, 115.4, 115.0. HRMS (ESI)m / zcalcd for C 11 H 12 N3O + ([M + H] + ) 202.0975, found 202.0977.

[0600] Step 3: Synthesis of 4-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6ma)

[0601]

[0602] Using the method of Preparation Example 5, compound 6ma (46 mg, 29%) was obtained as a white solid.

[0603] TLC R f 0.53 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.00 (s, 2H), 8.27 (d,J= 4.9 Hz, 1H), 8.14 (d,J= 8.1 Hz, 1H), 7.46-7.12 (m, 3H), 7.15-6.69 (m, 3H), 6.36 (d,J= 2.3 Hz, 1H), 6.12 (dd,J= 8.8, 2.4 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 161.3, 161.2, 158.5, 153.2, 149.2, 144.2, 132.4, 129.8, 129.8, 127.2, 125.7, 119.6, 116.7, 107.4, 105.1, 103.8. HRMS (ESI)m / zcalcd for C 18 H 14 N3O3 + ([M + H] + ) 320.1030, found 320.1032.

[0604]

[0605] Example 50: Synthesis of 4-chloro-6-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6mb)

[0606]

[0607] Using the method of Preparation Example 5, compound 6mb (138 mg, 79%) was obtained as a white solid.

[0608] TLC R f 0.25 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.80 (s, 1H), 9.96 (s, 1H), 8.29 (dd,J= 4.8, 1.5 Hz, 1H), 8.15 (dd,J= 8.0, 1.5 Hz, 1H), 7.36 (dd,J= 8.0, 4.7 Hz, 1H), 7.33-7.24 (m, 2H), 7.03-6.89 (m, 3H), 6.52 (s, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 159.2, 158.6, 156.4, 152.0, 149.1, 144.6, 132.6, 129.7, 129.7, 126.8, 126.2, 119.7, 116.6, 110.6, 106.5, 104.7. HRMS (ESI)m / zcalcd for C 18 H 13 ClN3O3 + ([M + H] + ) 354.0640, found 354.0641.

[0609]

[0610] Example 51: Synthesis of 4-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol (6mc)

[0611]

[0612] Using the method of Manufacturing Example 5, compound 6mc (133 mg, 80%) was obtained as a white solid.

[0613] TLC R f 0.33 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 9.97 (s, 2H), 8.25 (dd,J= 4.7, 1.5 Hz, 1H), 8.11 (dd,J= 8.0, 1.5 Hz, 1H), 7.34 (dd,J= 8.0, 4.8 Hz, 1H), 7.30-7.20 (m, 2H), 7.00-6.90 (m, 2H), 6.69 (d,J= 1.0 Hz, 1H), 6.39 (s, 1H), 1.77 (d,J= 0.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.3, 159.2, 158.5, 153.4, 149.2, 144.1, 132.6, 130.3, 129.9, 127.3, 125.6, 119.5, 116.6, 115.1, 104.5, 103.2, 16.0. HRMS (ESI)m / zcalcd for C 19 H 16 N3O3 + ([M + H] + ) 334.1186, found 334.1187.

[0614]

[0615] Example 52: Synthesis of 4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6na)

[0616] Step 1: Synthesis of N-(4-(4-methylpiperazin-1-yl)phenyl)-3-nitropyridin-2-amine (3'n)

[0617]

[0618] Compound 3'n (862 mg, 86%) was obtained as a white solid using the method of Manufacturing Example 3-2.

[0619] TLC R f 0.45 (10:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.51 (dd,J= 8.3, 1.8 Hz, 1H), 8.47 (dd,J= 4.5, 1.8 Hz, 1H), 7.50-7.40 (m, 2H), 6.98-6.93 (m, 2H), 6.91 (dd,J= 8.3, 4.5 Hz, 1H), 3.13 (dd,J= 6.3, 3.8 Hz, 4H), 2.46 (t,J= 5.0 Hz, 4H), 2.23 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 155.9, 150.5, 148.7, 136.0, 130.1, 128.5, 124.8, 115.9, 114.2, 55.1, 48.8, 46.2. HRMS (ESI)m / zcalcd for C 16 H 20 N5O2 + ([M + H] + ) 314.1612, found 314.1612.

[0620] Step 2: Synthesis of N2-(4-(4-methylpiperazin-1-yl)phenyl)pyridine-2,3-diamine (4'n)

[0621]

[0622] Compound 4'n (588 mg, 96%) was obtained as a white solid using the method of Manufacturing Example 4-2.

[0623] TLC R f 0.38 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (dd,J= 9.1, 6.9 Hz, 3H), 7.43 (dd,J= 4.9, 1.7 Hz, 1H), 6.90-6.83 (m, 2H), 6.82 (d,J= 1.7 Hz, 1H), 6.53 (dd,J= 7.5, 4.8 Hz, 1H), 4.97 (s, 2H), 3.10-3.00 (m, 4H), 2.46 (t,J= 4.9 Hz, 4H), 2.22 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 145.7, 144.9, 135.1, 134.8, 131.6, 120.3, 119.5, 116.6, 115.1, 55.2, 49.6, 46.1. HRMS (ESI)m / zcalcd for C 16 H 22 N5 + ([M + H] + ) 284.1870, found 284.1871.

[0624] Step 3: Synthesis of 4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6na)

[0625]

[0626] Using the method of Preparation Example 5, compound 6na (46 mg, 26%) was obtained as a white solid.

[0627] TLC R f 0.45 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.98 (s, 1H), 8.26 (dd,J= 4.7, 1.5 Hz, 1H), 8.13 (dd,J= 8.0, 1.5 Hz, 1H), 7.35 (dd,J= 8.0, 4.8 Hz, 1H), 7.33-7.27 (m, 2H), 7.15-7.05 (m, 2H), 6.93 (d,J= 8.8 Hz, 1H), 6.36 (d,J= 2.4 Hz, 1H), 6.12 (dd,J= 8.8, 2.4 Hz, 1H), 3.27 (t,J= 5.1 Hz, 4H), 2.51 (d,J= 12.8 Hz, 4H), 2.26 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 161.3, 161.0, 153.2, 151.5, 149.3, 144.2, 132.6, 129.9, 129.1, 126.4, 125.8, 119.6, 115.9, 107.4, 105.2, 103.7, 54.9, 47.9, 46.2. HRMS (ESI)m / zcalcd for C 23 H 24 N5O2 + ([M + H] + ) 402.1925, found 402.1925.

[0628]

[0629] Example 53: Synthesis of 4-chloro-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol (6nb)

[0630]

[0631] Compound 6nb (138 mg, 79%) was obtained as a white solid using the method of Preparation Example 5.

[0632] TLC R f 0.48 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.74 (s, 1H), 8.30 (dd,J= 4.7, 1.5 Hz, 1H), 8.16 (dd,J= 8.0, 1.5 Hz, 1H), 7.37 (dd,J= 8.0, 4.8 Hz, 1H), 7.30 (d,J= 8.9 Hz, 2H), 7.12 (d,J= 9.0 Hz, 2H), 7.02 (s, 1H), 6.55 (s, 1H), 3.30-3.22 (m, 4H), 2.51 (p,J= 1.8 Hz, 4H), 2.26 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 159.0, 156.4, 152.0, 151.6, 149.1, 144.6, 132.8, 129.8, 129.0, 126.3, 126.1, 119.6, 116.0, 110.6, 106.8, 104.6, 54.7, 48.1, 46.1. HRMS (ESI)m / zcalcd for C 23 H 23 ClN5O2 + ([M + H] + ) 436.1535, found 436.1536.

[0633]

[0634] Example 54: Synthesis of 4-methyl-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol hydrochloride (6nc)

[0635]

[0636] The solid obtained using the method of Manufacturing Example 5 was acidified with 1N HCl (1.0 mL) and evaporated to obtain compound 6nc (27 mg, 18%), an HCl salt, as a white solid.

[0637] TLC R f 0.37 (15:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.09 (s, 1H), 8.31 (dd,J= 4.7, 1.4 Hz, 1H), 8.16 (dd,J= 8.1, 1.5 Hz, 1H), 7.44-7.33 (m, 3H), 7.23-7.15 (m, 2H), 6.77 (s, 1H), 6.44 (s, 1H), 3.98 (d,J= 12.1 Hz, 3H), 3.33-2.99 (m, 4H), 2.86 (d,J= 4.7 Hz, 4H), 1.80 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 160.7, 158.1, 151.9, 150.5, 147.3, 145.8, 131.8, 129.0, 126.4, 124.6, 122.3, 121.1, 116.5, 115.9, 103.1, 102.2, 52.3, 45.5, 42.4, 15.9. HRMS (ESI)m / zcalcd for C 24 H 26 N5O2 + ([M + H] + ) 416.2081, found 416.2084.

[0638]

[0639] Example 55: Synthesis of {4-[2-(2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6oa)

[0640] Step 1: Synthesis of [4-(3-nitro-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (3'o)

[0641]

[0642] Compound 3'o (1.03 g, 99%) was obtained as a red solid using the method of Manufacturing Example 3-2.

[0643] TLC R f 0.50 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.34 (s, 1H), 8.53 (ddd,J= 8.3, 1.8, 0.8 Hz, 1H), 8.48 (dt,J= 4.5, 1.8 Hz, 1H), 7.57-7.46 (m, 2H), 7.44 (d,J= 8.7 Hz, 2H), 6.94 (dd,J= 8.3, 4.5 Hz, 1H), 1.49 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 155.8, 153.3, 150.3, 136.6, 136.0, 133.0, 128.8, 124.1, 118.8, 114.5, 79.4, 28.6. HRMS (ESI)m / zcalcd for C 16 H 19 N4O4 + ([M + H] + ) 331.1401, found 331.1401.

[0644] Step 2: Synthesis of [4-(3-amino-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (4'o)

[0645]

[0646] Compound 4'o (705 mg, 75%) was obtained as a pink solid using the method of Manufacturing Example 4-1.

[0647] TLC R f 0.20 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.57 (s, 1H), 7.51 (dd,J= 9.0, 3.2 Hz, 2H), 7.45 (dt,J= 4.8, 1.1 Hz, 1H), 7.29 (d,J= 8.5 Hz, 2H), 6.86 (dd,J= 7.6, 1.6 Hz, 1H), 6.56 (dd,J= 7.5, 4.9 Hz, 1H), 5.00 (s, 2H), 1.47 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 153.4, 144.6, 137.4, 134.9, 132.8, 131.8, 119.7, 119.3, 119.2, 115.5, 79.0, 28.7. HRMS (ESI)m / zcalcd for C 16 H 21 N4O2 + ([M + H] + ) 301.1659, found 301.1662.

[0648] Step 3: Synthesis of {4-[2-(2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6oa)

[0649]

[0650] Using the method of Manufacturing Example 5, compound 6oa (108 mg, 78%) was obtained as a white solid.

[0651] TLC R f 0.25 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (brs, 1H), 10.14 (brs, 1H), 9.73 (brs, 1H), 8.32 (dd,J= 4.8, 1.5 Hz, 1H), 8.20 (dt,J= 7.9, 1.2 Hz, 1H), 7.79-7.62 (m, 2H), 7.42 (m, 3H), 6.93 (d,J= 8.8 Hz, 1H), 6.40 (s, 1H), 6.18 (d,J= 8.8 Hz, 1H), 1.57 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 161.3, 160.8, 153.2, 153.1, 149.1, 144.3, 140.7, 132.7, 130.0, 129.8, 128.9, 125.9, 119.7, 119.1, 107.5, 105.3, 103.7, 80.0, 28.6. HRMS (ESI)m / zcalcd for C 23 H 23 N4O4 + ([M + H] + ) 419.1714, found 419.1716.

[0652]

[0653] Example 56: Synthesis of {4-[2-(5-chloro-2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6ob)

[0654]

[0655] Using the method of Preparation Example 5, compound 6ob (77.0 mg, 51%) was obtained as a white solid.

[0656] TLC R f 0.25 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (brs, 1H), 9.68 (brs, 1H), 8.12 (m, 1H), 7.96 (m, 1H), 7.68 (d,J= 8.8 Hz, 2H), 7.36 (d,J= 8.8 Hz, 2H), 7.26 (m, 1H), 6.74 (s, 1H), 5.97 (m, 1H), 1.52 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 163.4, 159.9, 153.3, 153.1, 149.2, 143.6, 140.6, 132.8, 129.9, 129.0, 128.5, 125.2, 119.6, 119.3, 113.7, 105.4, 100.8, 80.2, 28.5. HRMS (ESI)m / zcalcd for C 23 H 22 ClN4O4 + ([M + H] + ) 453.1324, found 453.1326.

[0657]

[0658] Example 57: Synthesis of {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6oc)

[0659]

[0660] Using the method of Preparation Example 5, compound 6oc (139 mg, 97%) was obtained as a white solid.

[0661] TLC R f 0.45 (1:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.14 (brs, 1H), 9.97 (brs, 1H), 9.65 (s, 1H), 8.26 (dd,J= 4.8, 1.5 Hz, 1H), 8.12 (dd,J= 8.0, 1.5 Hz, 1H), 7.65 (d,J= 8.6 Hz, 2H), 7.35 (m, 3H), 6.75 (t,J= 1.5 Hz, 1H), 6.39 (s, 1H), 1.80 (s, 3H), 1.52 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 159.3, 158.7, 153.3, 153.2, 149.2, 144.1, 140.6, 132.9, 130.6, 130.0, 128.9, 125.8, 119.6, 119.1, 115.2, 104.9, 103.1, 79.9, 28.6, 16.0. HRMS (ESI)m / zcalcd for C 24 H 25 N4O4 + ([M + H] + ) 433.1870, found 433.1870.

[0662]

[0663] Example 58: Synthesis of {3-[2-(4-hydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6ra)

[0664] Step 1: Synthesis of [3-(3-nitro-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (3'r)

[0665]

[0666] Using the method of Manufacturing Example 3-2, compound 3'r (927 mg, 89%) was obtained as a red solid.

[0667] TLC R f 0.45 (4:1 hexanes / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.39 (s, 1H), 8.54 (ddd,J= 8.3, 1.8, 1.0 Hz, 1H), 8.51 (dt,J= 4.6, 1.9 Hz, 1H), 7.75 (d,J= 2.7 Hz, 1H), 7.33-7.28 (m, 1H), 7.26-7.17 (m, 2H), 6.99 (ddd,J= 8.4, 4.5, 1.5 Hz, 1H), 1.48 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 155.5, 153.2, 150.0, 140.4, 139.1, 136.0, 129.3, 129.2, 117.1, 114.9, 114.7, 113.1, 79.5, 28.6. HRMS (ESI)m / zcalcd for C 16 H 19 N4O4 + ([M + H] + ) 331.1401, found 331.1402.

[0668] Step 2: Synthesis of [3-(3-amino-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (4'r)

[0669]

[0670] Compound 4'r (902 mg, 96%) was obtained as a pink solid using the method of Manufacturing Example 4-1.

[0671] TLC R f 0.40 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.74-7.62 (m, 2H), 7.48 (dd,J= 4.8, 1.6 Hz, 1H), 7.42-7.29 (m, 1H), 7.06 (t,J= 8.1 Hz, 1H), 6.88 (ddt,J= 7.1, 3.4, 1.5 Hz, 2H), 6.61 (dd,J= 7.6, 4.8 Hz, 1H), 5.08 (s, 2H), 1.48 (s, 9H).13 C NMR (100 MHz, DMSO-d6) δ 153.3, 144.1, 143.0, 1400, 134.8, 132.4, 128.7, 120.0, 116.2, 112.8, 111.0, 108.9, 79.2, 28.6. HRMS (ESI)m / zcalcd for C 16 H 21 N4O2 + ([M + H] + ) 301.1659, found 301.1661.

[0672] Step 3: Synthesis of {3-[2-(4-hydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6ra)

[0673]

[0674] Using the method of Manufacturing Example 5, compound 6ra (128 mg, 92%) was obtained as a white solid.

[0675] TLC R f 0.32 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.01 (s, 1H), 9.68 (s, 1H), 8.28 (dd,J= 4.8, 1.5 Hz, 1H), 8.16 (dd,J= 8.0, 1.5 Hz, 1H), 7.65 (t,J= 2.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.46 (t,J= 8.0 Hz, 1H), 7.38 (dd,J= 8.0, 4.8 Hz, 1H), 7.04 (ddd,J= 8.0, 2.1, 1.0 Hz, 1H), 6.87 (d,J= 8.8 Hz, 1H), 6.35 (d,J= 2.4 Hz, 1H), 6.13 (dd,J= 8.8, 2.4 Hz, 1H), 1.46 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 161.4, 160.8, 153.1, 152.9, 148.9, 144.3, 141.3, 136.5, 132.8, 130.4, 130.0, 126.1, 122.0, 119.8, 118.9, 117.6, 107.6, 105.1, 103.7, 80.0, 28.5. HRMS (ESI)m / zcalcd for C 23 H 23 N4O4 + ([M + H] + ) 419.1714, found 419.1714.

[0676]

[0677] Example 59: Synthesis of {3-[2-(5-chloro-2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6rb)

[0678]

[0679] Using the method of Preparation Example 5, compound 6rb (102 mg, 68%) was obtained as a white solid.

[0680] TLC R f 0.25 (1:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 10.77 (s, 1H), 9.67 (s, 1H), 8.31 (d,J= 4.9 Hz, 1H), 8.17 (d,J= 8.0 Hz, 1H), 7.66 (s, 1H), 7.59 (d,J= 8.3 Hz, 1H), 7.45 (t,J= 8.0 Hz, 1H), 7.39 (dd,J= 8.1, 4.7 Hz, 1H), 7.05 (ddd,J= 7.9, 2.1, 1.0 Hz, 1H), 7.02 (s, 1H), 6.51 (s, 1H), 1.47 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 158.6, 156.4, 153.1, 151.7, 148.8, 144.6, 141.2, 136.2, 133.1, 130.2, 130.1, 126.6, 121.7, 119.8, 118.8, 117.5, 110.6, 107.0, 104.6, 80.0, 28.5. HRMS (ESI)m / zcalcd for C 23 H 22 ClN4O4 + ([M + H] + ) 453.1324, found 453.1325.

[0681]

[0682] Example 60: Synthesis of {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (6rc)

[0683]

[0684] Using the method of Preparation Example 5, compound 6rc (68.3 mg, 59%) was obtained as a white solid.

[0685] TLC R f 0.38 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 9.99 (s, 1H), 9.66 (s, 1H), 8.27 (dd,J= 4.8, 1.5 Hz, 1H), 8.14 (dd,J= 8.0, 1.5 Hz, 1H), 7.64 (t,J= 2.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.47 (t,J= 8.0 Hz, 1H), 7.37 (dd,J= 8.0, 4.8 Hz, 1H), 7.05 (dt,J= 8.0, 2.0, 1.0 Hz, 1H), 6.73 (d,J=1.0 Hz, 1H), 6.40 (s, 1H), 1.90-1.68 (m, 3H), 1.46 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 159.4, 158.7, 153.1, 153.0, 148.9, 144.2, 141.3, 136.6, 132.9, 130.6, 130.2, 126.0, 122.1, 119.7, 118.9, 117.8, 115.3, 104.6, 103.1, 80.0, 28.5, 15.9. HRMS (ESI)m / zcalcd for C 24 H 25 N4O4 + ([M + H] + ) 433.1870, found 433.1871.

[0686]

[0687] Manufacturing Example 6: Synthesis of TFA salt and amine

[0688] Manufacturing Example 6-1: Synthesis of TFA salt compound

[0689] In a 5 mL oven-dried round-bottom flask with a sidearm, the boc-protected amine compound (238 μmol) and TFA (0.36 mL, 2.38 mmol) were suspended in anhydrous CH2Cl2 (1.5 mL). The reaction mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was concentrated, and CH2Cl2 (5 mL) was added. The formed solid was filtered and dried to obtain the TFA salt compound as a yellow solid.

[0690] Manufacturing Example 6-2: Synthesis of amine compounds

[0691] The TFA salt prepared in Manufacturing Example 6-1 was neutralized by adding it to a saturated NaHCO3 aqueous solution (2 mL), and the resulting solid was filtered to obtain a free amine compound as an ivory-colored solid.

[0692]

[0693] Example 61: Synthesis of 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6qa)

[0694]

[0695] Compound 6qa (67 mg, 89%) was obtained as an ivory-colored solid by the method of Manufacturing Example 6-2.

[0696] TLC R f 0.45 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 10.02 (s, 1H), 8.26 (dt,J= 4.7, 1.2 Hz, 1H), 8.12 (dt,J= 7.9, 1.2 Hz, 1H), 7.34 (dd,J= 8.0, 4.8 Hz, 1H), 7.08 (d,J= 8.6 Hz, 2H), 6.94 (d,J= 8.8 Hz, 1H), 6.72 (d,J= 8.6 Hz, 2H), 6.37 (s, 1H), 6.11 (d,J= 8.8 Hz, 1H), 5.53 (brs, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 161.5, 161.3, 153.3, 150.1, 149.4, 144.2, 132.2, 129.5, 129.2, 125.6, 123.6, 119.5, 114.7, 107.3, 104.9, 103.7. HRMS (ESI)m / zcalcd for C 18 H 15 N4O2 + ([M + H] + ) 319.1190, found 319.1188.

[0697]

[0698] Example 62: Synthesis of 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol trifluoroacetic acid salt (6pb)

[0699]

[0700] Compound 6pb (8.2 mg) was obtained as a yellow solid by the method of Manufacturing Example 6-1.

[0701] TLC R f 0.25 (1:1 hexane / EtOAc).1 H NMR (400 MHz, DMSO-d6) δ 11.51 (brs, 1H), 10.84 (brs, 1H), 8.34 (dd,J= 4.8, 1.5 Hz, 1H), 8.18 (dd,J= 8.0, 1.5 Hz, 1H), 7.41 (dd,J= 8.0, 4.7 Hz, 1H), 7.18 (d,J= 8.4 Hz, 2H), 7.10 (s, 1H), 6.84 (d,J= 8.4 Hz, 2H), 6.57 (s, 1H), 4.35 (brs, 3H). HRMS (ESI)m / zcalcd for C 18 H 14 ClN4O2 + ([M] + ) 353.0800, found 353.0800.

[0702]

[0703] Example 63: Synthesis of 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol (6qb)

[0704]

[0705] Compound 6qb (74 mg, total yield 89%) was obtained as an ivory-colored solid by the method of Manufacturing Example 6-2.

[0706] TLC R f 0.30 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 10.78 (s, 1H), 8.30 (dd,J= 4.7, 1.7 Hz, 1H), 8.18-8.11 (m, 1H), 7.36 (dd,J= 8.0, 4.9 Hz, 1H), 7.10 (d,J= 8.4 Hz, 2H), 7.05 (s, 1H), 6.73 (d,J= 8.6 Hz, 2H), 6.57 (s, 1H), 5.63-5.45 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 159.6, 156.4, 152.0, 150.2, 149.2, 144.6, 132.2, 129.4, 129.1, 126.0, 123.2, 119.7, 114.7, 110.6, 106.2, 104.7. HRMS (ESI)m / zcalcd for C 18 H 14 ClN4O2 + ([M + H] + ) 353.0800, found 353.0801.

[0707]

[0708] Example 64: Synthesis of 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol trifluoroacetic acid salt (6pc)

[0709]

[0710] Compound 6pc (11 mg) was obtained as a yellow solid by the method of Manufacturing Example 6-1.

[0711] TLC R f 0.20 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (brs, 1H), 8.35 (d,J= 4.8 Hz, 1H), 8.17 (dd,J= 8.0, 1.5 Hz, 1H), 7.44 (dd,J= 8.0, 4.8 Hz, 1H), 7.16 (d,J= 8.6 Hz, 2H), 6.85 (s, 1H), 6.83 (d,J= 8.6 Hz, 2H), 6.44 (s, 1H), 5.76 (brs, 5H), 1.82 (s, 3H). HRMS (ESI)m / zcalcd for C 19 H 17 N4O2 + ([M] + ) 333.1346, found 333.1348.

[0712]

[0713] Example 65: Synthesis of 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol (6qc)

[0714]

[0715] Compound 6qc (104 mg, total yield 97%) was obtained as an ivory-colored solid by the method of Manufacturing Example 6-2.

[0716] TLC R f 0.35 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 10.02 (brs, 1H), 8.25 (dd,J= 4.8, 1.5 Hz, 1H), 8.09 (dd,J= 8.0, 1.5 Hz, 1H), 7.33 (dd,J= 8.0, 4.8 Hz, 1H), 7.08 (d,J= 8.6 Hz, 2H), 6.78 (d,J= 1.1 Hz, 1H), 6.74 (d,J= 8.6 Hz, 2H), 6.40 (s, 1H), 5.53 (brs, 2H), 1.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.6, 159.3, 153.4, 150.2, 149.4, 144.1, 132.3, 130.2, 129.3, 125.4, 123.8, 119.4, 115.0, 114.6, 104.3, 103.2, 16.1. HRMS (ESI)m / zcalcd for C 19 H 17 N4O2 + ([M + H] + ) 333.1346, found 333.1345.

[0717]

[0718] Example 66: Synthesis of 4-[3-(3-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol, trifluoroacetic acid salt (6sa)

[0719]

[0720] Compound 6sa (15.1 mg) was obtained as a yellow solid by the method of Manufacturing Example 6-1.

[0721] TLC R f 0.15 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 10.08 (s, 1H), 8.35 (ddd,J= 4.8, 2.4, 1.5 Hz, 1H), 8.20 (ddd,J= 7.7, 6.1, 1.5 Hz, 1H), 7.92-7.86 (m, 1H), 7.60 (t,J= 8.1 Hz, 1H), 7.44 (ddd,J= 8.0, 4.8, 1.0 Hz, 1H), 7.33-7.25 (m, 1H), 6.98 (dd,J= 8.7, 2.2 Hz, 1H), 6.92-6.62 (m, 1H), 6.37 (dd,J= 16.5, 2.3 Hz, 1H), 6.18 (ddd,J= 12.8, 8.8, 2.3 Hz, 1H). HRMS (ESI)m / zcalcd for C 18 H 15 N4O2 + ([M] + ) 319.1190, found 319.1190.

[0722]

[0723] Example 67: Synthesis of 4-[3-(3-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6ta)

[0724]

[0725] Compound 6ta (69.0 mg, total yield 99%) was obtained as an ivory-colored solid by the method of Manufacturing Example 6-2.

[0726] TLC R f 0.45 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.03 (s, 1H), 8.28 (dd,J= 4.8, 1.5 Hz, 1H), 8.14 (dd,J= 8.0, 1.5 Hz, 1H), 7.36 (dd,J= 8.0, 4.8 Hz, 1H), 7.22 (t,J= 7.9 Hz, 1H), 6.94 (d,J= 8.8 Hz, 1H), 6.76 (dt,J= 7.9, 2.0, 1.0 Hz, 1H), 6.62 (t,J= 2.0 Hz, 1H), 6.54 (ddd,J= 7.7, 2.0, 1.0 Hz, 1H), 6.37 (d,J= 2.4 Hz, 1H), 6.12 (dd,J= 8.8, 2.4 Hz, 1H), 5.47 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 161.4, 161.3, 152.8, 150.5, 148.9, 144.3, 136.8, 132.3, 130.6, 129.8, 125.8, 119.7, 115.4, 115.1, 113.4, 107.5, 104.7, 103.7. HRMS (ESI)m / zcalcd for C 18 H 15 N4O2 + ([M + H] + ) 319.1190, found 319.1188.

[0727]

[0728] Example 68: Synthesis of 4-[3-(3-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol (6tb)

[0729]

[0730] Compound 6tb (67.8 mg, total yield 87%) was obtained as an ivory-colored solid by the method of Manufacturing Example 6-2.

[0731] TLC R f 0.25 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.94 (s, 1H), 8.30 (d,J= 4.8 Hz, 1H), 8.16 (d,J= 8.0 Hz, 1H), 7.38 (dd,J= 8.0, 4.8 Hz, 1H), 7.23 (t,J= 7.9 Hz, 1H), 7.03 (s, 1H), 6.78 (ddd,J= 7.9, 2.1, 1.0 Hz, 1H), 6.63 (t,J= 2.1 Hz, 1H), 6.60-6.44 (m, 2H), 5.49 (brs, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 159.4, 156.6, 151.5, 150.6, 148.8, 144.7, 136.4, 132.4, 130.5, 129.6, 126.2, 119.8, 115.2, 115.1, 113.2, 110.7, 106.0, 104.7. HRMS (ESI)m / zcalcd for C 18 H 14 ClN4O2 + ([M + H] + ) 353.0800, found 353.0799.

[0732]

[0733] Example 69: Synthesis of 4-[3-(3-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol (6tc)

[0734]

[0735] Compound 6tc (76.1 mg, total yield 99%) was obtained as an ivory-colored solid by the method of Manufacturing Example 6-2.

[0736] TLC R f 0.20 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.70 (brs, 1H), 10.00 (s, 1H), 8.27 (dd,J= 4.8, 1.5 Hz, 1H), 8.13 (dd,J= 8.0, 1.5 Hz, 1H), 7.36 (dd,J= 8.0, 4.8 Hz, 1H), 7.24 (t,J= 7.9 Hz, 1H), 6.84-6.74 (m, 2H), 6.62 (t,J= 2.1 Hz, 1H), 6.59-6.52 (m, 1H), 6.41 (s, 1H), 5.49 (brs, 1H), 1.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.4, 159.4, 152.9, 150.4, 148.9, 144.2, 136.9, 132.2, 130.5, 130.4, 125.6, 119.7, 115.6, 115.2, 115.1, 113.6, 104.0, 103.1, 16.0. HRMS (ESI)m / zcalcd for C 19 H 17 N4O2 + ([M + H] + ) 333.1346, found 333.1346.

[0737] The structures of the compounds of Examples 1 to 69 are as shown in Table 1 below.

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747] <Experimental Example>

[0748] Experimental Example 1. Evaluation of BTK inhibitory activity

[0749] 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 33 P-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.

[0750] 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.

[0751] 2) IC 50 : 10 dose IC in 3-fold serial dilutions starting at 100 μM, 30 μM, or 10 μM 50The test was performed in mode 1. The reaction was performed at 10 μM ATP.

[0752] 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 1 μM < IC 50 am.

[0753] Example Compound #% Enzyme Activity IC 50BTKBTK Example 16a89.76++ Example 26b11.45++ Example 36c48.86++ Example 46d99.31++ Example 56e95.61++ Example 66f96.76++ Example 76g98.77++ Example 86h96.10++ Example 96i98.54++ Example 106j83.15++ Example 116k56.28++ Example 126l95.34++ Example 136m72.44++ Example 146n61.33++ Example 156o16.94++ Example 166aa41.79++ Example 176ab122.70++ Example 186ac57.18++Example 196ba106.76++Example 206bb105.05++Example 216bc70.84++Example 226da105.35++Example 236db104.38++Example 246dc116.05++Example 256ea5.67+++Example 266eb3.35+++Example 276ec2.16+++Example 286fa53.53++Example 296fb73.70++Example 306fc60.50++Example 316ga38.95++Example 326gb101.72++Example 336gc57.27++Example 346ha24.27++Example 356hb31.62++Example 366hc15.16++Example 376ia27.17++Example 386ib63.91++Example 396ic58.75++Example 406ja95.29++Example 416jb93.01++Example 426jc105.02++Example 436ka58.97++Example 446kb87.72++Example 456kc66.96++Example 466la3.13+++Example 476lb97.21++Example 486lc23.14+++Example 496ma1.21+++Example 506mb2.65+++Example 516mc0.92+++Example 526na12.11++Example 536nb5.03+++Example 546nc0.85++++Example 556oa71.27++Example 566ob94.24++Example 576oc64.19++Example 586ra86.15++Example 596rb65.90++Example 606rc57.92++Example 616qa2.92++++Example 626pb6.15++++Example 636qb6.29++++Example 646pc2.47++++Example 656qc4.96++++Example 666sa13.96+++Example 676ta4.12+++Example 686tb6.91+++Example 696tc3.42++++.

[0754] According to Table 2 above, the imidazopyridine compounds according to the present invention were found to have excellent activity in inhibiting BTK.

[0755]

[0756] 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 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, R1 is -OH, -C1-C 10 Alkyl, -C1-C5 alkoxy, -C1-C5 haloalkoxy, -NHC(=O)-(C1-C5 alkyl), -NHC(=O)O-(C1-C5 alkyl), -C(=O)NH2, -NR a R b , unsubstituted or substituted -O-phenyl, unsubstituted or substituted C3-C8heterocycloalkyl containing one or more nitrogen atoms, or unsubstituted or substituted -(C1-C3alkyl)-(C3-C8heterocycloalkyl containing one or more nitrogen atoms), wherein substitution is substitution with at least one C1-C3alkyl, -NH2, or -NHC(=O)O-(C1-C5alkyl); R a and R b is hydrogen or C1-C5 alkyl; R2 is -OH, -C1-C5alkoxy, or halogen; n is an integer from 0 to 3; Is or C3-C8 heteroaryl containing unsubstituted or substituted nitrogen or oxygen atoms, wherein the substitution is at least one C1-C3 alkyl; R3 is halogen, -OH, -C1-C5 alkyl, -C1-C5 alkoxy, -C1-C5 haloalkoxy, -NO2 or -NH2; R4 is hydrogen, -OH, or -C1-C5alkoxy; R5 is halogen, -C1-C5 alkyl, or -C1-C5 alkoxy; m is an integer from 0 to 3. In the first paragraph, R1 is -OH, -C1-C5 alkyl, -C1-C3 alkoxy, -C1-C5 haloalkoxy, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)O-(C1-C5 alkyl), -C(=O)NH2, -NR a R b , unsubstituted or substituted -O-phenyl, unsubstituted or substituted C3-C6 heterocycloalkyl containing one or more nitrogen atoms, or unsubstituted or substituted -(C1-C3 alkyl)-(C3-C6 heterocycloalkyl containing one or more nitrogen atoms), wherein substitution is substitution with at least one C1-C3 alkyl, -NH2, or -NHC(=O)O-(C1-C5 alkyl); R a and R b A compound represented by the formula 1, wherein the compound is hydrogen or C1-C3 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In the first paragraph, R1 is -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -NHC(=O)-(C1-C3 alkyl), -NHC(=O)O-(C1-C5 alkyl), -C(=O)NH2, -NH2, -NH-CH3, -N-(CH3)2, unsubstituted or substituted -O-phenyl, unsubstituted or substituted pyrrolidine, unsubstituted or substituted piperidine, unsubstituted or substituted piperazine, unsubstituted or substituted morpholine, unsubstituted or substituted -(C1-C3 alkyl)-pyrrolidine, unsubstituted or substituted -(C1-C3 alkyl)-piperidine, A compound represented by the formula 1, which is -(C1-C3 alkyl)-piperazine, or unsubstituted or substituted -(C1-C3 alkyl)-morpholine, wherein the substitution is substitution with at least one C1-C3 alkyl, -NH2, or -NHC(=O)O-(C1-C5 alkyl), an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In the first paragraph, R1 is -OH, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -NHC(=O)-CH3, -NHC(=O)-CH2CH3, -NHC(=O)O-(C(CH3)3), -C(=O)NH2, -NH2, -N-(CH3)2, unsubstituted or substituted , unsubstituted or substituted , unsubstituted or substituted or unsubstituted or substituted A compound represented by the formula 1, wherein the substitution is substitution with at least one C1-C3 alkyl, -NH2, or -NHC(=O)O-(C1-C5 alkyl), an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In claim 1, the compound represented by chemical formula 1 is a compound represented by chemical formulas 1-1 to 1-4 below, a compound represented by chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] [Chemical Formula 1-2] [Chemical Formula 1-3] [Chemical Formula 1-4] . In the first paragraph, Is , unsubstituted or substituted furan or unsubstituted or substituted pyridine, wherein the substitution is at least one C1-C3 alkyl; R3 is chloro (Cl), fluorine (F), -OH, -C1-C3 alkyl, -C1-C3 alkoxy, or -NO2; R4 is hydrogen (H), -OH, or -C1-C3alkoxy; R5 is chloro (Cl), fluorine (F), -C1-C3 alkyl, or -C1-C3 alkoxy; A compound represented by chemical formula 1, wherein m is an integer from 0 to 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In the first paragraph, Is , , , , unsubstituted or substituted furan or unsubstituted or substituted pyridine, wherein the substitution is at least one C1-C3 alkyl; R3 is chloro (Cl), fluorine (F), -OH, -C1-C3 alkyl, -C1-C3 alkoxy, or -NO2; R4 is hydrogen (H), -OH, or -C1-C3alkoxy; R5 is chloro (Cl), fluorine (F), -C1-C3 alkyl, or -C1-C3 alkoxy; A compound represented by chemical formula 1, wherein m is an integer from 0 to 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 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 represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: 4-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)phenol; 4-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 2-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,4-diol; 2-(2,5-dimethoxyphenyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine; 2-(4-fluorophenyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine; 2-(furan-2-yl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine; 3-(4-methoxyphenyl)-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine; 3-(4-methoxyphenyl)-2-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridine; 3-(4-methoxyphenyl)-2-(6-methylpyridin-2-yl)-3H-imidazo[4,5-b]pyridine; 4-chloro-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 2,4-Dichloro-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 3-(4-methoxyphenyl)-2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridine; 4-Ethyl-6-(3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-chloro-6-(3-(4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-chloro-6-(3-(4-(morpholinomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-chloro-6-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol; 4-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-chloro-6-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-methyl-6-(3-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol); 4-chloro-6-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-methyl-6-(3-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-chloro-6-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(3-hydroxy-4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol; 4-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-chloro-6-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(4-(difluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol; 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol; 4-(3-(4-(tert-butyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol; N-(4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide; N-(4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide; N-(4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)acetamide; 4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide; 4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide; 4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzamide; tert-Butyl (4-(4-(2-(2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate; tert-Butyl (4-(4-(2-(5-chloro-2,4-dihydroxyphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate; tert-Butyl (4-(4-(2-(2,4-dihydroxy-5-methylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy)phenyl)carbamate; 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-chlorobenzene-1,3-diol; 4-(3-(4-(4-aminophenoxy)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol; 4-[3-(4-Dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 4-Chloro-6-[3-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 4-[3-(4-Dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol; 4-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-chloro-6-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-(3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-6-methylbenzene-1,3-diol; 4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-chloro-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol; 4-Methyl-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene-1,3-diol hydrochloride; {4-[2-(2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester; {4-[2-(5-chloro-2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester; {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester; {3-[2-(4-hydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester; {3-[2-(5-chloro-2,4-dihydroxy-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester; {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-b]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester; 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 4-[3-(4-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol trifluoroacetic acid salt; 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol; 4-[3-(4-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol trifluoroacetic acid salt; 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-benzene-1,3-diol; 4-[3-(3-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol trifluoroacetic acid salt; 4-[3-(3-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 4-[3-(3-amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-chloro-benzene-1,3-diol; and 4-[3-(3-Amino-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-6-methyl-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 8, 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 or cancer. In claim 9, 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 9. 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 9. 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 8, 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 or cancer. In claim 13, 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 method 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 method for preventing or treating a Bruton's tyrosine kinase-mediated disease, wherein the cancer is a B-cell malignancy in claim 13. Use of a compound according to any one of claims 1 to 8, 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 or cancer. 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, A use selected from the group consisting of pemphigus, systemic lupus erythematosus, hidradenitis, dermatosis, immunoglobulin G4-related disease, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia. The use according to claim 16, wherein the cancer is a B cell malignancy. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, 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 or cancer.

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