Novel imidazopyridine or imidazopyrazine derivative and uses thereof

Abstract

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

Description

Novel imidazopyridine or imidazopyrazine derivatives and uses thereof

[0001] The present invention relates to a novel imidazopyridine or imidazopyrazine 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, the challenge is to develop noncovalent inhibitors that exhibit sufficiently high exposure, low clearance, and sustained on-target inhibition, similar to covalent irreversible inhibitors. Current advances in this non-covalent inhibitor field have led to the development of non-covalent BTK inhibitors such as BMS-986142, which has completed a phase 2 clinical study for rheumatoid arthritis (RA), and fenobrutinib, which has completed clinical trials in RA, systemic lupus erythematosus (SLE), and chronic spontaneous urticaria (CSU).

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

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

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

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

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

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

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

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

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

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

[0017] In the present invention, the term “C1-C8 alkoxy” refers to a straight-chain or branched-chain alkoxy having 1 to 8 carbon atoms. Specifically, it may be methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, etc., but is not limited thereto.

[0018] 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, may be substituted with halogen or C1-C3 alkyl. 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.

[0019] 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.

[0020] 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.

[0021] Novel imidazopyridine or imidazopyrazine compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof

[0022] 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:

[0023] [Chemical Formula 1]

[0024]

[0025] In the above chemical formula 1,

[0026] Is or And,

[0027] Is or And,

[0028] R1 is -C1-C5 alkoxy, C3-C8 heterocycloalkyl containing unsubstituted or substituted nitrogen or oxygen atom, unsubstituted or substituted -(C1-C3 alkylene)-(C3-C8 heterocycloalkyl containing nitrogen or oxygen atom), -NR a R b or -NO2, wherein said substitution is halogen or -C1-C5 alkyl,

[0029] R a and R b may be the same or different, and each independently represents hydrogen, -C1-C3 alkyl or -C(=O)O-C1-C5 alkyl,

[0030] n is an integer from 1 to 3,

[0031] R2 to R6 may be the same or different, and each independently represent hydrogen, halogen, -C1-C5 alkyl, -C1-C5 alkoxy, -NR c R d , -OH, -NO2 or -CN (except when R2 to R6 are all hydrogen),

[0032] R7 is halogen, -C1-C5 alkyl, -C1-C5 alkoxy, -NR c R d , -OH, -NO2 or -CN,

[0033] R c and R d may be the same or different, and each independently represents hydrogen or -C1-C3 alkyl,

[0034] m is an integer from 1 to 3,

[0035] X1 to X4 may be the same or different, and are each independently N or -CH. (However, this does not apply when X1 to X3 are -CH and X4 is N.)

[0036]

[0037] Specifically, the above R1 to R7 or R a Inland R dThe C1-C5 alkyl, C1-C3 alkylene, C1-C5 alkoxy, C3-C8 heterocycloalkyl mentioned in may be selected from the specific substituents mentioned below:

[0038] The C1-C5 alkyl may be straight-chain or branched methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 2-pentyl, or 3-pentyl, and the C1-C3 alkylene may be straight-chain or branched methylene, ethylene, propylene, and the like.

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

[0040] The above C3-C8 heterocycloalkyl may contain one or more nitrogen or oxygen atoms, and may be tetrahydrofuranyl, azetidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, or hexahydro-2H-furo[3,2-b]pyrrole.

[0041]

[0042] Specifically, the compound represented by Chemical Formula 1 may be any one compound selected from the group consisting of compounds represented by Chemical Formulas 1-1 to 1-4 below:

[0043] [Chemical Formula 1-1]

[0044]

[0045] [Chemical Formula 1-2]

[0046]

[0047] [Chemical Formula 1-3]

[0048]

[0049] [Chemical Formula 1-4]

[0050]

[0051]

[0052] Specifically, R1 can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentoxy, unsubstituted or substituted pyrrolidine, unsubstituted or substituted piperidine, unsubstituted or substituted piperazine, unsubstituted or substituted morpholine, unsubstituted or substituted -(C1-C3 alkylene)-pyrrolidine, unsubstituted or substituted -(C1-C3 alkylene)-piperidine, -(C1-C3 alkylene)-piperazine, unsubstituted or substituted -(C1-C3 alkylene)-morpholine, -NH2, -NH-CH3, -N-(CH3)2, or -NH-C(=O)-O-C1-C5 alkyl, wherein said substitution can be -C1-C5 alkyl.

[0053] Also, n can be 1 or 2, and preferably 1.

[0054]

[0055] Specifically Is , , , , , , , , or It could be.

[0056]

[0057] Specifically, R2 is hydrogen, or -OH, R3 is hydrogen, halogen, or -C1-C3 alkoxy, R4 is hydrogen, -C1-C3 alkoxy, or -OH, R5 is hydrogen, halogen, -C1-C3 alkyl, -OH, or -NO2, and R6 is hydrogen or -C1-C3 alkoxy, except when R2 to R6 are all hydrogen.

[0058]

[0059] Specifically, R7 can be -OH, -NO2 or -NH2, and more specifically, R7 can be -OH or -NH2.

[0060] Also, m can be 1 or 2, preferably 1.

[0061]

[0062] Specifically Is , , , , , , , or It could be.

[0063] More specifically Is , , , , , , , , , , or It could be.

[0064]

[0065] 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:

[0066] 4-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6a);

[0067] 2-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol (6b);

[0068] 2,4-Dichloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6c);

[0069] 4-Chloro-6-[1-(4-morpholin-4-yl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (10a);

[0070] 4-Chloro-6-[1-(4-morpholin-4-ylmethyl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (15a);

[0071] 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1, 3-diol (18a);

[0072] 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol(18b);

[0073] 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol(18c);

[0074] 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-4-nitro-phenol(18e);

[0075] 2,4-Dichloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene- 1,3-diol(18f);

[0076] 4-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol (23a);

[0077] 2-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,4-diol (23b);

[0078] 4-Chloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol (23c);

[0079] 4-Chloro-6-[1-(4-morpholin-4-yl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (27a);

[0080] 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1, 3-diol (31a);

[0081] 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol(31b);

[0082] 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,4-diol (31c);

[0083] 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-4-nitro-phenol(31d);

[0084] 2,4-Dichloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene- 1,3-diol (31e);

[0085] 4-Chloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol(31f);

[0086] 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,3-diol (35a);

[0087] 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,4-diol (35b);

[0088] 5-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,2,4-triol(35c);

[0089] 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-4-nitro-phenol(35d);

[0090] 2-Chloro-4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol(35f);

[0091] 3-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine (35 g);

[0092] 6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-3-ol(35h);

[0093] 5-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine(35i);

[0094] 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol(35j);

[0095] 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,4-diol (39a);

[0096] 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-nitro-phenol (39b);

[0097] 4-Chloro-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol(39c);

[0098] 3-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine(39d);

[0099] 5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine(39e);

[0100] 6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-3-ol(39f);

[0101] 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,3-diol (39 g);

[0102] 4-Methyl-6-{1-[4-(4-methyl-piperazin-1-yl)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-benzene-1,3-diol (42a);

[0103] {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-carbamic acid tert-butyl ester (42b);

[0104] 4-[1-(4-Amino-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol (43b);

[0105] {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-carbamic acid tert-butyl ester (42c);

[0106] 4-[1-(3-Amino-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol (43c);

[0107] 4-Methyl-6-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-imidazo[4,5-c]pyridin-2-yl}-benzene-1,3-diol (46a);

[0108] {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (46b);

[0109] 4-[3-(4-Amino-phenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol (47b);

[0110] {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (46c); and

[0111] 4-[3-(3-Amino-phenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol (47c).

[0112]

[0113] 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.

[0114]

[0115] pharmaceutical composition

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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).

[0150] Hereinafter, the present invention will be described in detail using examples to aid understanding. However, the examples according to the present invention may be modified in various ways, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0151] The reagents and solvents mentioned below were purchased from Korea Fisher Scientific Co., Ltd. and Sejin CI Co., Ltd., unless otherwise specified.

[0152] 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.

[0153] 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.

[0154] Flash chromatography was performed on E. Merck 230-400 mesh silica gel 60.

[0155] 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.

[0156] NMR spectra were recorded using an Agilent (Santa Clara, CA, USA) Unity 400 instrument or a Bruker (Switchen, Fallanden) vANCE EO anobay 00 Hz MR spectrometer system installed at the 24°C Ewha Pharmaceutical Development Research Core Center. NMR chemical shifts were measured using TMS ( 1 H, 0 ppm), CDCl3( 1 H, 7.26 ppm; 13 C, 77.2 ppm), DMSO-d6 ( 1 H, 2.50 ppm; 13 C, 39.5 ppm), (CD3)2CO ( 1 H, 2.05 ppm; 13C, 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).

[0157] 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.

[0158]

[0159] <Example>

[0160] Examples 1 to 10 below were synthesized based on the following reaction scheme 1.

[0161] [Reaction Formula 1]

[0162]

[0163]

[0164] Manufacturing Example 1: Synthesis of imidazopyridines (6a-6c)

[0165] Step 1: Synthesis of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(2-nitro-pyridin-3-yl)-amine (3)

[0166]

[0167] 3-Fluoro-2-nitro-pyridine (1) (250 mg, 1.76 mmol), p-anisidine (2) (260 mg, 2.11 mmol), and K2CO3 (486 mg, 3.52 mmol) were suspended in anhydrous DMF (2.0 mL) in a 5 mL microwave vial. The reaction mixture was stirred at 140 °C for 3 h under microwave irradiation. Upon completion of the reaction, the precipitate was filtered and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator and purified by column chromatography (4:1 hexanes / EtOAc) to give compound 3 (360 mg, 83%) as a red solid.

[0168] TLC: R f 0.32 (2:1 hexances / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.90 (dd, J = 3.9, 1.5 Hz, 1H), 7.56-7.41 (m, 2H), 7.26 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 3.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 150.7, 141.5, 139.0, 136.5, 131.1, 130.6, 126.8, 125.8, 114.9, 55.4. HRMS (ESI) m / z calcd for C 12 H 12 N3O3 + ([M + H] + ) 246.0873 found 246.0873.

[0169] Step 2: Synthesis of N3-(4-methoxy-phenyl)-pyridine-2,3-diamine (4)

[0170]

[0171] Compound 3 (360 mg, 1.47 mmol) and Pd / C (36.0 mg) were suspended in EtOH (8.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The inside of the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 8 h under a hydrogen-filled balloon. Upon completion of the reaction, the reaction mixture was placed in Celite ® The residue was filtered through a plug and washed with MeOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compound 4 (244 mg, 77%) as a pink solid.

[0172] TLC: R f 0.13 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 5.0, 1.6 Hz, 1H), 7.22 (dd, J = 7.6, 1.6 Hz, 1H), 6.88-6.76 (m, 4H), 6.65 (dd, J = 7.6, 5.0 Hz, 1H), 4.92 (s, 1H), 4.55 (brs, 2H), 3.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 153.9, 152.5, 139.7, 137.5, 126.3, 123.0, 119.6, 115.0, 113.2, 55.7. HRMS (ESI) m / z calcd for C 12 H 14 N3O + ([M + H] + ) 216.1131 found 216.1133.

[0173] Step 3: Synthesis of imidazopyridines (6a-6c)

[0174]

[0175] Compound 4 (100 mg, 464 μmol), aldehyde 5a-c (557 μmol), and Na2S2O5 (176 mg, 928 μmol) were suspended in anhydrous DMF (2.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm at room temperature. 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, the precipitate was filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compounds 6a-c as a white solid.

[0176]

[0177] Manufacturing Example 2: Synthesis of imidazopyridine (18a-f)

[0178] Step 1: Synthesis of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(2-nitro-pyridin-3-yl)-amine (16)

[0179]

[0180] 3-Fluoro-2-nitro-pyridine (1) (50.0 mg, 352 μmol), 2,4-ethylenedioxyanline (2') (63.8 mg, 422 μmol), and K2CO3 (97.3 mg, 704 μmol) were suspended in anhydrous DMF (1.0 mL) in a 5 mL microwave vial. The reaction mixture was stirred at 140 °C for 4.5 h under microwave irradiation. Upon completion of the reaction, the precipitate was filtered and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (5:1 hexanes / EtOAc) to give compound 16 (75.9 mg, 79%) as a red solid.

[0181] TLC: R f 0.30 (2:1 hexanes / EtOAc). 1H NMR (400 MHz, CDCl3+TMS) δ 9.07 (brs, 1H), 7.96 (dd, J = 4.0, 1.5 Hz, 1H), 7.56 (dd, J = 8.6, 1.5 Hz, 1H), 7.34 (ddd, J = 8.6, 4.0, 0.7 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 6.74 (ddd, J = 8.5, 2.5, 0.6 Hz, 1H), 4.30 (s, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 144.3, 143.4, 142.2, 137.2, 134.8, 132.2, 131.0, 126.6, 118.2, 117.5, 114.4, 64.8, 64.1. HRMS (ESI) m / z calcd for C 13 H 12 N3O4 + ([M + H] + ) 274.0822, found 274.0825.

[0182] Step 2: Synthesis of N3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-pyridine-2,3-diamine (17)

[0183]

[0184] Compound 16 (35.0 mg, 128 μmol) and Pd / C (3.5 mg) were suspended in EtOH (0.8 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The flask was purged and stirred at room temperature under a hydrogen-filled balloon for 3 h. Upon completion of the reaction, the reaction mixture was filtered through a Celite ® The residue was filtered through a plug and washed with MeOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compound 17 (24.0 mg, 77%) as a pink solid.

[0185] TLC: R f0.132 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (dd, J = 5.1, 1.6 Hz, 1H), 7.28 (dd, J = 7.6, 1.6 Hz, 1H), 7.26 (s, 1H), 6.81-6.73 (m, 1H), 6.65 (dd, J = 7.6, 5.1 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 6.34 (dd, J = 8.3, 2.7 Hz, 1H), 4.97 (brs, 2H), 4.27-4.19 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 153.1, 144.1, 140.5, 138.7, 137.4, 125.4, 124.8, 117.8, 113.1, 110.8, 106.1, 64.8, 64.3. HRMS (ESI) m / z calcd for C 13 H 14 N3O2 + ([M + H] + ) 244.1081, found 244.1086.

[0186] Step 3: Synthesis of imidazopyridines (18a-18f)

[0187]

[0188] Compound 17 (50.0 mg, 206 μmol), aldehyde 7a-f (246 μmol), and Na2S2O5 (78.2 mg, 411 μmol) were suspended in anhydrous DMF (1.0 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 precipitate was filtered and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compounds 18a-f as white solids.

[0189]

[0190] Example 1: 4-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6a)

[0191]

[0192] Compound 6a (120 mg, 78%) was obtained as a white solid using the method of Manufacturing Example 1.

[0193] TLC: R f 0.18 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (brs, 1H), 10.03 (brs, 1H), 8.46 (dd, J = 4.8, 1.5 Hz, 1H), 7.53-7.43 (m, 3H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 7.18 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.12 (dd, J = 8.8, 2.4 Hz, 1H), 3.87 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 161.2, 160.6, 159.8, 153.4, 152.8, 144.9, 129.5, 129.0, 128.9, 128.6, 118.8, 118.4, 115.5, 107.2, 104.6, 103.4, 55.7. HRMS (ESI) m / z calcd for C 19 H 16 N3O3 + ([M + H] + ) 334.1186, found 334.1191.

[0194]

[0195] Example 2: 2-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol (6b)

[0196]

[0197] Compound 6b (110 mg, 71%) was obtained as a white solid using the method of Manufacturing Example 1.

[0198] TLC: R f 0.35 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (brs, 1H), 8.94 (brs, 1H), 8.50 (dd, J = 4.7, 1.5 Hz, 1H), 7.55 (dd, J = 8.1, 1.5 Hz, 1H), 7.43 (d, J = 8.9 Hz, 2H), 7.31 (dd, J = 8.1, 4.7 Hz, 1H), 7.13 (d, J = 9.0 Hz, 2H), 6.78-6.74 (m, 2H), 6.56 (dd, J = 2.0, 1.3 Hz, 1H), 3.85 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.5, 153.3, 152.9, 150.5, 149.0, 145.0, 128.9, 128.4, 119.6, 118.9, 118.6, 117.6, 115.2, 114.8, 113.9, 55.5. HRMS (ESI) m / z calcd for C 19 H 16 N3O3 + ([M + H] + ) 334.1186, found 334.1189.

[0199]

[0200] Example 3: 2,4-Dichloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (6c)

[0201]

[0202] Compound 6c (78.0 mg, 42%) was obtained as a white solid using the method of Manufacturing Example 1.

[0203] TLC: R f 0.35 (1:2 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 13.90 (brs, 1H), 10.83 (brs, 1H), 8.51 (dd, J = 4.8, 1.5 Hz, 1H), 7.58 (d, J = 8.9 Hz, 2H), 7.53 (dd, J = 8.1, 1.5 Hz, 1H), 7.33 (dd, J = 8.1, 4.8 Hz, 1H), 7.24 (d, J = 8.9 Hz, 2H), 6.83 (s, 1H), 3.89 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 160.3, 155.4, 152.2, 151.7, 151.1, 145.42, 129.1, 129.0, 127.7, 126.0, 119.4, 118.8, 115.7, 111.3, 110.4, 105.6, 55.7. HRMS (ESI) m / z calcd for C 19 H 14 Cl2N3O3 + ([M + H] + ) 402.0407, found 402.0407.

[0204]

[0205] Example 4: 4-Chloro-6-[1-(4-morpholin-4-yl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (10a)

[0206] Step 1: Synthesis of (4-morpholin-4-yl-phenyl)-(2-nitro-pyridin-3-yl)-amine (8)

[0207]

[0208] 3-Fluoro-2-nitro-pyridine (1) (50.0 mg, 352 μmol), 4-(4-morpholino)aniline (75.3 mg, 422 μmol), and K2CO3 (97.3 mg, 704 μmol) were suspended in anhydrous DMF (1.0 mL) in a 5 mL microwave vial. The reaction mixture was stirred at 140 °C for 3.5 h under microwave irradiation. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator and purified by column chromatography (2:1 hexanes / EtOAc) to give compound 8 (73.5 mg, 70%) as a red solid.

[0209] TLC: R f 0.22 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, CDCl3+TMS) δ 9.12 (brs, 1H), 7.95 (dd, J = 4.0, 1.5 Hz, 1H), 7.50 (dd, J = 8.6, 1.5 Hz, 1H), 7.32 (ddd, J = 8.7, 4.0, 0.7 Hz, 1H), 7.21-7.13 (m, 2H), 7.00-6.91 (m, 2H), 3.97-3.82 (m, 4H), 3.31-3.07 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 149.7, 141.8, 139.6, 136.9, 131.0, 130.1, 126.6, 126.3, 116.4, 66.6, 48.9. HRMS (ESI) m / z calcd for C 15 H 17 N4O3 + ([M + H] + ) 301.1295, found 301.1301.

[0210] Step 2: Synthesis of N3-(4-morpholin-4-yl-phenyl)-pyridine-2,3-diamine (9)

[0211]

[0212] Compound 8 (107 mg, 356 μmol) and Pd / C (36.0 mg) were suspended in EtOH (8.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The inside of the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 7 h under a hydrogen-filled balloon. Upon completion of the reaction, the precipitate was removed by filtration using Celite. ® The residue was filtered through a plug and washed with MeOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compound 9 (57.2 mg, 59%) as a pink solid.

[0213] TLC: R f 0.13 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3+TMS) δ 7.83 (dd, J = 5.0, 1.6 Hz, 1H), 7.24 (dd, J = 7.6, 1.6 Hz, 1H), 6.91-6.75 (m, 4H), 6.65 (dd, J = 7.6, 5.0 Hz, 1H), 4.94 (brs, 1H), 4.54 (brs, 2H), 3.94-3.78 (m, 4H), 3.19-2.97 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 152.0, 145.9, 138.6, 136.6, 126.6, 122.6, 119.5, 117.2, 113.1, 66.7, 50.1. HRMS (ESI) m / z calcd for C 15 H 19 N4O + ([M + H] + ) 271.1553, found 271.1555.

[0214] Step 3: Synthesis of 4-chloro-6-[1-(4-morpholin-4-yl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (10a)

[0215]

[0216] Compound 9 (50.0 mg, 185 μmol), 5-chloro-2,4-dihydroxy-benzaldehyde (69.8 mg, 370 μmol), and Na2S2O5 (70.3 mg, 370 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, the precipitate was filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compound 10a (53.9 mg, 69%) as an ivory solid.

[0217] TLC: R f 0.24 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J = 4.8, 1.5 Hz, 1H), 7.44 (dd, J = 8.0, 1.5 Hz, 1H), 7.39 (d, J = 9.0 Hz, 2H), 7.23 (dd, J = 8.0, 4.8 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 6.88 (s, 1H), 6.41 (s, 1H), 3.90-3.67 (m, 4H), 3.25 (dd, J = 5.8, 3.9 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) 161.3, 159.9, 153.5, 153.3, 152.0, 144.9, 129.4, 128.8, 128.6, 126.9, 118.7, 118.3, 116.2, 112.6, 105.0, 102.5, 66.4, 48.4. HRMS (ESI) m / z calcd for C 22 H 20 N4O3 + ([M + H] + ) 423.1218, found 423.1220.

[0218]

[0219] Example 5: 4-Chloro-6-[1-(4-morpholin-4-ylmethyl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (15a)

[0220] Step 1: (4-Morpholin-4-ylmethyl-phenyl)-(2-nitro-pyridin-3-yl)-amine (13)

[0221]

[0222] 3-Fluoro-2-nitro-pyridine (1) (126 mg, 884 μmol), compound 12 (170 mg, 884 μmol), and K2CO3 (244 mg, 1.77 mmol) were suspended in anhydrous DMF (2.0 mL) in a 5 mL microwave vial. The reaction mixture was stirred at 140 °C for 7 h under microwave irradiation. Upon completion of the reaction, the precipitate was filtered and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compound 13 (170 mg, 61%) as a red solid.

[0223] TLC: R f 0.20 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (brs, 1H), 7.96 (dd, J = 4.0, 1.4 Hz, 1H), 7.69 (dd, J = 8.6, 1.4 Hz, 1H), 7.60-7.52 (m, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.31-7.20 (m, 2H), 3.57 (d, J = 4.6 Hz, 4H), 3.46 (s, 2H), 2.37 (d, J = 4.6 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) δ 148.1, 143.2, 138.1, 137.8, 135.1, 130.9, 130.6, 127.2, 123.8, 66.7, 62.4, 53.6. HRMS (ESI) m / z calcd for C 16 H 19 N4O3 + ([M + H] + ) 315.1452, found 315.1452.

[0224] Step 2: Synthesis of 4-morpholin-4-ylmethyl-phenylamine (14)

[0225]

[0226] Compound 13 (168 mg, 534 μmol), Fe (179 mg, 3.21 mmol), and NH4Cl (257 mg, 4.81 mmol) were suspended in MeOH / H2O (1 / 1, 2.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred in an oil bath at 90 °C for 17 h. Upon completion of the reaction, the precipitate was filtered and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (EtOAc only) to give compound 14 (91.2 mg, 60%) as an ivory solid.

[0227] TLC: R f 0.20 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (dd, J = 5.1, 1.6 Hz, 1H), 7.26 (dd, J = 7.8, 1.4 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.52 (dd, J = 7.5, 5.0 Hz, 1H), 5.59 (s, 2H), 3.55 (t, J = 4.7 Hz, 4H), 2.39-2.20 (m, 4H), 1.77 (d, J = 11.9 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 153.9, 144.0, 141.6, 130.4, 128.3, 127.0, 124.1, 115.8, 113.0, 66.7, 62.6, 53.6. HRMS (ESI) m / z calcd for C 16 H 21 N4O + ([M + H] + ) 285.1715, found 285.1710.

[0228] Step 3: Synthesis of 4-chloro-6-[1-(4-morpholin-4-ylmethyl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (15a)

[0229]

[0230] Compound 14 (80.0 mg, 281 μmol), 5-chloro-2,4-dihydroxy-benzaldehyde (79.6 mg, 422 μmol), and Na2S2O5 (107 mg, 562 μmol) were suspended in anhydrous DMF (1.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred overnight at 110 °C. Upon completion of the reaction, the precipitate was filtered and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:2 hexane / EtOAc) to give compound 15a (60.0 mg, 49%) as an ivory solid.

[0231] TLC: Rf 0.32 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (brs, 1H), 10.84 (brs, 1H), 8.49 (dd, J = 4.8, 1.5 Hz, 1H), 7.65-7.54 (m, 3H), 7.51 (d, J = 8.3 Hz, 2H), 7.30 (dd, J = 8.1, 4.8 Hz, 1H), 6.82 (s, 1H), 6.55 (s, 1H), 3.72-3.48 (m, 6H), 2.42 (t, J = 4.6 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ158.5, 156.2, 152.9, 151.9, 145.0, 139.6, 134.4, 130.8, 129.2, 128.4, 127.2, 118.9, 118.5, 110.2, 105.7, 104.2, 66.2, 61.8, 53.0. HRMS (ESI) m / z calcd for C 23 H 22 N4O3 + ([M + H] + ) 437.1375, found 437.1375.

[0232]

[0233] Example 6: 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1, 3-diol (18a)

[0234]

[0235] Using the method of Manufacturing Example 2, compound 18a (18.0 mg, 22%) was obtained as an ivory-colored solid.

[0236] TLC: R f 0.25 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, Acetone-d6) δ 8.41 (d, J = 5.0 Hz, 1H), 7.55 (dd, J = 8.0, 1.3 Hz, 1H), 7.27 (dd, J = 8.0, 5.0 Hz, 1H), 7.10 (dd, J = 2.4, 0.4 Hz, 1H), 7.07 (dd, J = 8.6, 0.4 Hz, 1H), 7.02 (dd, J = 8.6, 2.4 Hz, 1H), 6.86 (s, 1H), 6.59 (s, 1H), 4.40-4.19 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 161.0, 159.0, 155.5, 154.7, 147.6, 147.0, 146.7, 132.1, 131.4, 131.2, 123.0, 121.5, 121.2, 120.9, 119.0, 112.9, 108.6, 106.8, 66.9, 66.8. HRMS (ESI) m / z calcd for C 20 H 15 ClN3O2 + ([M + H] + ) 396.0746, found 396.0747.

[0237]

[0238] Example 7: 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (18b)

[0239]

[0240] Compound 18b (50.0 mg, 67%) was obtained as a white solid using the method of Manufacturing Example 2.

[0241] TLC: R f 0.45 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (brs, 1H), 10.03 (brs, 1H), 8.45 (dd, J = 4.8, 1.5 Hz, 1H), 7.50 (dd, J = 8.0, 1.5 Hz, 1H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 8.5, 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.15 (dd, J = 8.8, 2.4 Hz, 1H), 4.48-4.18 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 161.6, 161.0, 153.6, 153.1, 145.2, 144.7, 144.6, 129.8, 129.3, 129.3, 120.9, 119.0, 118.8, 118.7, 116.8, 107.6, 104.9, 103.7, 64.6, 64.6. HRMS (ESI) m / z calcd for C 20 H 16 N3O4 + ([M + H] + ) 362.1135, found 362.1136.

[0242]

[0243] Example 8: 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol (18c)

[0244]

[0245] Compound 18c (73.9 mg, 99%) was obtained as a white solid using the method of Manufacturing Example 2.

[0246] TLC: R f 0.30 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (brs, 1H), 8.94 br(s, 1H), 8.49 (dd, J = 4.7, 1.5 Hz, 1H), 7.58 (dd, J = 8.1, 1.5 Hz, 1H), 7.31 (dd, J = 8.1, 4.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.94 (dd, J = 8.6, 2.4 Hz, 1H), 6.79-6.76 (m, 2H), 6.58 (dd, J = 2.2, 1.1 Hz, 1H), 4.32 (td, J = 5.1, 3.6 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 153.6, 153.2, 151.0, 149.4, 145.4, 144.5, 144.4, 129.3, 129.2, 120.5, 120.1, 119.4, 119.2, 118.6, 118.0, 116.5, 115.2, 114.3, 64.60, 64.55. HRMS (ESI) m / z calcd for C 20 H 16 N3O4 + ([M + H] + ) 362.1135, found 362.1136.

[0247]

[0248] Example 9: 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-4-nitro-phenol (18e)

[0249]

[0250] Compound 18e (44.2 mg, 55%) was obtained as a white solid using the method of Manufacturing Example 2.

[0251] TLC: R f 0.45 (1:2 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (dd, J = 4.7, 1.5 Hz, 1H), 8.25-8.18 (m, 2H), 7.72 (dd, J = 8.1, 1.5 Hz, 1H), 7.37 (dd, J = 8.1, 4.7 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.09-7.02 (m, 2H), 6.98 (dd, J = 8.5, 2.4 Hz, 1H), 4.39-4.16 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 163.4, 153.8, 151.3, 145.7, 144.6, 144.4, 139.5, 129.1, 128.6, 128.0, 127.0, 120.4, 119.9, 119.6, 118.6, 117.8, 116.3, 116.0, 64.6, 64.6. HRMS (ESI) m / z calcd for C 20 H 15 N4O5 + ([M + H] + ) 391.1037, found 391.1039.

[0252]

[0253] Example 10: 2,4-Dichloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene- 1,3-diol (18f)

[0254]

[0255] Compound 18f (16.0 mg, 18%) was obtained as a white solid using the method of Manufacturing Example 2.

[0256] TLC: R f 0.35 (1:2 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.52 (dd, J = 8.3, 1.8 Hz, 1H), 8.49 (dd, J = 4.5, 1.8 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 4.5, 1.8 Hz, 1H) 8.6, 2.5 Hz, 1H), 6.99-6.89 (m, 2H), 3.76 (d, J = 1.9 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 155.8, 152.8, 152.1, 151.5, 145.9, 145.2, 144.8, 129.3, 128.5, 126.5, 121.2, 119.9, 119.3, 119.0, 117.2, 111.8, 110.8, 106.0, 64.8, 64.7. HRMS (ESI) m / z calcd for C 20 H 14 Cl2N3O4 + ([M + H] + ) 430.0356, found 430.0360.

[0257]

[0258] Examples 11 to 20 below were synthesized based on the following reaction scheme 2.

[0259] [Reaction Formula 2]

[0260]

[0261]

[0262] Manufacturing Example 3: Synthesis of imidazopyridine (23a-c)

[0263] Step 1: Synthesis of (2-chloro-pyridin-3-yl)-(4-methoxy-phenyl)-amine (20)

[0264]

[0265] p-Anisidine (99.1 mg, 805 μmmol) was suspended in anhydrous THF (1.0 mL) in a 10 mL oven-dried round-bottom flask with a side arm. Na-HMDS (148 mg, 805 μmol in THF) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. 2,3-Dichloroprazine (19) (100 mg, 671 μmol) was added, and the reaction mixture was stirred at room temperature for 18 h. Upon completion of the reaction, saturated aqueous NH4Cl solution (30 mL) was added to the reaction mixture and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated using a rotary evaporator. The residue was purified by column chromatography (4:1 hexanes / EtOAc) to give compound 20 (66.7 mg, 42%) as a yellow solid.

[0266] TLC: R f 0.45 (4:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 2.7 Hz, 1H), 7.56-7.37 (m, 2H), 7.02-6.79 (m, 2H), 3.80 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 159.9, 147.7, 135.5, 129.5, 118.8, 117.8, 112.5, 112.0, 44.2. HRMS (ESI) m / z calcd for C 11 H 11 ClN3O + ([M + H] + ) 236.0585, found 236.0587.

[0267] Step 2: Synthesis of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(2-nitro-pyridin-3-yl)-amine (22)

[0268]

[0269] In a 5 mL microwave vial, compound 20 (66.7 mg, 283 μmol) and NaN3 (46.0 mg, 707 μmol) were suspended in anhydrous DMF (1.0 mL). The reaction mixture was stirred at 110 °C for 10 h under microwave irradiation. Upon completion of the reaction, the reaction mixture was poured into ice water, and the resulting solid was filtered and washed with water (10 mL). The filtered solid product 21 was used in the next step without further purification. TLC: Rf 0.30 (2:1 hexanes / EtOAc).

[0270] Next, compound 21 (68.5 mg, 283 μmol) and SnCl2 (537 mg, 2.83 mmol) were suspended in concentrated HCl (1.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred at 100 °C for 3 h. Upon completion of the reaction, the reaction mixture was diluted with water (5 mL) and the pH was adjusted to 10 with saturated aqueous K2CO3 solution. The aqueous layer was extracted with CH2Cl2 (3 X 60 mL), and the combined organic layers were concentrated using a rotary evaporator. The residue was purified by column chromatography (1:1 hexane / EtOAc) to give compound 22 (22.4 mg, 37%) as a yellow solid.

[0271] TLC: R f 0.13 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (brs, 1H), 7.61-7.55 (m, 2H), 7.34-7.27 (m, 2H), 6.93-6.82 (m, 2H), 6.21 (brs, 2H), 3.72 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) 160.1, 142.8, 133.5, 130.1, 119.4, 119.2, 113.3, 112.8, 41.8. HRMS (ESI) m / z calcd for C 11 H 13 N4O+ ([M + H] + ) 217.1084, found 217.1087.

[0272] Step 3: Synthesis of imidazopyrazines (23a-23c)

[0273]

[0274] Compound 22 (50.0 mg, 231 μmol), aldehyde 20a-c (277 μmol), and Na2S2O5 (87.8 mg, 462 μmol) were suspended in anhydrous DMF (1.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred overnight at 110 °C. Upon completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compounds 23a-c as an ivory solid.

[0275]

[0276] Manufacturing Example 4: Imidazopyrazine (31a-31f)

[0277] Step 1: Synthesis of (3-chloro-pyrazin-2-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (28)

[0278]

[0279] 1,4-Benzadioxan-6-amine (122 mg, 1.23 mmol) was suspended in anhydrous THF (1.0 mL) in a 10 mL oven-dried round-bottom flask with a side arm. Na-HMDS (148 mg, 805 μmol in THF) was added dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. 2,3-Dichloroprazine (19) (100 mg, 0.67 mmol) was added, and the reaction mixture was stirred at room temperature for 14 h. Upon completion of the reaction, saturated aqueous NH4Cl solution (5 mL) was added to the reaction mixture, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were concentrated using a rotary evaporator and purified by chromatography (4:1 Hex / EtOAc) to give compound 28 (74.0 mg, 42%) as a yellow solid.

[0280] TLC: R f 0.50 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.74 (d, J = 2.6 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.8, 2.5 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 4.28-4.15 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 149.0, 142.8, 140.3, 139.6, 134.1, 132.6, 132.1, 116.4, 115.3, 111.0, 64.1, 64.0. HRMS (ESI) m / z calcd for C 12 H 11 ClN3O2 + ([M + H] + ) 264.0534, found 264.0536.

[0281] Step 2: Synthesis of N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-pyrazine-2,3-diamine (30)

[0282]

[0283] Compound 28 (74.0 mg, 0.281 mmol) and NaN3 (45.6 mg, 0.702 mmol) were suspended in anhydrous DMF (1.0 mL) in a 10 mL microwave vial. The reaction mixture was stirred at 140 °C for 10 h under microwave irradiation. Upon completion of the reaction, the reaction mixture was poured into ice water, and the resulting solid was filtered and washed with water (10 mL). The filtered solid product 29 was used in the next step without further purification. TLC: Rf 0.35 (2:1 hexanes / EtOAc).

[0284] Next, compound 29 (681 mg, 2.52 mmol) and SnCl2 (4.78 g, 25.2 mmol) were suspended in concentrated HCl (10 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred at 100 °C for 3 h. Upon completion of the reaction, the reaction mixture was diluted with water (50 mL) and the pH was adjusted to 10 with saturated aqueous K2CO3 solution. The aqueous layer was extracted with CH2Cl2 (3 X 300 mL), and the combined organic layers were concentrated using a rotary evaporator. The residue was purified by column chromatography (1:1 hexane / EtOAc) to give compound 30 (391 mg, 63%) as a yellow solid.

[0285] TLC: R f 0.40 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.32 (s, 2H), 7.04 (dd, J = 8.8, 2.6 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.21 (s, 2H), 4.33-4.11 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 145.2, 143.3, 140.2, 138.5, 135.2, 131.1, 128.6, 117.0, 113.1, 108.7, 64.7, 64.4. HRMS (ESI) m / z calcd for C 12 H 13 N4O2 + ([M + H] + ) 245.1033, found 245.1032.

[0286] Step 3: Synthesis of imidazopyrazines (31a-31f)

[0287]

[0288] Compound 30 (60.0 mg, 246 μmol), aldehyde 21a-f (295 μmol), and Na2S2O5 (93.5 mg, 492 μmol) were suspended in anhydrous DMF (1.0 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, the precipitate was filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexane / EtOAc) to give compounds 31a-f as an ivory solid.

[0289]

[0290] Example 11: 4-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol (23a)

[0291]

[0292] Compound 23a (62.8 mg, 81%) was obtained as a white solid using the method of Manufacturing Example 3.

[0293] TLC: R f 0.25 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.49-8.42 (m, 1H), 8.26 (d, J = 4.7 Hz, 1H), 7.46-7.37 (m, 2H), 7.15-7.05 (m, 2H), 6.92 (d, J = 8.8 Hz, 1H), 6.29 (s, 1H), 6.12 (s, 1H), 3.82 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 161.2, 159.9, 159.1, 155.3, 146.0, 141.5, 139.3, 137.6, 129.8, 128.6, 127.0, 114.3, 106.9, 104.1, 102.6, 55.0. HRMS (ESI) m / z calcd for C 18 H 15 N4O3 + ([M + H] + ) 335.1139, found 335.1143.

[0294]

[0295] Example 12: 2-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,4-diol (23b)

[0296]

[0297] Compound 23b (63.0 mg, 79%) was obtained as a white solid using the method of Manufacturing Example 3.

[0298] TLC: R f 0.35 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (brs, 1H), 9.05 (brs, 1H), 8.57 (d, J = 2.7 Hz, 1H), 8.37 (d, J = 2.7 Hz, 1H), 7.39 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 6.78 (dd, J = 8.8, 2.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 3.82 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.4, 155.6, 149.9, 149.2, 147.2, 141.8, 140.1, 138.7, 128.6, 127.3, 120.0, 117.5, 115.6, 114.7, 114.5, 55.4. HRMS (ESI) m / z calcd for C 18 H 15 N4O3 + ([M + H] + ) 335.1139, found 335.1143.

[0299]

[0300] Example 13: 4-Chloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol (23c)

[0301]

[0302] Compound 23c (7.00 mg, 16%) was obtained as a white solid using the method of Manufacturing Example 3.

[0303] TLC: R f 0.27 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ11.64 (brs, 1H), 10.85 (brs, 1H), 8.53 (d, J = 2.7 Hz, 1H), 8.33 (d, J = 2.7 Hz, 1H), 7.44 (d, J = 9.0 Hz, 2H), 7.28-6.99 (m, 3H), 6.50 (s, 1H), 3.84 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 159.2, 158.1, 154.8, 146.9, 141.9, 140.0, 138.3, 130.2, 129.0, 127.3, 114.7, 110.8, 105.8, 104.1, 55.6. HRMS (ESI) m / z calcd for C 18 H 14 ClN4O3 + ([M + H] + ) 369.0749, found 369.0752.

[0304]

[0305] Example 14: 4-Chloro-6-[1-(4-morpholin-4-yl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (27a)

[0306] Step 1: Synthesis of (3-chloro-pyrazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (24)

[0307]

[0308] 4-(4-Morpholino)aniline (861 mg, 4.83 mmol) was suspended in anhydrous THF (6.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm, and Na-HMDS (1.03 g in THF, 5.64 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. 2,3-Dichloropyrazine (19) (600 mg, 3.73 mmol) was added, and the reaction mixture was stirred at room temperature for 18 h. Upon completion of the reaction, saturated aqueous NH4Cl solution (50 mL) was added to the reaction mixture, and the aqueous layer was extracted with EtOAc (3 X 200 mL). The combined organic layers were concentrated using a rotary evaporator and purified by column chromatography (4:1 Hex / EtOAc) to give compound 24 (459 mg, 42%) as a yellow solid.

[0309] TLC: R f 0.45 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.71 (d, J = 2.6 Hz, 1H), 7.50-7.40 (m, 2H), 6.96-6.85 (m, 2H), 3.88-3.59 (m, 4H), 3.18-2.92 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 149.2, 147.6, 140.4, 134.0, 131.7, 131.0, 123.3, 115.2, 66.1, 48.9. HRMS (ESI) m / z calcd for C 14 H 16 ClN4O + ([M + H] + ) 291.1007, found 291.100.

[0310] Step 2: Synthesis of N-(4-morpholin-4-yl-phenyl)-pyrazine-2,3-diamine (26)

[0311]

[0312] Compound 24 (438 mg, 1.51 mmol) and NaN3 (246 mg, 3.78 mmol) were suspended in anhydrous DMF (5.0 mL) in a 10 mL microwave vial. The reaction mixture was stirred at 140 °C for 8 h under microwave irradiation. Upon completion of the reaction, the reaction mixture was poured into ice water, and the resulting solid was filtered and washed with water (20 mL). The filtered solid product 25 was used in the next step without further purification. TLC: Rf 0.27 (1:1 hexane / EtOAc).

[0313] Next, compound 25 (450 mg, 1.51 mmol) and SnCl2 (2.87 g, 15.1 mmol) were suspended in a concentrated HCl (6.2 mL) solution in a 50 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred at 100 °C for 3 h. Upon completion of the reaction, the reaction mixture was diluted with water (20 mL) and the pH was adjusted to 10 with saturated aqueous K2CO3 solution. The aqueous layer was extracted with CH2Cl2 (3 X 300 mL), and the combined organic layers were concentrated using a rotary evaporator. The residue was purified by column chromatography (1:2 hexane / EtOAc) to give compound 26 (343 mg, 84%) as a yellow solid.

[0314] TLC: R f 0.13 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.58-7.51 (m, 2H), 7.29 (s, 2H), 6.94-6.85 (m, 2H), 6.21 (s, 2H), 3.79-3.70 (m, 4H), 3.08-2.96 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 146.1, 144.6, 140.1, 133.4, 130.3, 128.2, 120.6, 115.7, 66.2, 49.30. HRMS (ESI) m / z calcd for C14 H 18 N5O + ([M + H] + ) 272.1506, found 272.1507.

[0315] Step 3: Synthesis of 4-chloro-6-[1-(4-morpholin-4-yl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol (27a)

[0316]

[0317] Compound 26 (50.0 mg, 0.184 mmol), 5-chloro-2,4-dihydroxy-benzaldehyde (41.6 mg, 221 μmol), and Na2S2O5 (69.9 mg, 368 μmol) were suspended in anhydrous DMF (0.5 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, the precipitate was filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (2:1 hexanes / EtOAc) to give compound 27a (19.7 mg, 25%) as an ivory solid.

[0318] TLC: R f 0.35 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (brs, 1H), 10.88 (brs, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 2.7 Hz, 1H), 7.35 (d, J = 9.0 Hz, 2H), 7.16 (s, 1H), 7.11 (d, J = 9.0 Hz, 2H), 6.55 (s, 1H), 3.88-3.60 (m, 4H), 3.24-3.04 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 158.6, 157.0, 155.2, 151.8, 147.2, 142.3, 140.5, 139.0, 130.7, 128.6, 125.8, 115.6, 110.9, 106.9, 104.5, 66.4, 48.4. HRMS (ESI) m / z calcd for C 21 H 19 ClN5O3 + ([M + H] + ) 424.1171, found 424.1171.

[0319]

[0320] Example 15: 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1, 3-diol (31a)

[0321]

[0322] Compound 31a (14.0 mg, 14%) was obtained as a white solid using the method of Manufacturing Example 4.

[0323] TLC: R f 0.25 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.91 (dd, J = 8.4, 2.5 Hz, 1H), 6.76 (s, 1H), 4.50-4.28 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 158.5, 157.0, 155.0, 147.2, 144.6, 144.0, 142.2, 140.5, 139.0, 130.8, 128.0, 121.0, 118.1, 117.1, 111.0, 107.0, 104.5, 64.7, 64.6. HRMS (ESI) m / z calcd for C 19 H 13 ClN4O4 + ([M + H] + ) 397.0698, found 397.0699.

[0324]

[0325] Example 16: 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol (31b)

[0326]

[0327] Compound 31b (22.8 mg, 26%) was obtained as a white solid using the method of Manufacturing Example 4.

[0328] TLC: R f 0.25 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (brs, 1H), 8.50 (d, J = 2.7 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 8.6, 2.4 Hz, 1H), 6.36 (d, J = 2.3 Hz, 1H), 6.20 (dd, J = 8.8, 2.3 Hz, 1H), 4.51-4.16 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 162.2, 160.9, 156.1, 147.0, 144.6, 144.2, 142.4, 140.3, 138.6, 130.7, 128.3, 121.2, 118.2, 117.3, 108.0, 105.1, 103.6, 64.6, 64.5. HRMS (ESI) m / z calcd for C 19 H 15 N4O4 + ([M + H] + ) 363.1088, found 363.1088.

[0329]

[0330] Example 17: 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,4-diol (31c)

[0331]

[0332] Compound 31c (41.3 mg, 46%) was obtained as a white solid using the method of Manufacturing Example 4.

[0333] TLC: R f 0.30 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (brs, 1H), 9.02 (brs, 1H), 8.57 (d, J = 2.7 Hz, 1H), 8.38 (d, J = 2.7 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.89 (dd, J = 8.6, 2.4 Hz, 1H), 6.80 (dd, J = 8.8, 2.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 2.8 Hz, 1H), 4.30 (tt, J = 5.1, 2.6 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) δ 159.8, 156.0, 150.3, 149.7, 147.6, 142.28, 140.6, 139.1, 129.1, 127.7, 120.5, 117.9, 116.1, 115.1, 115.0, 55.9. HRMS (ESI) m / z calcd for C 19 H 15 N4O4 + ([M + H] + ) 363.1088, found 363.1090.

[0334]

[0335] Example 18: 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-4-nitro-phenol (31d)

[0336]

[0337] Compound 31d (40.6 mg, 42%) was obtained as a white solid using the method of Preparation Example 4.

[0338] TLC: R f 0.35 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 2.6 Hz, 1H), 8.43 (d, J = 2.6 Hz, 1H), 8.21 (dd, J = 9.2, 2.7 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.23-7.15 (m, 2H), 7.01 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 8.5, 2.5 Hz, 1H), 4.44-4.32 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 162.9, 154.0, 147.8, 144.4, 143.8, 142.0, 140.9, 139.7, 139.6, 128.5, 128.1, 127.6, 120.6, 117.8, 117.5, 117.0, 116.6, 64.6, 64.5. HRMS (ESI) m / z calcd for C 19 H 14 N5O5 + ([M + H] + ) 392.0989, found 392.0991.

[0339]

[0340] Example 19: 2,4-Dichloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene- 1,3-diol (31e)

[0341]

[0342] Compound 31e (14.0 mg, 14%) was obtained as a white solid using the method of Manufacturing Example 4.

[0343] TLC: R f 0.30 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (brs, 1H), 11.06 (brs, 1H), 8.59 (d, J = 2.7 Hz, 1H), 8.39 (d, J = 2.7 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.06 (dd, J = 8.6, 2.4 Hz, 1H), 7.00 (s, 1H), 4.50-4.21 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 155.7, 153.9, 153.3, 146.1, 145.1, 144.4, 142.3, 141.0 139.6, 127.5, 127.4, 121.6, 118.5, 117.6, 112.2, 110.9, 106.2, 64.7, 64.6. HRMS (ESI) m / z calcd for C 19 H 13 Cl2N4O4 + ([M + H] + ) 431.0308, found 431.0313.

[0344]

[0345] Example 20: 4-Chloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol (31f)

[0346]

[0347] Using the method of Manufacturing Example 4, compound 31f (34.0 mg, 33%) was obtained as a white solid.

[0348] TLC: R f 0.19 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 2.7 Hz, 1H), 8.37 (d, J = 2.7 Hz, 1H), 7.22 (s, 1H), 7.00-6.85 (m, 2H), 6.75 (dd, J = 8.6, 2.5 Hz, 1H), 6.66 (s, 1H), 4.38-4.18 (m, 4H), 3.84 (s, 3H), 3.74 (s, 3H), 3.41 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 156.2, 152.5, 152.1, 148.7, 143.7, 143.6, 143.0, 142.0, 140.3, 138.8, 128.3, 120.0, 117.4, 116.1, 115.5, 109.4, 98.0, 64.6, 64.5, 56.6, 56.3, 56.1. HRMS (ESI) m / z calcd for C 22 H 21 N4O5 + ([M + H] + ) 421.1506, found 421.1512.

[0349]

[0350] Examples 21 to 29 below were synthesized based on the following reaction scheme 3.

[0351] [Reaction Formula 3]

[0352]

[0353]

[0354] Manufacturing Example 5: Synthesis of imidazopyridine (35a-j)

[0355] Step 1: Synthesis of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-nitro-pyridin-4-yl)-amine (33)

[0356]

[0357] In a 5 mL oven-dried round-bottom flask with a sidearm, 4-chloro-3-nitropyridine (32) (50.0 mg, 315 μmol), 3,4-ethylenedioxyaniline (57.2 mg, 378 μmol), and K2CO3 (87.2 mg, 631 μmol) were suspended in isopropanol (0.5 mL). The reaction mixture was stirred at 80 °C for 3 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (10 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (4:1 hexanes / EtOAc) to give compound 33 (83.3 mg, 97%) as a red solid.

[0358] TLC: R f 0.50 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (brs, 1H), 9.32 (s, 1H), 8.24 (d, J = 7.0 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.84 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 149.9, 148.3, 146.5, 143.8, 142.6, 130.0, 129.93, 119.1, 117.8, 115.1, 110.3, 64.1, 64.0. HRMS (ESI) m / z calcd for C 13 H 11 N3O4 + ([M + H] + ) 274.0822, found 274.0824.

[0359] Step 2: Synthesis of N4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-pyridine-3,4-diamine (34)

[0360]

[0361] Compound 33 (1.72 g, 6.31 mmol) and Pd / C (172 mg) were suspended in EtOH (15.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The flask was purged and stirred at room temperature under a hydrogen-filled balloon for 7 h. Upon completion of the reaction, the reaction mixture was placed in Celite ® The residue was filtered through a plug and washed with MeOH (50.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give compound 34 (904 mg, 87%) as a pink solid.

[0362] TLC: R f 0.32 (5:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (brs, 1H), 7.58 (d, J = 5.4 Hz, 1H), 7.24 (s, 1H), 6.84-6.78 (m, 1H), 6.73 (d, J = 5.3 Hz, 1H), 6.64-6.57 (m, 2H), 4.79 (brs, 2H), 4.34-4.15 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 143.6, 139.0, 138.9, 137.7, 135.9, 134.9, 132.7, 117.4, 114.1, 109.6, 107.3, 64.2, 63.9. HRMS (ESI) m / z calcd for C 13 H 14 N3O2 + ([M + H] + ) 244.1081, found 244.1090.

[0363] Step 3: Synthesis of imidazopyridines (35a-j)

[0364]

[0365] Compound 34 (100 mg, 411 μmol), aldehyde 22a-j (493 μmol), and Na2S2O5 (156 mg, 822 μmol) were suspended in anhydrous DMF (1.0 mL) in a 10 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred overnight at 110 °C. Upon completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (50:1 CH2Cl2 / MeOH) to give compounds 35a-j as an ivory-colored solid.

[0366]

[0367] Example 21: 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,3-diol (35a)

[0368]

[0369] Compound 35a (143 mg, 83%) was obtained as a white solid using the method of Manufacturing Example 5.

[0370] TLC: R f 0.30 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (brs, 1H), 9.96 (brs, 1H), 9.01 (d, J = 1.0 Hz, 1H), 8.34 (d, J = 5.5 Hz, 1H), 7.15 (dd, J = 5.5, 1.1 Hz, 1H), 7.10-7.05 (m, 2H), 6.95 (dd, J = 8.6, 2.5 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.17 (dd, J = 8.7, 2.4 Hz, 1H), 4.33 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 159.8, 152.9, 144.2, 144.0, 142.4, 140.9, 140.4, 137.6, 129.8, 128.7, 120.2, 118.2, 116.1, 107.0, 105.7, 104.9, 103.0, 64.1, 64.0. HRMS (ESI) m / z calcd for calcd for C 20 H 16 N3O4 + ([M + H] + ) 362.1135, found 362.1136.

[0371] Example 22: 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,4-diol (35b)

[0372]

[0373] Compound 35b (121 mg, 81%) was obtained as a white solid using the method of Preparation Example 5.

[0374] TLC: R f 0.28 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (brs, 1H), 9.05 (d, J = 1.0 Hz, 1H), 8.95 (brs, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.22 (dd, J = 5.6, 1.0 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.90 (dd, J = 8.6, 2.5 Hz, 1H), 6.75 (d, J = 1.7 Hz, 2H), 6.61 (t, J = 1.7 Hz, 1H), 4.32 (tt, J = 4.7, 3.0 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 153.0, 150.5, 149.5, 144.4, 144.3, 143.0, 141.6, 141.3, 138.8, 129.0, 120.3, 119.8, 118.4, 117.8, 116.2, 115.8, 115.0, 106.4, 64.6, 64.5. HRMS (ESI) m / z calcd for C 20 H 16 N3O4 + ([M + H] + ) 362.1135, found 362.1138.

[0375]

[0376] Example 23: 5-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,2,4-triol (35c)

[0377]

[0378] Compound 35c (138 mg, 89%) was obtained as a white solid using the method of Manufacturing Example 5.

[0379] TLC: R f 0.32 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (brs, 1H), 9.73 (brs, 1H), 9.25 (brs, 1H), 8.51 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 6.0 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.95 (dd, J = 8.6, 2.5 Hz, 1H), 6.56 (s, 1H), 6.37 (s, 1H), 4.42-4.19 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 156.4, 152.8, 150.7, 144.9, 144.5, 143.97, 138.7, 138.3, 137.0, 128.6, 120.4, 118.7, 116.4, 115.5, 104.2, 103.5, 64.64, 64.58. HRMS (ESI) m / z calcd for calcd for C 20 H 16 N3O5 + ([M + H] + ) 378.1084, found 378.1087.

[0380]

[0381] Example 24: 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-4-nitro-phenol (35d)

[0382]

[0383] Compound 35d (19.0 mg, 12%) was obtained as a white solid using the method of Preparation Example 5.

[0384] TLC: R f 0.35 (1:2 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (brs, 1H), 9.15 (d, J = 1.1 Hz, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.22 (dd, J = 9.1, 2.8 Hz, 1H), 7.37 (dd, J = 5.6, 1.1 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.94 (dd, J = 8.6, 2.4 Hz, 1H), 4.42-4.13 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 163.2, 151.3, 144.5, 144.2, 143.2, 142.1, 141.3, 139.5, 139.1, 128.5, 128.1, 127.6, 120.1, 118.4, 117.4, 116.7, 116.0, 106.6, 64.60, 64.56. HRMS (ESI) m / z calcd for C 20 H 15 N4O5 + ([M + H] + ) 391.1037, found 391.1040.

[0385]

[0386] Example 25: 2-Chloro-4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol (35f)

[0387]

[0388] Using the method of Preparation Example 5, compound 35f (139 mg, 86%) was obtained as a white solid.

[0389] TLC: R f 0.25 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 13.55 (brs, 1H), 10.81 (brs, 1H), 9.06 (d, J = 1.0 Hz, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.15-7.10 (m, 2H), 7.02 (dd, J = 8.6, 2.4 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 6.34 (d, J = 9.0 Hz, 1H), 4.52-4.18 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 157.2, 157.0, 152.6, 145.1, 144.8, 143.2, 141.6, 140.7, 137.0, 128.8, 126.8, 120.9, 119.0, 116.9, 108.5, 107.3, 106.3, 105.4, 64.7, 64.6. HRMS (ESI) m / z calcd for C 20 H 15 ClN3O4 + ([M + H] + ) 396.0746, found 396.0747.

[0390]

[0391] Example 26: 3-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine (35 g)

[0392]

[0393] Using the method of Manufacturing Example 5, compound 35 g (126 mg, 89%) was obtained as a white solid.

[0394] TLC: R f 0.20 (50:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.01 (dd, J = 4.8, 1.9 Hz, 1H), 7.28 (dd, J = 7.6, 1.9 Hz, 1H), 7.22 (dd, J = 5.6, 1.0 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.92 (brs, 2H), 6.89 (dd, J = 8.6, 2.5 Hz, 1H), 6.46 (dd, J = 7.6, 4.8 Hz, 1H), 4.42-4.20 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 158.4, 152.1, 150.5, 144.4, 144.3, 143.0, 141.9, 141.7, 139.6, 138.8, 129.0, 120.6, 118.6, 116.5, 111.6, 106.6, 106.4, 64.6, 64.5. HRMS (ESI) m / z calcd for C 19 H 16 N5O2 + ([M + H] + ) 346.1299, found 346.1297.

[0395]

[0396] Example 27: 6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-3-ol (35h)

[0397]

[0398] Using the method of Preparation Example 5, compound 35h (79.0 mg, 55%) was obtained as a white solid.

[0399] TLC: R f 0.23 (50:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (brs, 1H), 9.05 (d, J = 1.0 Hz, 1H), 8.35 (d, J = 5.6 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.31 (dd, J = 8.6, 2.8 Hz, 1H), 7.22 (dd, J = 5.6, 1.1 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.5 Hz, 1H), 4.43-4.21 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 155.2, 152.7, 143.9, 143.8, 142.83, 142.3, 142.2, 139.9, 139.6, 137.7, 130.1, 126.6, 123.1, 120.5, 117.9, 116.3, 106.6, 64.6, 64.5. HRMS (ESI) m / z calcd for C 19 H 15 N4O2 + ([M + H] + ) 347.1139, found 347.1144.

[0400]

[0401] Example 28: 5-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine (35i)

[0402]

[0403] Compound 35i (136 mg, 96%) was obtained as a white solid using the method of Preparation Example 5.

[0404] TLC: R f 0.18 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 1.0 Hz, 1H), 8.29 (d, J = 5.5 Hz, 1H), 8.06 (dd, J = 2.5, 0.8 Hz, 1H), 7.56 (dd, J = 8.7, 2.5 Hz, 1H), 7.15 (dd, J = 5.5, 1.0 Hz, 1H), 7.09-7.03 (m, 2H), 6.92 (dd, J = 8.5, 2.5 Hz, 1H), 6.47 (brs, 2H), 6.41 (dd, J = 8.7, 0.8 Hz, 1H), 4.45-4.25 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 160.8, 153.2, 149.5, 144.6, 144.5, 142.4, 142.2, 141.3, 140.2, 137.8, 129.2, 120.8, 118.7, 116.8, 113.5, 107.7, 106.2, 64.60, 64.57. HRMS (ESI) m / z calcd for C 19 H 16 N5O2 + ([M + H] + ) 346.1299, found 346.1297.

[0405]

[0406] Example 29: 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol (35j)

[0407]

[0408] Compound 35j (130 mg, 80%) was obtained as a white solid using the method of Manufacturing Example 5.

[0409] TLC: R f 0.48 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (brs, 1H), 10.72 (brs, 1H), 9.03 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 5.5 Hz, 1H), 7.21 (dd, J = 5.5, 1.1 Hz, 1H), 7.11-7.04 (m, 3H), 6.96 (dd, J = 8.6, 2.5 Hz, 1H), 6.53 (s, 1H), 4.32 (tt, J = 5.0, 3.2 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) δ 158.5, 153.4, 150.7, 147.1, 144.4, 144.3, 142.6, 138.9, 134.8, 134.0, 129.08, 120.05, 118.6, 116.6, 114.1, 111.7, 106.4, 64.6, 64.5. HRMS (ESI) m / z calcd for C 20 H 15 ClN3O4 + ([M + H] + ) 396.0746, found 396.0744.

[0410]

[0411] Examples 30 to 36 below were synthesized based on the following reaction scheme 4.

[0412] [Reaction Formula 4]

[0413]

[0414]

[0415] Manufacturing Example 6: Synthesis of imidazopyridine (39a-g)

[0416] Step 1: Synthesis of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-nitro-pyridin-3-yl)-amine (37)

[0417]

[0418] 3-Chloro-4-nitropyridine (36) (1.00 g, 6.31 mmol), 3,4-ethylenedioxyaniline (953 mg, 6.31 mmol), and K3PO4 (2.68 g, 12.6 mmol) were added to a 100 mL oven-dried round-bottom flask with a side arm. Pd2(dba)3 (462 mg, 505 μmol) and Xantphos (620 mg, 1.07 mmol) were added to the reaction flask in a glovebox. 1,4-Dioxane (28 mL) was added to the reaction mixture via syringe, and the reaction mixture was stirred in an oil bath at 80 °C for 15 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitate was filtered through Celite® and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator and purified by column chromatography (2:1 hexanes / EtOAc) to obtain compound 37 (1.67 g, 97%) as a red solid.

[0419] TLC: R f 0.48 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, CDCl3) δ 8.99 (brs, 1H), 8.63 (s, 1H), 8.01 (d, J = 5.7 Hz, 1H), 7.89 (dd, J = 5.7, 0.5 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H), 6.78 (ddd, J = 8.5, 2.6, 0.6 Hz, 1H), 4.30 (s, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 143.9, 141.8, 141.6, 137.0, 136.8, 136.2, 131.5, 118.0, 117.7, 117.0, 113.9, 64.1, 64.0. HRMS (ESI) m / z calcd for C 13 H 12 N3O4 + ([M + H] +) 274.0822, found 274.0823.

[0420] Step 2: Synthesis of N3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-pyridine-3,4-diamine (38)

[0421]

[0422] Compound 37 (2.00 g, 7.32 mmol) and Pd / C (200 mg) were suspended in EtOH (20 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The flask was purged and stirred at room temperature under a hydrogen-filled balloon for 15 h. Upon completion of the reaction, the reaction mixture was filtered through a Celite® plug and washed with MeOH (100 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (20:1 CH2Cl2 / MeOH) to give compound 38 (1.74 g, 98%) as a pink solid.

[0423] TLC: R f 0.25 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (brs, 1H), 7.82 (d, J = 5.4 Hz, 1H), 6.88 (s, 1H), 6.66 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 5.4 Hz, 1H), 6.21 (dd, J = 8.6, 2.6 Hz, 1H), 6.15 (d, J = 2.6 Hz, 1H), 5.63 (brs, 2H), 4.35-3.90 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 149.6, 144.1, 143.2, 141.0, 139.8, 137.0, 125.9, 117.7, 109.5, 109.3, 104.8, 64.8, 64.7. HRMS (ESI) m / z C 13 H 14 N3O2 + ([M + H] +) 244.1081, found 244.1080.

[0424] Step 3: Synthesis of imidazopyridines (39a-g)

[0425]

[0426] Compound 38 (100 mg, 411 μmol), aldehyde 40a-g (493 μmol), and Na2S2O5 (156 mg, 822 μmol) were suspended in anhydrous DMF (1.0 mL) in a 10 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, the precipitate was filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator and purified by column chromatography (1:1 hexane / EtOAc) to give compounds 39a-g as an ivory solid.

[0427]

[0428] Example 30: 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,4-diol (39a)

[0429]

[0430] Compound 39a (107 mg, 72%) was obtained as a white solid using the method of Manufacturing Example 6.

[0431] TLC: R f 0.15 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (brs, 1H), 8.98 (brs, 1H), 8.51 (d, J = 1.0 Hz, 1H), 8.44 (d, J = 5.5 Hz, 1H), 7.78 (dd, J = 5.5, 1.0 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 8.6, 2.4 Hz, 1H), 6.82-6.72 (m, 2H), 6.62 (dd, J = 2.1, 1.2 Hz, 1H), 4.43-4.19 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 154.1, 150.8, 149.5, 146.1, 144.5, 144.4, 142.8, 134.4, 134.1, 129.1, 120.3, 120.2, 118.5, 117.9, 116.3, 115.7, 114.6, 113.7, 64.6, 64.5. HRMS (ESI) m / z calcd for C 20 H 16 N3O4 + ([M + H] + ) 362.1135, found 362.1137.

[0432]

[0433] Example 31: 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-nitro-phenol (39b)

[0434]

[0435] Compound 39b (71.6 mg, 46%) was obtained as a white solid using the method of Preparation Example 6.

[0436] TLC: R f 0.38 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (brs, 1H), 8.70 (d, J = 1.0 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.29 (dd, J = 9.1, 2.8 Hz, 1H), 7.89 (dd, J = 5.5, 1.0 Hz, 1H), 7.21 (dd, J = 2.1, 0.8 Hz, 1H), 7.16-7.01 (m, 3H), 4.36 (td, J = 5.3, 3.7 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 163.3, 152.3, 146.5, 144.5, 144.3, 142.8, 139.5, 134.4, 134.2, 128.6, 128.2, 127.7, 120.1, 118.4, 117.5, 116.5, 116.1, 114.2, 64.60, 64.55. HRMS (ESI) m / z calcd for C 20 H 15 N4O5 + ([M + H] + ) 391.1037, found 391.1038.

[0437]

[0438] Example 32: 4-Chloro-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol (39c)

[0439]

[0440] Compound 39c (54.3 mg, 33%) was obtained as a white solid using the method of Manufacturing Example 6.

[0441] TLC: R f 0.25 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 10.78 (s, 1H), 8.50 (d, J = 1.0 Hz, 1H), 8.43 (d, J = 5.5 Hz, 1H), 7.76 (dd, J = 5.5, 1.0 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.06 (s, 1H), 7.03 (dd, J = 8.6, 2.4 Hz, 1H), 6.55 (s, 1H), 4.33 (ddp, J = 5.4, 3.5, 2.2, 1.8 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 158.6, 156.6, 153.4, 145.9, 144.7, 144.5, 142.8, 134.3, 133.8, 130.4, 129.0, 120.6, 118.6, 116.5, 113.5, 110.7, 106.8, 104.5, 64.7, 64.6. HRMS (ESI) m / z calcd for C 20 H 15 ClN3O4 + ([M + H] + ) 396.0746, found 396.0746.

[0442]

[0443] Example 33: 3-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine (39d)

[0444]

[0445] Using the method of Manufacturing Example 6, compound 39d (95.7 mg, 67%) was obtained as a white solid.

[0446] TLC: R f 0.35 (EtOAc only). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 1.0 Hz, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.03 (dd, J = 4.8, 1.9 Hz, 1H), 7.79 (dd, J = 5.5, 1.0 Hz, 1H), 7.30 (dd, J = 7.7, 1.9 Hz, 1H), 7.12 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 7.00-6.88 (m, 3H), 6.47 (dd, J = 7.7, 4.8 Hz, 1H), 4.32 (qd, J = 5.2, 4.4, 1.8 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 158.2, 156.4, 152.3, 144.6, 144.4, 143.0, 141.3, 138.5, 130.5, 128.9, 120.5, 118.6, 116.4, 110.6, 107.2, 106.3, 104.4, 64.7, 64.6. HRMS (ESI) m / z calcd for C 19 H 16 N5O2 + ([M + H] + ) 346.1299, found 346.1301.

[0447]

[0448] Example 34: 5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine (39e)

[0449]

[0450] Using the method of Preparation Example 6, compound 39e (72.2 mg, 51%) was obtained as a white solid.

[0451] TLC: R f 0.45 (1:1 hexane / EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 5.5 Hz, 1H), 8.09 (dd, J = 2.4, 0.8 Hz, 1H), 7.67 (dd, J = 5.5, 1.0 Hz, 1H), 7.57 (dd, J = 8.7, 2.5 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 8.6, 2.5 Hz, 1H), 6.52 (s, 2H), 6.41 (dd, J = 8.8, 0.8 Hz, 1H), 5.76 (s, 1H), 4.34 (td, J = 5.2, 3.6 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 160.9, 154.3, 149.8, 144.6, 142.5, 138.0, 135.5, 133.5, 129.3, 118.7, 116.8, 113.8, 113.3, 113.3, 107.7, 64.6, 64.5. HRMS (ESI) m / z calcd for C 19 H 16 N5O2 + ([M + H] + ) 346.1299, found 346.1308.

[0452]

[0453] Example 35: 6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-3-ol (39f)

[0454]

[0455] Compound 39f (77.3 mg, 54%) was obtained as a white solid using the method of Manufacturing Example 6.

[0456] TLC: R f 0.42 (10:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.51 (d, J = 1.0 Hz, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.02 (dd, J = 8.6, 0.7 Hz, 1H), 7.96 (d, J = 2.8) Hz, 1H), 7.75 (dd, J = 5.5, 1.0 Hz, 1H), 7.30 (dd, J = 8.6, 2.8 Hz, 1H), 7.00-6.96 (m, 2H), 6.87 (dd, J = 8.6, 2.5 Hz, 1H), 4.48-4.04 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 155.2, 153.6, 147.4, 143.9, 143.8, 142.6, 139.5, 137.8, 135.4, 134.4, 130.1, 127.0, 123.1, 120.5, 117.9, 116.4, 114.3, 64.53, 64.49. HRMS (ESI) m / z calcd for C 19 H 15 N4O3 + ([M + H] + ) 347.1139, found 347.1142.

[0457]

[0458] Example 36: 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,3-diol (39 g)

[0459]

[0460] Using the method of Manufacturing Example 6, compound 39 g (43.6 mg, 61%) was obtained as a white solid.

[0461] TLC: R f 0.40 (10:1 CH2Cl2 / MeOH). 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 2H), 10.05 (s, 2H), 8.47-8.39 (m, 2H), 7.74 (dd, J = 5.5, 1.0 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 8.5, 2.5 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.18 (dd, J = 8.8, 2.4 Hz, 1H), 4.35 (ddd, J = 6.8, 5.3, 2.7 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 161.7, 160.9, 154.4, 145.5, 144.7, 144.6, 142.9, 134.4, 133.6, 130.3, 129.3, 120.7, 118.8, 116.7, 113.0, 107.7, 104.3, 103.6, 64.63, 64.56. HRMS (ESI) m / z calcd for C 20 H 16 N3O4 + ([M + H] + ) 362.1135, found 362.1138.

[0462]

[0463] Examples 37 to 41 below were synthesized based on the following reaction scheme 5.

[0464] [Reaction Formula 5]

[0465]

[0466]

[0467] Example 37: 4-Methyl-6-{1-[4-(4-methyl-piperazin-1-yl)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-benzene-1,3-diol (42a)

[0468] Step 1: Synthesis of [4-(4-methyl-piperazin-1-yl)-phenyl]-(3-nitro-pyridin-4-yl)-amine (40a)

[0469]

[0470] In a 50 mL oven-dried round-bottom flask with a sidearm, 4-chloro-3-nitropyridine (200 mg, 1.26 mmol), 4-(4-methylpiperazin-1-yl)aniline (241 mg, 1.26 mmol), Pd2(dba)3 (92.4 mg, 101 μmol), Xantphos (124 mg, 214 μmol), and K3PO4 (536 mg, 2.52 mmol) were suspended in anhydrous 1,4-dioxane (5.7 mL). The reaction mixture was cooled at 80 °C for 12 h, and the precipitate was filtered and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give compound 40a (347 mg, 88%) as a red solid.

[0471] TLC R f 0.50 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.08 (s, 1H), 8.20 (d, J = 6.2 Hz, 1H), 7.19 (d, J = 8.9 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 6.2 Hz, 1H), 3.18 (dd, J = 6.4, 3.6 Hz, 5H), 2.47 (t, J = 5.1 Hz, 4H), 2.23 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 152.8, 149.8, 148.3, 147.7, 129.8, 127.9, 126.9, 115.9, 109.6, 54.6, 47.9, 45.8. HRMS (ESI) m / z calcd for C 16 H 19 N4O4 + ([M + H] + ) 331.1401, found 331.1401.

[0472] Step 2: Synthesis of N4-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyridine-3,4-diamine (41a)

[0473]

[0474] Compound 40a (330 mg, 1.05 mmol) and 5% Pd / C (33 mg) were suspended in EtOH (10.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The flask was filled with hydrogen and evaporated. The mixture was stirred at room temperature for 5 h under a hydrogen-filled balloon. Upon completion of the reaction, the reaction mixture was filtered and placed in a Celite ® The residue was filtered through a plug and washed with MeOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (10:1 CH2Cl2 / MeOH) to give compound 41a (197 mg, 66%) as a pink solid.

[0475] TLC R f 0.20 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.70 - 7.46 (m, 1H), 7.23 (s, 1H), 7.02 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 5.4 Hz, 1H), 4.30 (s, 2H), 3.07 (t, J = 5.0 Hz, 4H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ147.5, 139.5, 138.9, 136.1, 133.2, 132.7, 123.0, 117.0, 106.9, 55.2, 49.1, 46.2. HRMS (ESI) m / z calcd for C 16 H 20 N5 + ([M + H] + ) 284.1870, found 284.1873.

[0476] Step 3: Synthesis of 4-methyl-6-{1-[4-(4-methyl-piperazin-1-yl)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-benzene-1,3-diol (42a)

[0477]

[0478] Compound 41a (100 mg, 353 μmol), 2,4-dihydroxy-5-methylbenzaldehyde (64.4 mg, 423 μmol), and Na2S2O5 (134 mg, 706 μmol) were suspended in anhydrous DMF (1.0 mL) in a 5 mL oven-dried round-bottom flask with a side arm. The reaction mixture was stirred at 110 °C overnight. The reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (20 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give compound 42a (77.2 mg, 53%) as an ivory solid.

[0479] TLC R f 0.35 (20:1 CH2Cl2 / MeOH). Mp: 256.4-256.8℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.00 (s, 1H), 8.99 (d, J = 1.0 Hz, 1H), 8.32 (d, J = 5.5 Hz, 1H), 7.30 (d, J = 9.0 Hz, 2H), 7.25 - 6.92 (m, 3H), 6.71 (d, J = 0.9 Hz, 1H), 6.38 (s, 1H), 3.27 (t, J = 5.1 Hz, 4H), 2.47 (s, 4H), 2.24 (s, 3H), 1.79 (d, J = 0.8 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 158.8, 158.0, 153.3, 151.3, 142.2, 141.0, 140.2, 137.6, 130.2, 127.8, 126.1, 115.7, 114.7, 105.6, 104.3, 102.5, 54.3, 47.5, 45.7, 15.4. HRMS (ESI) m / z calcd for C 24 H 26 N5O2 + ([M + H] + ) 416.2081, found 416.2081.

[0480]

[0481] Example 38: {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-carbamic acid tert-butyl ester (42b)

[0482] Step 1: Synthesis of [4-(3-nitro-pyridin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester (40b)

[0483]

[0484] In a 50 mL oven-dried round-bottom flask with a sidearm, 4-chloro-3-nitropyridine (200 mg, 1.26 mmol), N-(tert-butoxycarbonyl)-1,4-phenylenediamine (263 mg, 1.26 mmol), Pd2(dba)3 (92.4 mg, 101 μmol), Xantphos (124 mg, 214 μmol), and K3PO4 (536 mg, 2.52 mmol) were suspended in anhydrous 1,4-dioxane (5.7 mL). The reaction mixture was stirred at 80 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitate was filtered and washed with MeOH (10 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (2:1 hexanes / EtOAc) to give compound 40b (392 mg, 94%) as a red solid.

[0485] TLC R f 0.30 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.51 (s, 1H), 9.08 (s, 1H), 8.20 (d, J = 6.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.36 - 7.09 (m, 2H), 6.78 (d, J = 6.2 Hz, 1H), 1.49 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 152.9, 152.8, 148.2, 147.3, 138.3, 131.1, 129.9, 126.5, 119.0, 109.6, 79.3, 28.13. HRMS (ESI) m / z calcd for C 16 H 19 N4O4 + ([M + H] + ) 331.1401, found 331.1399.

[0486] Step 2: Synthesis of [4-(3-amino-pyridin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester (41b)

[0487]

[0488] Compound 40b (370 mg, 1.12 mmol) and Pd / C (37 mg) were suspended in EtOH (10.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The air in the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 5 h under a hydrogen-filled balloon. Upon completion of the reaction, the reaction mixture was placed in Celite ® The residue was filtered through a plug and washed with MeOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (15:1 CH2Cl2 / MeOH) to give compound 41b (312 mg, 93%) as a pink solid.

[0489] TLC R f0.20 (15:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.82 (s, 1H), 7.58 (d, J = 5.3 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.29 (s, 1H), 7.10 - 6.95 (m, 2H), 6.74 (d, J = 5.3 Hz, 1H), 4.80 (s, 2H), 1.47 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 152.9, 139.1, 137.4, 136.3, 135.7, 134.2, 132.7, 121.0, 119.3, 107.2, 78.8, 28.2. HRMS (ESI) m / z calcd for C 16 H 21 N4O2 + ([M + H] + ) 301.1659, found 301.1660.

[0490] Step 3: Synthesis of {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-carbamic acid tert-butyl ester (42b)

[0491]

[0492] Compound 41b (300 mg, 999 μmol), 2,4-dihydroxy-5-methylbenzaldehyde (182 mg, 1.20 mmol), and Na2S2O5 (380 mg, 2.00 mmol) 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 at 110 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (50 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (5:1 hexanes / EtOAc) to give compound 42b (84.5 mg, 20%) as an ivory solid.

[0493] TLC R f 0.50 (10:1 CH2Cl2 / MeOH). Mp: 196.5-196.9℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.95 (s, 1H), 9.70 (s, 1H), 9.00 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.82 - 7.54 (m, 2H), 7.47 - 7.23 (m, 2H), 7.14 (dd, J = 5.5, 1.1 Hz, 1H), 6.77 (s, 1H), 6.37 (s, 1H), 1.81 (s, 3H), 1.51 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 159.3, 158.0, 153.7, 153.2, 142.8, 141.3, 140.8, 138.4, 133.9, 130.9, 130.1, 128.0, 119.4, 115.3, 106.1, 105.0, 103.0, 80.0, 28.6, 15.9. HRMS (ESI) m / z calcd for C 24 H 25 N4O4 + ([M + H] + ) 433.1870, found 433.1872.

[0494]

[0495] Example 39: 4-[1-(4-Amino-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol (43b)

[0496]

[0497] In a 5 mL oven-dried round-bottom flask with a sidearm, boc-protected amine compound 42b (Example 38, 50.0 mg, 116 μmol) and TFA (0.18 mL, 2.31 mmol) were suspended in anhydrous CH2Cl2 (0.8 mL). The reaction mixture was stirred at room temperature for 10 h. Upon completion of the reaction, the reaction mixture was concentrated, diluted with CH2Cl2 (50 mL), and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated and concentrated, and the residue was purified by column chromatography (1:2 hexanes / EtOAc) to give compound 43b (27.2 mg, 70%) as an ivory solid.

[0498] TLC R f 0.25 (2:1 hexanes / EtOAc). MP: 304.0-304.6℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.09 (s, 1H), 8.97 (s, 1H), 8.31 (d, J = 5.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7) Hz, 2H), 6.39 (s, 1H), 5.76 (s, 2H), 5.60 (s, 2H), 1.78 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.4, 159.1, 153.7, 150.4, 142.7, 141.7, 140.4, 137.7, 134.9, 130.2, 128.5, 123.7, 115.2, 114.8, 106.1, 103.1, 16.03. HRMS (ESI) m / z calcd for C 19 H 17 N4O2 + ([M + H] + ) 333.1346, found 333.1347.

[0499]

[0500] Example 40: {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-carbamic acid tert-butyl ester (42c)

[0501] Step 1: Synthesis of [3-(3-nitro-pyridin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester (40c)

[0502]

[0503] In a 50 mL oven-dried round-bottom flask with a sidearm, 4-chloro-3-nitropyridine (200 mg, 1.26 mmol), N-(tert-butoxycarbonyl)-1,3-phenylenediamine (263 mg, 1.26 mmol), Pd2(dba)3 (92.4 mg, 101 μmol), Xantphos (124 mg, 214 μmol), and K3PO4 (536 mg, 2.52 mmol) were suspended in anhydrous 1,4-dioxane (5.7 mL). The reaction mixture was stirred at 80 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitate was filtered and washed with MeOH (30 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (5:1 hexanes / EtOAc) to give compound 40c (244 mg, 58%) as a red solid.

[0504] TLC R f 0.40 (1:1 hexane / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.53 (s, 1H), 9.09 (s, 1H), 8.25 (d, J = 6.1 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 7.35 (dd, J = 6.4, 0.9 Hz, 2H), 6.95 (dt, J = 6.1, 2.2 Hz, 1H), 6.89 (d, J = 6.1 Hz, 1H), 1.47 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 153.0, 152.8, 148.2, 146.8, 140.8, 137.7, 130.3, 129.9, 119.1, 116.3, 115.0, 109.8, 79.4, 28.1. HRMS (ESI) m / z calcd for C 16 H 19 N4O4 + ([M + H] + ) 331.1401, found 331.1403.

[0505] Step 2: Synthesis of [3-(3-amino-pyridin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester (41c)

[0506]

[0507] Compound 40c (200 mg, 605 mmol) and Pd / C (20 mg) were suspended in EtOH (10.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The air in the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 12 h under a hydrogen-filled balloon. Upon completion of the reaction, the reaction mixture was placed in Celite ® The residue was filtered through a plug and washed with MeOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (10:1 CH2Cl2 / MeOH) to give compound 41c (147 mg, 81%) as a pink solid.

[0508] TLC R f 0.15 (EtOAc only). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.87 (s, 1H), 7.63 (d, J = 5.3 Hz, 1H), 7.46 (s, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.14 (t, J = 8.0) Hz, 1H), 7.05 - 6.96 (m, 1H), 6.92 (d, J = 5.3 Hz, 1H), 6.74 - 6.60 (m, 1H), 4.89 (s, 2H), 1.46 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 152.7, 142.1, 140.4, 138.8, 136.6, 136.0, 133.6, 129.2, 112.8, 111.4, 109.0, 108.8, 79.0, 28.1. HRMS (ESI) m / z calcd for C 16 H 21 N4O2 + ([M + H] + ) 301.1659, found 301.1665.

[0509] Step 3: Synthesis of {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-carbamic acid tert-butyl ester (42c)

[0510]

[0511] Compound 41c (100 mg, 333 μmol), 2,4-dihydroxy-5-methylbenzaldehyde (60.8 mg, 400 μmol), and Na2S2O5 (127 mg, 666 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 at 110 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (5 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (2:1 hexanes / EtOAc) to give compound 42c (87.0 mg, 60%) as an ivory solid.

[0512] TLC R f 0.40 (1:2 hexane / EtOAc). MP: 206.2-206.5℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.93 (s, 1H), 9.69 (s, 1H), 9.02 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 7.67 - 7.54 (m, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 5.5, 1.0 Hz, 1H), 7.02 (ddd, J = 7.8, 2.1, 1.0 Hz, 1H), 6.80 (d, J = 0.9 Hz, 1H), 6.38 (s, 1H), 1.83 (s, 3H), 1.45 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 158.8, 157.5, 153.0, 152.6, 142.4, 141.1, 140.5, 140.5, 138.0, 136.4, 130.6, 130.3, 120.4, 118.5, 116.0, 114.9, 105.6, 104.5, 102.5, 79.6, 28.0, 15.4. HRMS (ESI) m / z calcd for C 24 H 25 N4O4 + ([M + H]+ ) 433.1870, found 433.1881.

[0513]

[0514] Example 41: 4-[1-(3-Amino-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol (43c)

[0515]

[0516] In a 5 mL oven-dried round-bottom flask with a sidearm, boc-protected amine compound 42c (Example 40, 50.0 mg, 116 μmol) and TFA (0.18 mL, 2.31 mmol) were suspended in anhydrous CH2Cl2 (0.8 mL). The reaction mixture was stirred at room temperature for 10 h. Upon completion of the reaction, the reaction mixture was concentrated and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated and concentrated, and the residue was purified by column chromatography (1:4 hexanes / EtOAc) to give compound 43c (35.7 mg, 93%) as an ivory solid.

[0517] TLC R f 0.45 (EtOAc only). Mp: 299.3-299.7℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.00 (s, 1H), 9.01 (d, J = 1.0 Hz, 1H), 8.34 (d, J = 5.5 Hz, 1H), 7.27 (s, 1H), 7.15 (dd, J = 5.5, 1.0 Hz, 1H), 6.81 (d, J = 1.1 Hz, 2H), 6.60 (s, 1H), 6.57 (ddd, J = 7.6, 2.1, 0.9 Hz, 1H), 6.43 (s, 1H), 5.54 (s, 2H), 1.86-1.67 (m, 3H). 13C NMR (100 MHz, DMSO-d6) δ 159.0, 158.4, 152.7, 150.6, 142.4, 140.6, 140.2, 137.4, 136.7, 130.54, 130.1, 114.8, 114.8, 113.8, 111.6, 105.6, 103.8, 102.6, 15.5. HRMS (ESI) m / z calcd for C 19 H 17 N4O2 + ([M + H] + ) 333.1346, found 333.1352.

[0518]

[0519] Examples 42 to 46 below were synthesized based on the following reaction scheme 6.

[0520] [Reaction Formula 6]

[0521]

[0522]

[0523] Example 42: 4-Methyl-6-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-imidazo[4,5-c]pyridin-2-yl}-benzene-1,3-diol (46a)

[0524] Step 1: Synthesis of [4-(4-methyl-piperazin-1-yl)-phenyl]-(4-nitro-pyridin-3-yl)-amine (44a)

[0525]

[0526] In a 50 mL oven-dried round-bottom flask with a sidearm, 3-chloro-4-nitropyridine (300 mg, 1.89 mmol), 4-(4-methylpiperazin-1-yl)aniline (362 mg, 1.89 mmol), Pd2(dba)3 (139 mg, 151 μmol), Xantphos (186 mg, 322 μmol), and K3PO4 (804 mg, 3.78 mmol) were suspended in anhydrous 1,4-dioxane (8.6 mL). The reaction mixture was stirred at 80 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (10 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (50:1 CH2Cl2 / MeOH) to give compound 44a (564 mg, 95%) as a red solid.

[0527] TLC R f 0.50 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ(s, 1H), 8.41 (s, 1H), 7.95 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 5.6 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 9.0 Hz, 2H), 3.25 - 2.96 (m, 4H), 2.46 (t, J = 5.1 Hz, 4H), 2.23 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 149.7, 142.1, 137.8, 136.9, 136.1, 129.5, 126.6, 117.5, 116.6, 55.0, 48.5, 46.2. HRMS (ESI) m / z calcd for C 16 H 19 N4O4 + ([M + H] + ) 331.1401, found 331.1401.

[0528] Step 2: Synthesis of N3-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyridine-3,4-diamine (45a)

[0529]

[0530] Compound 44a (500 mg, 1.60 mmol) and 5% Pd / C (50 mg) were suspended in EtOH (10.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The air in the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 10 h under a hydrogen-filled balloon. Upon completion of the reaction, the reaction mixture was filtered through a Celite ® The residue was filtered through a plug and washed with MeOH (50.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (10:1 CH2Cl2 / MeOH) to give compound 45a (392 mg, 87%) as a pink solid.

[0531] TLC R f 0.20 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.78 (d, J = 5.3 Hz, 1H), 6.83-6.77 (m, 3H), 6.69-6.63 (m, 2H), 6.60 (d, J = 5.4 Hz, 1H), 5.66 (s, 2H), 3.01-2.90 (m, 4H), 2.47-2.39 (m, 5H), 2.20 (s, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 147.9, 144.5, 143.8, 142.1, 138.1, 125.6, 117.3, 116.6, 108.9, 54.8, 49.5, 45.8. HRMS (ESI) m / z calcd for C 16 H 22 N5 + ([M + H] + ) 284.1870, found 284.1872.

[0532] Step 3: Synthesis of 4-methyl-6-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-imidazo[4,5-c]pyridin-2-yl}-benzene-1,3-diol (46a)

[0533]

[0534] Compound 45a (150 mg, 882 μmol), 2,4-dihydroxy-5-methylbenzaldehyde (161 mg, 1.06 mmol), and Na2S2O5 (335 mg, 1.76 mmol) 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 at 110 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (5 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (30:1 CH2Cl2 / MeOH) to give compound 46a (214 mg, 58%) as an ivory solid.

[0535] TLC R f 0.35 (20:1 CH2Cl2 / MeOH). MP: 278.0-278.5℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 10.05 (s, 1H), 8.40 (t, J = 2.8 Hz, 2H), 7.72 (d, J = 5.5 Hz, 1H), 7.36 (d, J = 8.9 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 6.71 (s, 1H), 6.42 (s, 1H), 3.29 (t, J = 5.0 Hz, 4H), 2.51 (d, J = 2.0 Hz, 2H), 2.25 (s, 3H), 1.96 (d, J = 13.6 Hz, 1H), 1.80 (s, 3H), 1.45 (s, 1H), 1.20 (d, J = 15.5 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 159.7, 159.0, 154.7, 151.8, 145.5, 142.8, 134.5, 133.5, 130.6, 128.4, 126.6, 116.2, 115.3, 112.9, 104.4, 103.1, 54.8, 48.0, 46.2, 16.0. HRMS (ESI) m / z calcd for C 23 H 23 N4O4 + ([M + H] + ) 419.1714, found 419.1716.

[0536]

[0537] Example 43: {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (46b)

[0538] Step 1: Synthesis of [4-(4-nitro-pyridin-3-ylamino)-phenyl]-carbamic acid tert-butyl ester (44b)

[0539]

[0540] In a 50 mL oven-dried round-bottom flask with a sidearm, 3-chloro-4-nitropyridine (300 mg, 1.89 mmol), N-(tert-butoxycarbonyl)-1,4-phenylenediamine (394 mg, 1.89 mmol), Pd2(dba)3 (139 mg, 151 μmol), Xantphos (186 mg, 322 μmol), and K3PO4 (804 mg, 3.78 mmol) were suspended in anhydrous 1,4-dioxane (8.6 mL). The reaction mixture was stirred at 80 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitate was filtered and washed with MeOH (10 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (2:1 hexanes / EtOAc) to give compound 44b (597 mg, 96%) as a red solid.

[0541] TLC R f 0.35 (2:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.24 (s, 1H), 8.45 (s, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 5.6 Hz, 1H), 7.58 - 7.39 (m, 2H), 7.40 - 7.10 (m, 2H), 1.48 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 152.8, 141.7, 137.4, 137.0, 136.7, 136.2, 132.3, 125.2, 119.1, 117.1, 79.1, 28.1. HRMS (ESI) m / z calcd for C 16 H 19 N4O4 + ([M + H] + ) 331.1401, found 331.1402.

[0542] Step 2: Synthesis of [4-(4-amino-pyridin-3-ylamino)-phenyl]-carbamic acid tert-butyl ester (45b)

[0543]

[0544] Compound 44b (550 mg, 1.66 mmol) and Pd / C (55 mg) were suspended in EtOH (10.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The air in the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 10 h under a hydrogen-filled balloon. Upon completion of the reaction, the reaction mixture was placed in Celite ® The residue was filtered through a plug and washed with MeOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (20:1 CH2Cl2 / MeOH) to give compound 45b (320 mg, 64%) as a pink solid.

[0545] TLC R f0.25 (10:1 CH2Cl2 / MeOH). 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.94 (s, 1H), 7.81 (d, J = 5.4 Hz, 1H), 7.20 (d, J = 8.3 Hz, 2H), 6.94 (s, 1H), 6.64 - 6.55 (m, 3H), 5.58 (s, 2H), 1.45 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 153.0, 148.3, 144.8, 143.9, 140.7, 130.8, 124.6, 115.0, 109.1, 78.4, 28.2. HRMS (ESI) m / z calcd for C 16 H 21 N4O2 + ([M + H] + ) 301.1659, found 301.1663.

[0546] Step 3: Synthesis of {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (46b)

[0547]

[0548] Compound 45b (250 mg, 832 μmol), 2,4-dihydroxy-5-methylbenzaldehyde (152 mg, 1.00 mmol), and Na2S2O5 (316 mg, 1.66 mmol) 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 at 110 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with MeOH (5 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:1 hexanes / EtOAc) to give compound 46b (237 mg, 66%) as an ivory solid.

[0549] TLC R f0.30 (1:1 hexane / EtOAc). MP: 241.0-241.5℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 10.01 (s, 1H), 9.73 (s, 1H), 8.41 (s, 2H), 7.77 - 7.64 (m, 3H), 7.43 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 1.0 Hz, 1H), 6.40 (s, 1H), 1.81 (s, 3H), 1.51 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 159.6, 158.7, 154.7, 153.2, 145.8, 142.8, 141.0, 134.4, 133.5, 130.8, 130.1, 128.1, 119.4, 115.5, 113.1, 104.5, 103.1, 80.0, 28.6, 15.9. HRMS (ESI) m / z calcd for C 24 H 25 N4O4 + ([M + H] + ) 433.1870, found 433.1875.

[0550]

[0551] Example 44: 4-[3-(4-Amino-phenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol (47b)

[0552]

[0553] In a 5 mL oven-dried round-bottom flask with a sidearm, boc-protected amine compound 46b (Example 43, 150 mg, 347 μmol) and TFA (0.53 mL, 6.94 mmol) were suspended in anhydrous CH2Cl2 (2.3 mL). The reaction mixture was stirred at room temperature for 5 h. Upon completion of the reaction, the reaction mixture was concentrated and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated and concentrated, and the residue was purified by column chromatography (10:1 CH2Cl2 / MeOH) to give compound 47b (90.2 mg, 78%) as an ivory solid.

[0554] TLC R f 0.25 (10:1 CH2Cl2 / MeOH). Mp: 343.1-343.4℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.05 (s, 1H), 8.39 (d, J = 5.5 Hz, 1H), 8.37 (s, 1H), 7.70 (dd, J = 5.5, 1.0 Hz, 1H), 7.16 (d, J) = 8.7 Hz, 2H), 6.82 - 6.71 (m, 3H), 6.42 (s, 1H), 5.66 (s, 2H), 1.79 (d, J = 0.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.3, 159.2, 154.2, 150.0, 144.7, 142.3, 134.2, 133.0, 129.8, 128.0, 123.3, 114.8, 114.4, 112.3, 103.5, 102.7, 15.6. HRMS (ESI) m / z calcd for C 19 H 17 N4O2 + ([M + H] + ) 333.1346, found 333.1348.

[0555]

[0556] Example 45: {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (46c)

[0557] Step 1: Synthesis of [3-(4-nitro-pyridin-3-ylamino)-phenyl]-carbamic acid tert-butyl ester (44c)

[0558]

[0559] In a 5 mL oven-dried round-bottom flask with a sidearm, 3-chloro-4-nitropyridine (200 mg, 1.26 mmol), N-(tert-butoxycarbonyl)-1,3-phenylenediamine (263 mg, 1.26 mmol), Pd2(dba)3 (92.4 mg, 101 μmol), Xantphos (124 mg, 214 μmol), and K3PO4 (536 mg, 2.52 mmol) were suspended in anhydrous 1,4-dioxane (5.7 mL). The reaction mixture was stirred at 80 °C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitate was filtered and washed with MeOH (10 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (8:1 hexanes / EtOAc) to give compound 44c (299 mg, 72%) as a red solid.

[0560] TLC R f 0.25 (3:1 hexanes / EtOAc). 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.19 (s, 1H), 8.62 (s, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.91 (dd, J = 5.6, 0.5 Hz, 1H), 7.53 (t, J = 2.0 Hz, 1H), 7.35 - 7.18 (m, 2H), 6.92 (dd, J = 7.6, 0.9 Hz, 1H), 1.46 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 153.2, 142.8, 141.2, 139.6, 138.6, 138.2, 135.8, 130.2, 117.8, 117.2, 115.3, 112.9, 79.7, 28.6. HRMS (ESI) m / z calcd for C 16 H 19 N4O4 + ([M + H] + ) 331.1401, found 331.1401.

[0561] Step 2: Synthesis of [3-(4-amino-pyridin-3-ylamino)-phenyl]-carbamic acid tert-butyl ester (45c)

[0562]

[0563] Compound 44c (250 mg, 757 mmol) and Pd / C (25 mg) were suspended in EtOH (10.0 mL) in a 50 mL oven-dried round-bottom flask with a side arm. The air in the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 12 h under a hydrogen-filled balloon. Upon completion of the reaction, the reaction mixture was placed in Celite ® The residue was filtered through a plug and washed with MeOH (10.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (10:1 CH2Cl2 / MeOH) to give compound 45c (225 mg, 99%) as a pink solid.

[0564] TLC R f 0.15 (EtOAc only). 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.03 (s, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.19 (s, 1H), 7.07-6.96 (m, 2H), 6.87-6.76 (m, 1H), 6.69 (d, J = 5.4 Hz, 1H), 6.37-6.19 (m, 1H), 5.71 (s, 2H), 1.49 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 152.7, 149.2, 146.4, 145.2, 145.2, 140.3, 129.0, 123.7, 109.2, 108.4, 108.3, 104.2, 78.7, 28.1. HRMS (ESI) m / z calcd for C 16 H 21 N4O2 + ([M + H] + ) 301.1659, found 301.1665.

[0565] Step 3: Synthesis of {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester (46c)

[0566]

[0567] Compound 45c (200 mg, 666 μmol), 2,4-dihydroxy-5-methylbenzaldehyde (122 mg, 800 μmol), and Na2S2O5 (253 mg, 1.33 mmol) 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 at 110°C overnight. Upon completion of the reaction, the reaction mixture was filtered and filtered using Celite. ® The residue was filtered through a plug and washed with MeOH (5.0 mL). The filtrate was concentrated using a rotary evaporator, and the residue was purified by column chromatography (1:2 hexanes / EtOAc) to give compound 46c (75.5 mg, 26%) as an ivory solid.

[0568] TLC R f 0.40 (1:2 hexane / EtOAc). Mp: 309.8-310.4℃. 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.00 (s, 1H), 9.70 (s, 1H), 8.56 - 8.35 (m, 2H), 7.80 - 7.70 (m, 1H), 7.65 (dd, J = 9.7, 2.3 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.08 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 6.80 (d, J = 0.9 Hz, 1H), 6.39 (s, 1H), 1.83 (s, 3H), 1.46 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 159.2, 158.0, 154.0, 152.7, 145.5, 142.5, 141.1, 136.4, 133.5, 133.0, 130.6, 130.3, 120.4, 118.6, 116.1, 115.1, 112.7, 104.1, 102.6, 79.6, 28.0, 15.4. HRMS (ESI) m / z calcd for C 24 H 25 N4O4 + ([M + H] + ) 431.1725, found 431.1721.

[0569]

[0570] Example 46: 4-[3-(3-Amino-phenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol (47c)

[0571]

[0572] In a 5 mL oven-dried round-bottom flask with a sidearm, boc-protected amine compound 46c (Example 45, 50.0 mg, 116 μmol) and TFA (0.18 mL, 2.31 mmol) were suspended in anhydrous CH2Cl2 (0.8 mL). The reaction mixture was stirred at room temperature for 10 h. Upon completion of the reaction, the reaction mixture was concentrated and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated and concentrated, and the residue was purified by column chromatography (1:4 hexanes / EtOAc) to give compound 47c (27 mg, 71%) as an ivory solid.

[0573] TLC R f 0.40 (EtOAc only). MP: 329.2-329.5℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.06 (s, 1H), 8.61 - 8.13 (m, 2H), 7.72 (d, J = 5.5 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 6.82 (q, J = 4.1, 3.1 Hz, 2H), 6.78 - 6.53 (m, 2H), 6.42 (s, 1H), 5.55 (s, 2H), 1.80 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.3, 158.9, 153.6, 150.6, 144.9, 142.5, 136.7, 133.6, 133.0, 130.6, 130.1, 114.9, 114.8, 113.8, 112.4, 111.6, 103.4, 102.6, 15.5. HRMS (ESI) m / z calcd for C 19 H 17 N4O2 + ([M + H] + ) 333.1346, found 333.1352.

[0574]

[0575] The structures of the compounds of Examples 1 to 46 are as shown in Table 1 below.

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588] <Experimental Example>

[0589] Experimental Example 1. Evaluation of BTK inhibitory activity

[0590] 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. 50was 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.

[0591] 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.

[0592] 2) IC 50 : 10 dose IC in 3-fold serial dilutions starting at 100 μM, 30 μM, or 10 μM 50 The test was performed in mode 1. The reaction was performed at 10 μM ATP.

[0593] 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.

[0594] Example Compound #% Enzyme Activity IC 50BTKBTK Example 1 (6a) 98.84++ Example 2 (6b) 89.58++ Example 3 (6c) 80.30++ Example 4 (10a) 69.27++ Example 5 (15a) 76.52++ Example 6 (18a) 32.19++ Example 7 (18b) 30.50++ Example 8 (18c) 59.44++ Example 9 (18e) 98.26++ Example 10 (18f) 96.45++ Example 11 (23a) 90.30++ Example 12 (23b) 91.00++ Example 13 (23c) 83.85++ Example 14 (27a) 82.26++ Example 15(31a)50.84++Example 16(31b)55.02++Example 17(31c)77.38++Example 18(31d)86.38++Example 19(31e)83.50++Example 20(31f)92.86++Example 21(35a)0.76+++Example 22(35b)6.34++Example 23(35c)16.00++Example 24(35d)75.62++Example 25(35f)78.36++Example 26(35g)96.58++Example 27(35h)88.23++Example 28(35i)82.73++Example 29(35j)8.75+++Example 30(39a)4.80++Example 31(39b)69.26++Example 32(39c)4.29+++Example 33(39d)91.77++Example 34(39e)72.67++Example 35(39f)84.42++Example 36(39g)2.82+++Example 37(42a)6.20++Example 38(42b)53.49++Example 39(43b)2.10+++Example 40(42c)76.26++Example 41(43c)4.70+++Example 42(46a)2.65+++Example 43(46b)57.26++Example 44(47b)1.95+++Example 45(46c)61.73++Example 46(47c)20.23+++

[0595] According to Table 2 above, the imidazopyridine-based or imidazopyrazine-based compounds according to the present invention were found to have excellent activity in inhibiting BTK.

[0596] The specification omits detailed descriptions of matters that would be readily apparent and inferred by those skilled in the art. Furthermore, various modifications, other than the specific examples described herein, are possible without altering the technical spirit or essential configuration of the invention. Therefore, the present invention may be practiced in ways other than those specifically described and exemplified herein, as will be readily apparent to those skilled in the art.

Claims

A compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, Is or And, Is or And, R1 is -C1-C5 alkoxy, C3-C8 heterocycloalkyl containing unsubstituted or substituted nitrogen or oxygen atom, unsubstituted or substituted -(C1-C3 alkylene)-(C3-C8 heterocycloalkyl containing nitrogen or oxygen atom), -NR a R b or -NO2, wherein said substitution is halogen or -C1-C5 alkyl, R a and R b may be the same or different, and each independently represents hydrogen, C1-C3 alkyl, or -C(=O)O-C1-C5 alkyl; n is an integer from 1 to 3, R2 to R6 may be the same or different, and each independently represent hydrogen, halogen, -C1-C5 alkyl, -C1-C5 alkoxy, -NR c R d , -OH, -NO2 or -CN (except when R2 to R6 are both hydrogen), R7 is halogen, -C1-C5 alkyl, -C1-C5 alkoxy, -NR c R d , -OH, -NO2 or -CN, R c and R d may be the same or different, and each independently represents hydrogen or C1-C3 alkyl, m is an integer from 1 to 3, X1 to X4 may be the same or different, and are each independently N or -CH. (However, this does not apply to cases where X1 to X3 are -CH and X4 is N.) In the first paragraph, the compound represented by the chemical formula 1 is any one compound selected from the group consisting of compounds represented by the following chemical formulas 1-1 to 1-4, a compound, 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, A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentoxy, an unsubstituted or substituted pyrrolidine, an unsubstituted or substituted piperidine, an unsubstituted or substituted piperazine, an unsubstituted or substituted morpholine, an unsubstituted or substituted -(C1-C3 alkylene)-pyrrolidine, an unsubstituted or substituted -(C1-C3 alkylene)-piperidine, -(C1-C3 alkylene)-piperazine, an unsubstituted or substituted -(C1-C3 alkylene)-morpholine, -NH2, -NH-CH3, -N-(CH3)2, or -NH-C(=O)-O-C1-C5 alkyl. In the first paragraph, Is , , , , , , , , or A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof. In the first paragraph, R2 is hydrogen or -OH, R3 is hydrogen, halogen, or -C1-C3alkoxy, R4 is hydrogen, -C1-C3alkoxy, or -OH, R5 is hydrogen, halogen, -C1-C3 alkyl, -OH or -NO2, A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen, or -C1-C3 alkoxy (except when R2 to R6 are all hydrogen). In the first paragraph, A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R7 is -OH, -NO2, or -NH2. In the first paragraph, Is , , , , , , , or A compound, 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, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: 4-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 2-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol; 2,4-Dichloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 4-Chloro-6-[1-(4-morpholin-4-yl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 4-Chloro-6-[1-(4-morpholin-4-ylmethyl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1, 3-diol 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,4-diol; 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-4-nitro-phenol; 2,4-Dichloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene- 1,3-diol; 4-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol; 2-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,4-diol; 4-Chloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol; 4-Chloro-6-[1-(4-morpholin-4-yl-phenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-benzene-1,3-diol; 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1, 3-diol; 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol; 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,4-diol; 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-4-nitro-phenol; 2,4-Dichloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene- 1,3-diol; 4-Chloro-6-[1-(4-methoxy-phenyl)-1H-imidazo[4,5-b]pyrazin-2-yl]-benzene-1,3-diol; 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,3-diol; 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,4-diol; 5-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,2,4-triol; 2-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-4-nitro-phenol; 2-Chloro-4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol; 3-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine; 6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-3-ol; 5-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine; 4-Chloro-6-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol; 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,4-diol 2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-nitro-phenol; 4-Chloro-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1, 3-diol; 3-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine; 5-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-2-ylamine; 6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-pyridin-3-ol; 4-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-benzene-1,3-diol; 4-Methyl-6-{1-[4-(4-methyl-piperazin-1-yl)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-benzene-1,3-diol; {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-carbamic acid tert-butyl ester; 4-[1-(4-Amino-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol; {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-carbamic acid tert-butyl ester; 4-[1-(3-Amino-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol; 4-Methyl-6-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-imidazo[4,5-c]pyridin-2-yl}-benzene-1,3-diol; {4-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester; 4-[3-(4-amino-phenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methyl-benzene-1,3-diol; {3-[2-(2,4-dihydroxy-5-methyl-phenyl)-imidazo[4,5-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester; and 4-[3-(3-Amino-phenyl)-3H-imidazo[4,5-c]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 8, the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodine thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, autonomic dysfunction, asthma, chronic spontaneous urticaria, A pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase-mediated disease, wherein the disease is any one selected from the group consisting of pemphigus, systemic lupus erythematosus, hidradenitis, dermatosis, immunoglobulin G4-related disease, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia. A pharmaceutical composition for the prevention or treatment of a Bruton's tyrosine kinase-mediated disease, wherein the cancer is a B-cell malignancy in claim 10. A pharmaceutical composition for preventing or treating a Bruton's tyrosine kinase-mediated disease, wherein the 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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